Hydroxyurea – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Hydroxyurea is converted to a free radical nitroxide (NO) in vivo, and transported by diffusion into cells where it quenches the tyrosyl free radical at the active site of the M2 protein subunit of ribonucleotide reductase, inactivating the enzyme. The entire replicase complex, including ribonucleotide reductase, is inactivated and DNA synthesis is selectively inhibited, producing cell death in S phase and synchronization of the fraction of cells that survive. Repair of DNA damaged by chemicals or irradiation is also inhibited by hydroxyurea, offering potential synergy between hydroxyurea and radiation or alkylating agents. Hydroxyurea also increases the level of fetal hemoglobin, leading to a reduction in the incidence of vasoocclusive crises in sickle cell anemia. Levels of fetal hemoglobin increase in response to the activation of soluble guanylyl cyclase (sGC) by hydroxyurea-derived NO.

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The exact mechanism of the antineoplastic activity of hydroxyurea has not been fully determined. Some studies indicate that hydroxyurea interferes with the synthesis of DNA without interfering with the synthesis of RNA or protein. Although hydroxyurea may have multiple sites of action, it appears likely that the drug inhibits the incorporation of thymidine into DNA; in addition, it may directly damage DNA. Hydroxyurea can destroy the tyrosyl free radical that is formed as the catalytic center of ribonucleoside diphosphate reductase, the enzyme that catalyzes the reductive conversion of ribonucleotides to deoxyribonucleotides; this conversion is a critical and probably rate-limiting step in the synthesis of DNA. The drug is an S-phase inhibitor and may cause cells to arrest at the G1-S border, decrease the rate of cell progression into the S phase, and/or cause cells to accumulate in the S phase as a result of inhibiting DNA synthesis. Animal studies indicate that the cytotoxic effects of hydroxyurea are limited to those tissues with high rates of cellular proliferation and the effects are evident only in those cells that are actively synthesizing DNA.

Hydroxyurea has dose-dependent synergistic activity with cisplatin in vitroIn vivo Hydroxyurea showed activity in combination with cisplatin against the LX-1 and CALU-6 human lung xenografts, but minimal activity was seen with the NCI-H460 or NCI-H520 xenografts. Hydroxyurea was synergistic with cisplatin in the Lewis lung murine xenograft. Sequential exposure to Hydroxyurea 4 hours before cisplatin produced the greatest interaction.

Indications

  • Antineoplastic Agents; Antisickling Agents; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors
  • Hydroxyurea is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult and pediatric patients, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises.1
  • For management of melanoma, resistant chronic myelocytic leukemia, recurrent, metastatic, or inoperable carcinoma of the ovary and Sickle-cell anemia.
  • Siklos is indicated for the prevention of recurrent painful vaso-occlusive crises including acute chest syndrome in pediatric and adult patients suffering from symptomatic sickle-cell syndrome.
  • Prevention of vaso-occlusive complications of sickle cell disease in patients over 2 years of age
  • Hydroxyurea is an antimetabolite that is used in the treatment of cancer and to stimulate fetal hemoglobin production in sickle cell disease.
  • Hydroxyurea Capsules USP is indicated for the treatment of Resistant chronic myeloid leukemia. Locally advanced squamous cell carcinomas of the head and neck (excluding the lip) in combination with chemoradiation. /Included in US product label/
  • Hydroxyurea has been used in the treatment of psoriasis and is reportedly beneficial in the treatment of hypereosinophilic syndrome that does not respond to corticosteroid therapy.
  • Hydroxyurea is used to treat cancer of the white blood cells called chronic myeloid leukemia (CML). It may also be given together with radiation treatment for head and neck cancer (advanced squamous cell cancer). Hydroxyurea interferes with the growth of cancer cells, which are eventually destroyed by the body.
  • Essential Thrombocythemia (ET)
  • Hypereosinophilic Syndrome (HES)
  • Meningiomas
  • Polycythemia Vera (PV)
  • Sickle Cell Crisis
  • Inoperable Ovarian cancer

ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM’s MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Hydroxyurea is included in the database.

Use in Cancer

Hydroxyurea is approved to treat:

The use of hydroxyurea to treat cancer is approved for the Hydrea brand. Hydroxyurea is also approved to treat sickle cell anemia. This use is approved for the Droxia brand.

Hydroxyurea is also being studied in the treatment of other conditions and types of cancer.

