hydroxyurea

An antineoplastic drug, CH₄N₂O₂, that suppresses the production of blood cell precursors in the bone marrow and is used in the treatment of certain leukemias, carcinomas, and sickle cell anemia.

Key Terms: Mucositis, Mutagen, Myelosuppression.

Definition

Hydroxyurea, also known by its trade name Hydrea, is an antineoplastic agent, meaning it is used to treat cancer. It is taken orally.

Purpose

Hydroxyurea is used to treat the following conditions:

• Melanoma
• Chronic myelocytic leukemia that is resistant to other therapies
• Ovarian cancer that is recurrent, metastatic or inoperable.
• Squamous cell carcinoma of the head and neck, excluding the lip. (In this case, hydroxyurea is given with radiation therapy.)
• Sickle cell anemia
• Other: Hydroxyurea has shown promise in the management of thrombocytosis, a condition in which platelet levels are abnormally high

Description

Hydroxyurea belongs to antimetabolites, a group of compounds that interfere with the production of nucleic acids. Hydroxyurea exerts its anticancer activity by inhibiting ribonucleotide reductase, an enzyme required for DNA synthesis. When used in conjunction with radiation therapy, the effectiveness of hydroxyurea increases because it also inhibits the ability of cells damaged by radiation to repair themselves.

Recommended Dosage

Hydroxyurea dosages are calculated based on a person's weight as milligrams per kilogram (mg/kg). Doctors will usually use whichever value is lowest—the patient's actual weight or the patient's ideal weight—to calculate dosages. The drug is not given if white blood cell levels drop below 2500 mm³, or if red blood cell levels drop below 100,000 mm³. Usually, bone marrow recovery is rapid, and few doses are missed. Hydroxyurea is usually given for six weeks before its effectiveness can be adequately evaluated.

Hydroxyurea is administered in a capsule form, each containing 500 mg of the drug. If a patient is unable to swallow the capsule, its contents can be dissolved in a glass of water and swallowed immediately. The drug will not completely dissolve in water. Dosages have not been established for children in part because the cancers for which hydroxyurea is useful do not normally occur in that age group.

In the treatment of solid tumors, such as ovarian cancers, patients are usually given 80 mg/kg once every three days. Alternatively, a dose of 20–30 mg/kg may be given every day.

In head and neck cancers also treated with radiation, 80 mg/kg of hydroxyurea is given once every three days. The drug should be started a week before radiation therapy begins, and should continue for some time after radiation therapy.

When it is used to treat resistant chronic myelocytic leukemia, hydroxyurea is given in the dosage of 20–30 mg/kg once a day.

In thrombocytosis, doses of 15–30 mg/kg taken once a day are usually effective. Platelet levels return to a normal level within two to six weeks of therapy. In more severe cases, doses of 1.5–3.0 grams per day have been given with plateletpheresis, a procedure that removes platelets from the blood.

Precautions

This drug should not be administered to a person who has had a previous allergic reaction to it. Liver and kidney function should be evaluated prior to, and during, treatment. The drug may interfere with certain lab tests. For example, creatinine levels may be elevated. Patients taking hydroxyurea should stay well-hydrated, drinking up to 12 glasses per day of water or other fluids.

Hydroxyurea is potentially mutagenic, meaning that it causes mutations in DNA. Patients taking the drug should discuss the potential effects on their future conception plans. Hydroxyurea should not be administered to pregnant women, and women taking the drug should use birth control methods to prevent pregnancy. Hydroxyurea is excreted in breast milk; therefore, women taking the drug should not breast-feed.

Side Effects

Hydroxyurea and radiation therapy each cause adverse side effects. When they are used together, the incidence and severity of side effects may increase.

Bone marrow suppression is the major side effect of hyroxyurea therapy, and may develop within two days of the first dose. Blood tests are performed routinely to monitor for changes. Usually, leukopenia (decreased white blood cells) develops first. Reduced red blood cells and platelets can also occur, but generally not as frequently. If anemia develops, it should be corrected with whole blood transfusions. Hydroxyurea causes red blood cell abnormalities that are not severe and that do not reduce the red blood cell survival time.

