Hydroxyurea – Uses, Dosage, Side Effects, Interaction

Hydroxyurea has dose-dependent synergistic activity with cisplatin in vitro. In 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.

Use in Cancer

Hydroxyurea is approved to treat:

• Chronic myelogenous leukemia that is refractory? (does not respond to treatment).
• Squamous cell carcinoma of the head and neck (excluding the lip) that is locally advanced. It is used with chemoradiation.

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.