Contraindications

  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • inflammation of blood vessels in the skin
  • redness of skin following radiation therapy
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • anemia due to depressed bone marrow
  • lung tissue problem
  • chronic kidney disease stage 3A (moderate)
  • chronic kidney disease stage 3B (moderate)
  • chronic kidney disease stage 4 (severe)
  • chronic kidney disease stage 5 (failure)

Dosage

Strengths: 500 mg; 200 mg; 300 mg; 400 mg; 1000 mg; 100 mg

Chronic Myelogenous Leukemia

  • Oral Capsules (i.e., Hydrea): Individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards
  • As monotherapy or in conjunction with other antitumor agents or radiation therapy to treat neoplastic diseases.
  • Prophylactic administration of folic acid is recommended.
  • Blood counts should be monitored at least once a week during therapy.
  • Severe anemia should be corrected before initiating therapy.
  • For the treatment of resistant chronic myeloid leukemia (CML).
  • For the treatment of locally advanced squamous cell carcinomas of the head and neck (excluding lip), in combination with concurrent chemoradiation.

Head and Neck Cancer

  • Oral Capsules (i.e., Hydrea): Individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards
  • As monotherapy or in conjunction with other antitumor agents or radiation therapy to treat neoplastic diseases.
  • Prophylactic administration of folic acid is recommended.
  • Blood counts should be monitored at least once a week during therapy.
  • Severe anemia should be corrected before initiating therapy
  • For the treatment of resistant chronic myeloid leukemia (CML).
  • For the treatment of locally advanced squamous cell carcinomas of the head and neck (excluding lip), in combination with concurrent chemoradiation.

Sickle Cell Anemia

Oral Tablets (i.e., Siklos):

  • Initial dose: 15 mg/kg orally once a day
  • Increase 5 mg/kg/day every 8 weeks or if a painful crisis occurs; increase only if blood counts are in an acceptable range
  • Maximum dose: 35 mg/kg/day

BLOOD COUNTS IN THE ACCEPTABLE RANGE:

  • Neutrophils greater than or equal to 2000 cells/mm3
  • Platelets greater than or equal to 80,000/mm3
  • Hemoglobin greater than 5.3 g/dL
  • Reticulocytes greater than or equal to 80,000/mm3 if the hemoglobin concentration is less than 9 g/dL

Oral Capsules (i.e., Droxia):

  • Initial dose: 15 mg/kg orally once a day
  • Increase 5 mg/kg/day every 12 weeks; increase only if blood counts are in an acceptable range
  • Maximum dose: 35 mg/kg/day

BLOOD COUNTS IN THE ACCEPTABLE RANGE:

  • Neutrophils greater than or equal to 2500 cells/mm3
  • Platelets greater than or equal to 95,000/mm3
  • Hemoglobin greater than 5.3 g/dL
  • Reticulocytes greater than or equal to 95,000/mm3 if the hemoglobin concentration is less than 9 g/dL
  • Dosage is based on the actual or ideal patient weight, whichever is less.
  • Blood counts should be monitored every 2 weeks.
  • Tablets may be spilt or quartered along score lines, tablet doses can be rounded to the nearest 50 mg or 100 mg strength based on clinical judgment; capsules should be swallowed whole and should not be opened or chewed.
  • Prophylactic administration of folic acid is recommended.

Pediatric Dose for Sickle Cell Anemia

Oral Tablets (i.e., Siklos):

  • Initial dose: 20 mg/kg orally once a day
  • Increase 5 mg/kg/day every 8 weeks or if a painful crisis occurs; increase only if blood counts are in an acceptable range
  • Maximum dose: 35 mg/kg/day

BLOOD COUNTS IN THE ACCEPTABLE RANGE:

  • Neutrophils greater than or equal to 2000 cells/mm3
  • Platelets greater than or equal to 80,000/mm3
  • Hemoglobin greater than 5.3 g/dL
  • Reticulocytes greater than or equal to 80,000/mm3 if the hemoglobin concentration is less than 9 g/dL
  • Dosage is based on the actual or ideal patient weight, whichever is less.
  • Blood counts should be monitored every 2 weeks.
  • Tablets may be spilled or quartered along score lines, tablet doses can be rounded to the nearest 50 mg or 100 mg strength based on clinical judgment.
  • Prophylactic administration of folic acid is recommended.