Gastrointestinal symptoms are not as common as myelosuppression and are usually mild. These symptoms may include nausea, vomiting, diarrhea, and constipation. Usually, medications can control nausea and vomiting. Mucositis, a painful swelling of the mucous membranes, may also develop, especially if the patient is undergoing radiation treatment to the head and neck. Mucositis can be managed with medicated mouthwashes, good oral hygiene, and hydration to keep the mouth moist.

Headache and dizziness may occur. With long-term use, skin changes, such as hyperpigmentation of the skin and nails, have also been reported.

Hydroxyurea has also been linked to leg ulcers. Studies suggest that leg ulcers have been reported mainly in older patients who might be at an increased risk. There have also been reports of hydroxyurea causing leg ulceration when it is used in psoriasis for a prolonged period.

Interactions

Patients at risk for bone marrow suppression should inform their doctor about all medications they are taking, both prescription and non-prescription. Many over-the-counter medications contain aspirin, which acts as a blood-thinner, increasing the potential for bleeding. Patients with reduced platelets should not take aspirin.

—Tamara Brown, R.N.

trade name: Hydrea; drug class: antineoplastic; action: acts by inhibiting DNA synthesis without interfering with synthesis of RNA or protein; uses: melanoma, chronic myelocytic leukemia, recurrent or metastatic ovarian cancer.

Brand names: Droxia®, Hydrea®, Mylocel™

Chemical formula:

Español:
• Hidroxiurea, Cápsula oral

Hydroxyurea Oral capsule

What is this medicine?

HYDROXYUREA is a chemotherapy drug. It slows the growth of cancer cells. This medicine is used to treat certain leukemias, skin cancer, head and neck cancer, and advanced ovarian cancer. It is also used to control the painful crises of sickle cell anemia.

This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
• immune system problems
• infection (especially a virus infection such as chickenpox, cold sores, or herpes)
• kidney disease
• low blood counts, like low white cell, platelet, or red cell counts
• previous or ongoing radiation therapy
• an unusual or allergic reaction to hydroxyurea, other chemotherapy, other medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should I use this medicine?

Take this medicine by mouth with a glass of water. Follow the directions on the prescription label. Take your medicine at regular intervals. Do not take it more often than directed. Do not stop taking except on your doctor's advice.

People who are not taking this medicine should not be exposed to it. Wash your hands before and after handling your bottle or medicine. Caregivers should wear disposable gloves if they must touch the bottle or medicine. Clean up any medicine powder that spills with a damp disposable towel and throw the towel away in a closed container, such as a plastic bag.

Talk to your pediatrician regarding the use of this medicine in children. Special care may be needed.

Patients over 65 years old may have a stronger reaction and need a smaller dose.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.

What may interact with this medicine?

• didanosine
• other chemotherapy agents
• stavudine
• tenofovir
• vaccines

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medicine?

This drug may make you feel generally unwell. This is not uncommon, as chemotherapy can affect healthy cells as well as cancer cells. Report any side effects. Continue your course of treatment even though you feel ill unless your doctor tells you to stop. You will receive regular blood tests during your treatment.

Call your doctor or health care professional for advice if you get a fever, chills or sore throat, or other symptoms of a cold or flu. Do not treat yourself. This drug decreases your body's ability to fight infections. Try to avoid being around people who are sick.

This medicine may increase your risk to bruise or bleed. Call your doctor or health care professional if you notice any unusual bleeding.

Be careful brushing and flossing your teeth or using a toothpick because you may get an infection or bleed more easily. If you have any dental work done, tell your dentist you are receiving this medicine.

Avoid taking products that contain aspirin, acetaminophen, ibuprofen, naproxen, or ketoprofen unless instructed by your doctor. These medicines may hide a fever.

