Hydroxyurea, also referred to as hydroxycarbamide, is used for the treatment of cervical cancer, chronic myelogenous leukemia, essential thrombocythemia, and sickle-cell disease.
It also boosts fetal hemoglobin and reduces the number of attacks in sickle-cell disease patients.
Hydroxyurea comes in different strengths and dosage forms. Popular among these are:
- Tablets: 100mg (Siklos) and 1000mg (tripled-scored) (Siklos)
- Capsules: 100mg, 200, 250mg, 300, 400, and 500mg
- Hydroxyurea is used in the prevention of recurrent painful vaso-occlusive crisis in sickle-cell patients.
- It is also used in acute chest syndrome in adults, adolescents and children older than 2 years of age who are suffering from:
- symptomatic Sickle Cell Syndrome
- resistant chronic myelocytic leukaemia, and
- recurrent metastasise, or inoperable carcinoma of the ovary.
- Excluding the lips, Hydroxyurea, used concomitantly with irritation therapy, is intended for use in the local control of primarily squalors cell (epidemold) carcinomas of the head and neck.
How Hydroxyurea works
The specific mechanism of action of hydroxyurea is not fully understood.
One of the mechanisms by which hydroxyurea acts is the elevation of foetal haemoglobin (HbF) concentrations in sickle cell patients.
HbF interferes with the polymerization of HbS and thus impedes the sickling of red blood cell.
In all clinical studies, there was a significant increase in HbF from baseline after hydroxyurea use.
Recently, Hydroxyurea has shown to be associated with the generation of nitric oxide, suggesting that nitric oxide stimulates cyclic guanosine monophosphatase (cGMP) production, which then activates a protein kinase and increases the production of Hbf.
Other known pharmacological effects of hydroxyurea which may contribute to its beneficial effects in Sickle Cell Syndrome include the following:
- decrease of neutrophils
- increase of the water content of erythrocytes
- increase of the deformability of sickled cells and altered adhesion of red blood cells to the endothelium.
In addition, hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or protein.
Dosage & administration
All dosage should be based on the patient’s actual or ideal weight. Whichever is less.
A. Solid tumor
1. Intermittent therapy: 80mg/kg administered orally as a single dose every third day.
2. Continuous therapy 20 to 30mg/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.
3. Concomitant therapy: 80mg/kg administered orally as a single dose every third day.
Administration of hyroxyurea should begin at least seven day before initiation of irradiation and continued during radiotherapy. Its adminstration should actually continue indefinitely afterwards, provided that the patient may be under adequate observation and no evidences of unusual or severe reactions.
Adjustment of irradiation dosage is not usually necessary when hydroxyurea is used concomitantly.
B. Resistant chronic myelocytic leukaemia
Until the intermittent therapy regime has been evaluated, continuous therapy (20-30mg/kg administered orally as a single dose, daily) is recommended.
Indications based dosage
1. Solid Tumors
- Intermittent Therapy: 80 mg/kg given orally every 3 days, OR
- Continuous Therapy: 20-30 mg/kg given orally daily
2. Head and Neck Tumors
Concomitant therapy with irradiation: 80 mg/kg given orally every 3 days. Begin 7 days prior to initiation of irradiation
3. Chronic Myelocytic Leukemia, Resistant
- Continuous Therapy: 20-30 mg/kg given orally every day
4. Sickle Cell Disease
- Start: 15 mg/kg/day as single dose; monitor patient’s blood cell count every 2 weeks. Increase the dose by 5 mg/kg/day every 12 week. Dose is not increased if blood counts are between acceptable range and toxic. Do not exceed 35 mg/kg/day. Therapy is to be discontinued until hematologic recovery, if blood counts are considered toxic; treatment may, however, be resumed after reducing dose by 2.5 mg/kg/day from dose associated with hematological toxicity
5. Reduction in frequency of SCD painful crises and the need for blood transfusion
Siklos is used here.
It is indicated to reduce frequency of painful crises and the need for blood transfusions in adults with sickle cell anemia who have recurrent moderate-to-severe painful crises.
- Initial dose: 15 mg/kg given orally every day. Calculate rounded doses to the nearest 50-mg or 100-mg strength based on clinical judgment. Blood cell counts are to be monitored every 2 weeks. Dose of Siklos is to be adjusted based on blood counts. Increase dose 5 mg/kg/day every 8 weeks or if a painful crisis occurs. Continue therapy until mild myelosuppression (absolute neutrophil count 2,000-4,000/mcL) is achieved. Dosage should not exceed 35 mg/kg/day. Increase dosing only if blood counts are in an acceptable range or if a painful crisis occurs Do not increase if myelosuppression Occurs
5. Thrombocythemia, Essential (Off-label)
For an off-label treatment of thrombocythemia,15 mg/kg of Hydroxyurea, given orally every day, is recommended. Increase the dose to control platelets and maintain white blood cells count.