Dose Adjustments

SICKLE CELL ANEMIA:

  • Treatment for Sickle Cell Anemia should be interrupted if blood counts are in the toxic range:

TOXIC RANGE

  • Neutrophils less than 2000 cells/mm3 (younger patients with lower baseline counts may safely tolerate absolute neutrophil counts down to 1250/mm3)
  • Platelets less than 80,000/mm3
  • Hemoglobin less than 4.5 g/dL
  • Reticulocytes less than 80,000/mm3 if the hemoglobin concentration is less than 9 g/dL

Dosing After Hematologic Recovery:

  • Upon recovery, reduce from dose associated with hematologic toxicity:
  • Tablets: Reduce by 5 mg/kg/day; may titrate up or down every 8 weeks in 5 mg/kg/day increments
  • Capsules: Reduce by 2.5 mg/kg/day; may titrate up or down every 12 weeks in 2.5 mg/kg/day increments
  • Patients should be at a stable dose with no hematologic toxicity for 24 weeks.
  • Permanently discontinue if the patient develops hematologic toxicity twice.

NEOPLASTIC DISEASES:

  • Myelosuppression: Provide supportive care and modify dose or discontinue therapy as needed.
  • If cutaneous vasculitic ulcers occur, institute treatment and discontinue this drug.

Side Effects

The Most Common

  • nausea
  • vomiting
  • diarrhea
  • loss of appetite
  • weight gain
  • sores in the mouth and throat
  • constipation
  • rash
  • pale skin
  • dizziness
  • headache
  • hair loss
  • changes in skin and nails
  • fast heartbeat
  • ongoing pain that begins in the stomach area but may spread to the back
  • leg wounds or ulcers
  • pain, itching, redness, swelling, or blisters on the skin
  • pain in the upper right part of the stomach
  • blood in the urine
  • yellowing of the skin or eyes
  • numbness, burning, or tingling in the hands or feet
  • fever, cough, shortness of breath, and other breathing problems

More common

  • Black, tarry stools
  • blood in the urine or stools
  • chills
  • cough
  • fever
  • hoarseness
  • lower back or side pain
  • painful or difficult urination
  • pale skin
  • pinpoint red spots on the skin
  • sore throat
  • ulcers, sores, or white spots in the mouth
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • Blackening of the fingernails and toenails
  • trouble breathing
  • numbness, tingling, or burning pain in your hands or feet;
  • skin numbness or purple discoloration;
  • skin ulcers or open sores;
  • sudden chest pain, wheezing, dry cough, feeling short of breath;
  • low blood cell counts–fever, chills, tiredness, mouth sores, easy bruising, unusual bleeding, pale skin, cold hands, and feet, feeling light-headed; or
  • signs of liver or pancreas problems–loss of appetite, upper stomach pain (that may spread to your back), nausea or vomiting, fast heart rate, dark urine, jaundice (yellowing of the skin or eyes).

Rare

  • Confusion
  • dizziness
  • headache
  • joint pain
  • seeing, hearing, or feeling things that are not there
  • seizures
  • swelling of the feet or lower legs
  • Back, leg, or stomach pains
  • bleeding gums
  • bleeding under the skin
  • blisters on the skin
  • bluish or pale color on the skin of the fingers or toes
  • chest tightness
  • coldness of the fingers or toes
  • crater-like lesions on the skin
  • dark urine
  • drowsiness
  • fast heartbeat
  • general body swelling
  • hives, itching, skin rash
  • irritation
  • itching, pain, redness, or swelling on the leg
  • joint stiffness or swelling
  • loss of appetite
  • muscle spasms (tetany) or twitching seizures
  • nausea
  • nosebleeds
  • numbness or tingling of the fingers or toes
  • pain in the fingers or toes
  • sore on the leg
  • swelling of the eyelids, face, lips, hands, or feet
  • trembling
  • trouble swallowing
  • vomiting
  • weight loss
  • yellowing of the eyes or skin

Drug Interactions

Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned.

Pregnancy

Drugs that 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. HYDREA can cause fetal harm when administered to a pregnant woman. Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models,
including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1­ fold of the human dose given on an mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on an mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a 6 mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on an mg/m2 basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies on pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Lactation

Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy, although the evidence for this recommendation for hydroxyurea is very weak.[1,2] In doses used for sickle cell disease, hydroxyurea appears to be acceptable to use in nursing mothers. Avoiding breastfeeding for 3 hours after the mother’s dose can decrease the infant dose by about half. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breast milk.

How should this medicine be used?