Do not become pregnant while taking this medicine. Women should inform their doctor if they wish to become pregnant or think they might be pregnant. There is a potential for serious side effects to an unborn child. Men should inform their doctors if they wish to father a child. This medicine may lower sperm counts. Talk to your health care professional or pharmacist for more information. Do not breast-feed an infant while taking this medicine.

What side effects may I notice from receiving this medicine?

Side effects that you should report to your doctor or health care professional as soon as possible:
• allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
• low blood counts - this medicine may decrease the number of white blood cells, red blood cells and platelets. You may be at increased risk for infections and bleeding.
• signs of infection - fever or chills, cough, sore throat, pain or difficulty passing urine
• signs of decreased platelets or bleeding - bruising, pinpoint red spots on the skin, black, tarry stools, blood in the urine
• signs of decreased red blood cells - unusually weak or tired, fainting spells, lightheadedness
• breathing problems
• burning, redness or pain at the site of any radiation therapy
• changes in skin color
• confusion
• mouth sores
• pain, tingling, numbness in the hands or feet
• seizures
• skin ulcers
• trouble passing urine or change in the amount of urine
• vomiting

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
• headache
• loss of appetite
• red color to the face

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medicine?

Keep out of the reach of children.

Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Keep tightly closed. Throw away any unused medicine after the expiration date.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

An antineoplastic agent that blocks the conversion of ribonucleotides to deoxyribonucleotides, thus stopping DNA synthesis. Called also hydroxycarbamide.

Hydroxyurea
Systematic (IUPAC) name
hydroxyurea
Identifiers
CAS number	127-07-1
ATC code	L01XX05
PubChem	3657
DrugBank	APRD00023
ChemSpider	3530
Chemical data
Formula	CH4N2O2
Mol. mass	76.0547 g/mol
Pharmacokinetic data
Bioavailability	?
Metabolism	Liver
Half life	3-4 hours
Excretion	Renal and lungs
Therapeutic considerations
Pregnancy cat.	D (USA)
Legal status
Routes	Oral
Y(what is this?)  (verify)

Hydroxyurea or hydroxycarbamide (the latter being the recommended International Nonproprietary Name) (brand names include Hydrea and Droxia) is an antineoplastic drug used in myeloproliferative disorders, specifically polycythemia vera and essential thrombocytosis. It is also used to reduce the rate of painful attacks in sickle-cell disease and has antiretroviral properties in diseases such as AIDS.

Contents 1 Mechanism of action 2 Uses 3 Dose 4 Side effects 5 Contraindications 6 Use in pregnancy 7 References

Mechanism of action

One mechanism of action is believed to be based on its reduction of production of deoxyribonucleotides^[1] via inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free radicals as they are involved in the reduction NDPs.^[2]

In the treatment of sickle-cell disease, hydroxyurea increases the concentration of fetal haemoglobin. The precise mechanism of action is not yet clear, but it appears that hydroxyurea increases nitric oxide levels, causing soluble guanylyl cyclase activation with a resultant rise in cyclic GMP, and the activation of gammaglobulin synthesis necessary for fetal hemoglobin (by removing the rapidly dividing cells that preferentially produce sickle hemoglobin).^[2][3]

Uses

Hydroxyurea is used for the following indications:^{[citation needed]}

• Myeloproliferative disease (primarily polycythemia vera not responding to blood-letting^{[citation needed]} and essential thrombocytosis^[4])
• Sickle-cell disease^[5] (breaks down cells that are prone to sickle, as well as increasing fetal hemoglobin content)
• AIDS as an adjunct to ddI in combination antiretroviral therapies^[6]
• Second line treatment for psoriasis^[7] (slows down the rapid division of skin cells)
• Biochemical research as a DNA replication inhibitor^[8] that causes deoxyribonucleotide depletion and results in DNA double strand breaks near replication forks (see DNA repair)
• Treatment for Systemic Mastocytosis

Dose

The dose depends on the indication, but tends to be 500 milligrams once a day when treatment is initiated. In myeloproliferative disease, further increases are determined by the response of the cell count and whether myelosuppression (decreased production of other blood cells) develops.^{[citation needed]}