6. HIV, Adjunct Treatment (Off-label)
The recommended dosage here is 500mg of hydroxyurea given orally 12 hourly. This is to be used as an add-on to antiretrovirals.
7. Psoriasis (Off-label)
1000-1500 mg/day given orally 12 hourly daily.
Contraindication: When not to use Hydroxyurea
- Don’t use Hydroxyurea in patients with marked bone marrow depression, i.e. Leucopenia (< 2500 WBC) or thrombocytopenia (<100,000)
- Don not also use it in patients with severe anaemia.
Treatment with hydroxyurea should not be initiated if the bone marrow function is markedly depressed.
During treatment with hydroxyurea, bone marrow suppression may occur, and leucopenia is generally its first and most common manifestation.
Thrombocytopenia and anaemia occur less often, and are seldom seen without a preceding leucopenia).
It should be borne in mind that bone marrow depression is more likely in patients who have previously received radiotherapy of cytotoxic cancer chemotherapeutic agents; Hyroxyurea should be used cautiously in such patients.
Patients who have received irradiation therapy in the past may have an exacerbation of postirradiation erythema.
Severe anaemia must be corrected with white blood replacement before initiating therapy with hydroxyurea.
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.
Side effects of Hydroxyurea
- Psycho-neutral system: Rarely, headache, dizziness, hallucination and convulsions may occur.
- Gastrointestinal: Stomatitis, inappetence, nausea, vomiting, diarrhea and constipation may occur
- Haematologic: Primarily, bone marrow depression (leucopenia, neutropenia, anaemia and thrombocytopenia) may occur. Megaloblastic erythropolesia, which is self-limiting, is often seen early in the course of Hydroxyurea therapy.
- Urogenital System: Dysuria and alopecia occur very rarely, Hydroxyurea occasionally, may temporary, cause impairment of renal tubular function accompanied by elevation in serum uric acid, BUN, and creatinine levels.
- Central Nervous System: At a higher dose, general lethargy may be caused. Also, flush, chill, fever, and malaise have been reported.
- Dermatologic: Occasionally, maculopapular rash, and facial erythema may occur.
- Hepatic: Abnormal BSP retention, and elevation of hepatic enzymes has been reported
- Other: Very rare alopecia may be caused.
- Infections: both fungal, viral and bacterial infections
- Vitamin D deficiency (
It should be borne in mind that therapeutic doses of irradiation alone produce the same adverse reaction as Hydroxyurea; therefore, combined therapy of irradiation and hydroxyurea may cause an increase in the incidence and severity of these side effects.
Therapy with Hydroxyurea requires close supervision. The complete status of the blood, including bone marrow examination, if indicated, as well as kidney functions and liver function should be determined prior to, and repeatedly during treatment.
The determination of the hemoglobin level, total leukocyte counts, and platelets counts should be performed at least once a week throughout the course of the Hydroxyurea therapy.
If the white blood cell counts decrease to less than 2500/mm³ or the platelets counts to less than 100,000/mm³, therapy should be interrupted until the values rise significantly towards normal level.
Anaemia, if it occurs, should be managed with whole blood replacement, without interrupting Hydroxyurea therapy.
Patients who take the drug by emptying the content of the capsule into water should be reminded that this is a potent medication that must be handled with care.
Patients must be cautioned not to allow the powder to come in contact with the skin or mucous membranes.
Pain or discomfort from inflammation of the mucous membranes at the irradiated sites (mucositis) is usually controlled by measures such as topical anaesthetics 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.
Use in pregnancy
Hydroxyurea is not to be used by pregnant women or those wanting to get pregnant.
This is because it affects DNA synthesis.
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, Hydroxyurea should not be used in women who are or may become pregnant unless in the judgment of the physician, or if the potential benefits outweigh the possible hazards.
How to store Hydroxyurea
Preserve in well-closed containers. Store at temperature not exceeding 30ºC.
Keep all medicines away from the reach of children.
Black Box Warnings
- Severe myelosuppression may occur in patients receiving hydroxyurea.
- Do not give hydroxyurea in patients with markedly depressed bone marrow function.
- Monitor blood counts at baseline and throughout treatment
- Interrupt treatment and reduce dose as necessary