Hydroxyurea comes as a capsule and tablet to take by mouth. It is usually taken once a day with a glass of water. When hydroxyurea is used to treat certain types of cancer, it may be taken once every third day. Take hydroxyurea at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take hydroxyurea exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor may need to delay your treatment or adjust your dose of hydroxyurea depending on your response to treatment and any side effects that you may experience. Talk to your doctor about how you are feeling during your treatment. Do not stop taking hydroxyurea without talking to your doctor.

Your doctor will probably tell you to take another medication, folic acid (a vitamin), to decrease some of the side effects of this medication. Take this medication exactly as directed.

Swallow the capsules whole; do not split, chew, or crush them.

The hydroxyurea 1,000-mg tablets (Siklos) are scored so that they can easily be split into halves or quarters to provide smaller doses. Do not break the hydroxyurea 100-mg tablets into smaller parts. Your doctor will tell you how to break the tablets and how many tablets or parts of a tablet you should take.

If you are unable to swallow hydroxyurea tablets or portion(s) of tablets, you may dissolve your dose in water. Place your dose in a teaspoon and add a small amount of water. Wait about 1 minute to allow the tablet(s) to dissolve, then swallow the mixture right away.

You should wear rubber or latex gloves when you handle the capsules or tablets so that your skin does not come into contact with the medication. Wash your hands with soap and water before and after you touch the bottle or medication. If hydroxyurea gets into your eyes, immediately flush your eyes with water for at least 15 minutes. If the powder from a capsule or tablet spills, wipe it up immediately with a damp disposable towel. Then place the towel in a closed container, such as a plastic bag, and throw it away in a trash can that is out of the reach of children and pets. Clean the spill area using a detergent solution followed by clean water.

What special precautions should I follow?

Before taking hydroxyurea,

  • tell your doctor and pharmacist if you are allergic to hydroxyurea, any other medications, or any of the inactive ingredients in hydroxyurea capsules or tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: certain medications for HIV (human immunodeficiency virus) such as didanosine (Videx) and stavudine (Zerit) and interferon (Actimmune, Avonex, Betaseron, Infergen, Intron A, others). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), high levels of uric acid in your blood, or leg ulcers; if you are being treated with or have ever been treated with radiation therapy, cancer chemotherapy, or hemodialysis; or if you have or have ever had kidney or liver disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. You should not become pregnant or breastfeed while you are taking hydroxyurea. You will need to have a pregnancy test before you begin treatment with hydroxyurea. If you are a female, you should use effective birth control while taking hydroxyurea and for at least 6 months after stopping your treatment. If you are a male, you and your female partner should use effective birth control while taking hydroxyurea and for at least 6 months (Siklos) or at least 1 year (Droxia, Hydrea) after stopping your treatment. Talk to your doctor about birth control methods that you can use during and after your treatment and how long you should continue their use. If you become pregnant while taking hydroxyurea, call your doctor immediately. Hydroxyurea may harm the fetus.
  • you should know that this medication may decrease fertility in men. Talk to your doctor about the risks of taking hydroxyurea.
  • do not have any vaccinations without talking to your doctor.

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/016295s040lbl.pdf
  2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016295Orig1s047,s048Lbl.pdf
  3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016295s041s042lbl.pdf
  4. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208843s003lbl.pdf
  5. https://pubchem.ncbi.nlm.nih.gov/compound/Hydroxyurea
  6. https://go.drugbank.com/drugs/DB01005
  7. https://www.drugs.com/mtm/hydroxyurea.html
  8. https://www.cancer.gov/about-cancer/treatment/drugs/hydroxyurea
  9. https://medlineplus.gov/druginfo/meds/a682004.html
  10. https://www.mayoclinic.org/drugs-supplements/hydroxyurea-oral-route/side-effects/drg-20068109
  11. https://www.webmd.com/drugs/2/drug-174597/hydroxyurea-sickle-cell-oral/details/list-contraindications
  12. https://cameochemicals.noaa.gov/help/reference/terms_and_conditions.htm?d_f=false
  13. https://cameochemicals.noaa.gov/chemical/20514https://cameochemicals.noaa.gov/browse/react
  14. NCI Thesaurus Tree
  15. VSNHCAURESNICA-UHFFFAOYSA-N
  16. IARC Classification
  17. Nucleic Acid Synthesis Inhibitors
  18. PubChem
  19. Therapeutic category of drugs in Japan
    Anatomical Therapeutic Chemical (ATC) classification
    Target-based classification of drugs
  20. NCBI