In sickle-cell disease, the initial daily dose is 15 mg per kilogram body weight (or less in reduced kidney function); after two weeks, a fall in the hemoglobin and platelet count and an increase in MCV (mean corpuscular volume) (size of the red blood cells) is to be expected. The dose is then increased every two weeks with monitoring of the full blood count until the dose is either 35 mg/kg or cytopenias develop.^[2]

Side effects

Reported side-effects are: drowsiness, nausea, vomiting and diarrhea, constipation, mucositis, anorexia, stomatitis, bone marrow toxicity (which may take 7–21 days to recover after the drug has been discontinued), alopecia (hair loss), skin changes, abnormal liver enzymes, creatinine and blood urea nitrogen.^{[citation needed]}

Due to its effect on the bone marrow, regular monitoring of the full blood count is vital, as well as early response to possible infections. In addition, renal function, uric acid and electrolytes, as well as liver enzymes, are commonly checked.^{[citation needed]}

Hydroxyurea has been used primarily for the treatment of myeloproliferative diseases, which has an inherent risk of transforming to acute myeloid leukemia. There has been a longstanding concern that hydroxyurea itself carries a leukemia risk, but large studies have shown that the risk is either absent or very small. Nevertheless, it has been a barrier for its wider use in patients with sickle-cell disease.^[2]

Contraindications

Contraindications are: severe anemia, neutropenia.^{[citation needed]}

Use in pregnancy

Category D - investigational or post-marketing data show risk to the fetus. However, potential benefits may outweigh the potential risk. Generally this rating is reserved for drugs with no safer alternatives.^{[citation needed]}

References

1. ^ hydroxyurea at Dorland's Medical Dictionary
2. ^ ^{a b c d} Platt OS (2008). "Hydroxyurea for the treatment of sickle cell anemia". N. Engl. J. Med. 358 (13): 1362–9. doi:10.1056/NEJMct0708272. PMID 18367739. 
3. ^ Cokic VP, Smith RD, Beleslin-Cokic BB, et al. (2003). "Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase". J Clin Invest 111 (2): 231–9. doi:10.1172/JCI16672. PMID 12531879. http://www.jci.org/articles/view/16672.  Full text at PMC: 151872
4. ^ Harrison CN, Campbell PJ, Buck G, et al. (July 2005). "Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia". N. Engl. J. Med. 353 (1): 33–45. doi:10.1056/NEJMoa043800. PMID 16000354. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=16000354&promo=ONFLNS19. 
5. ^ Lanzkron S, Strouse JJ, Wilson R, et al. (June 2008). "Systematic review: Hydroxyurea for the treatment of adults with sickle cell disease". Ann. Intern. Med. 148 (12): 939–55. PMID 18458272. 
6. ^ Frank I, Bosch RJ, Fiscus S, et al. (September 2004). "Activity, safety, and immunological effects of hydroxyurea added to didanosine in antiretroviral-naive and experienced HIV type 1-infected subjects: a randomized, placebo-controlled trial, ACTG 307". AIDS Res. Hum. Retroviruses 20 (9): 916–26. doi:10.1089/aid.2004.20.916. PMID 15597521. 
7. ^ Sharma VK, Dutta B, Ramam M (2004). "Hydroxyurea as an alternative therapy for psoriasis". Indian J Dermatol Venereol Leprol 70 (1): 13–7. PMID 17642550. http://www.ijdvl.com/article.asp?issn=0378-6323;year=2004;volume=70;issue=1;spage=13;epage=17;aulast=Sharma. 
8. ^ Koç A, Wheeler LJ, Mathews CK, Merrill GF (January 2004). "Hydroxyurea arrests DNA replication by a mechanism that preserves basal dNTP pools". J. Biol. Chem. 279 (1): 223–30. doi:10.1074/jbc.M303952200. PMID 14573610. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=14573610. 

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