Hydroxyurea (Capsules) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Teva Czech Industries, s.r.o. (Czech Republic)

ATC Code

L01XX05 (Hydroxycarbamide)

Active Substance

Hydroxycarbamide

Dosage Form

Hydroxyurea

Capsules 500 mg: 100 pcs.

Dosage Form, Packaging, and Composition

Capsules in the form of cylindrical tubes with hemispherical ends, with a pink body and a light green cap; the contents of the capsules are a white powder.

Excipients: potato starch.

Capsule shell composition: gelatin, titanium dioxide (E171), indigo carmine (E132), quinoline yellow dye (E104), red iron oxide dye (E172), erythrosine dye (E127).

100 pcs. – polyethylene bags (1) – metal cans.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Hydroxycarbamide is a phase-specific cytostatic drug (antimetabolite, according to some data – of alkylating action), acting in the S phase of the cell cycle.

It blocks cell growth in the G1-S interphase, which is essential for concurrent radiation therapy, as synergistic sensitivity of tumor cells in the G1 phase to irradiation appears. By enhancing the action of the RNA reductase inhibitor – ribonucleoside diphosphate reductase, it causes suppression of DNA synthesis. The drug does not affect RNA and protein synthesis.

Pharmacokinetics

After oral administration, it is rapidly absorbed from the gastrointestinal tract. C_max of the drug in blood plasma is reached 1-4 hours after administration. Food intake does not affect the absorption of the drug.

It is rapidly distributed throughout body tissues and penetrates the blood-brain barrier. In the cerebrospinal fluid, 10-20% is determined, and in ascitic fluid – 15-50% of the concentration in blood plasma.

T_1/2 is 3-4 hours. It is partially metabolized in the liver and kidneys. 80% of hydroxyurea is excreted in the urine within 12 hours, with 50% unchanged and in small amounts as urea. The drug is also excreted through the respiratory tract as carbon dioxide. It is not detected in plasma after 24 hours.

Indications

• Chronic myeloid leukemia;
• Polycythemia vera;
• Essential thrombocythemia;
• Osteomyelofibrosis;
• Melanoma;
• Malignant tumors of the head and neck, excluding lip cancer (in combination with radiation therapy);
• Cervical cancer (in combination with radiation therapy).

ICD codes

Dosage Regimen

When choosing the regimen and doses in each individual case, one should be guided by data from specialized literature.

The drug is administered orally.

If swallowing is difficult, the capsule can be opened, its contents dissolved in a glass of water, and drunk entirely. In this case, some water-insoluble excipients may remain on the surface of the solution.

During treatment with the drug, a sufficiently large amount of fluid should be consumed.

Solid tumors

• 80 mg/kg once daily every 3 days (6-7 doses).
• 20-30 mg/kg daily for 3 weeks.

Head and neck cancer, cervical cancer

80 mg/kg once daily, every third day in combination with radiation therapy.

Treatment with the drug is started at least 7 days before the start of radiation therapy and continues during radiation therapy. After radiation therapy, the drug is continued for an unlimited time under strict observation of the patient and in the absence of unusual or severe toxicity reactions.

Resistant chronic myeloid leukemia

Continuous therapy. From 20 to 30 mg/kg daily once a day.

The effectiveness of the drug is assessed after 6 weeks of treatment. In case of pronounced clinical remission, treatment can be continued indefinitely. Treatment should be suspended if the white blood cell count is less than 2500/µL, and platelets are less than 100,000/µL. After 3 days, a blood test is repeated. Treatment is resumed when the white blood cell and red blood cell counts begin to increase noticeably.

Polycythemia vera

Treatment begins with a daily dose of 15-20 mg/kg. The dose is set individually, aiming to maintain hematocrit below 45% and platelet count below 400,000/µL. In most patients, these indicators can be achieved by continuously using Hydroxycarbamide at a daily dose of 500 to 1000 mg.

Essential thrombocythemia

The drug is usually prescribed at an initial daily dose of 15 mg/kg; then a dose is selected that maintains the platelet count below 600,000/µL without reducing the white blood cell count below 4000/µL.

Adverse Reactions

From the hematopoietic system: leukopenia, anemia, thrombocytopenia.

From the digestive system: stomatitis, gum bleeding, anorexia, nausea, vomiting, diarrhea or constipation, ulceration of the gastrointestinal mucosa. Increased activity of liver enzymes.

From the skin and skin appendages: maculopapular rash, facial erythema and peripheral erythema, dermatomyositis-like skin changes. In some cases, as a result of daily use of the drug for several years, patients experienced hyperpigmentation, erythema, skin and nail atrophy, scaling, purple papules. In rare cases, alopecia, skin cancer are noted.

From the nervous system: headache, dizziness, increased fatigue, drowsiness, disorientation; rarely – hallucinations and convulsions.

From the urinary system: increased content of uric acid, blood urea nitrogen and creatinine in blood plasma, urinary retention, interstitial nephritis. In rare cases, dysuria is noted.

Other: chills, general malaise, increased ESR, skin allergic reactions, fertility disorders (azoospermia, cessation of menstruation). In rare cases, acute pulmonary reactions associated with the use of the drug have been reported: diffuse pulmonary infiltration, fever and shortness of breath.

Contraindications

• Leukopenia below 2500/µL;
• Thrombocytopenia below 100,000/µL;
• Pregnancy;
• Breastfeeding period;
• Hypersensitivity to hydroxycarbamide or any other excipient included in the drug.

With caution – in hepatic and/or renal insufficiency, anemia (should be corrected before starting treatment).

Use in Pregnancy and Lactation

Contraindication: pregnancy and lactation period.

Use in Hepatic Impairment

With caution – in hepatic insufficiency.

Use in Renal Impairment

With caution – in renal insufficiency.

Pediatric Use

The safety and efficacy of hydroxycarbamide use in children have not been established.

Special Precautions

Treatment with the drug should be carried out under medical supervision. Before and periodically during treatment with the drug, it is necessary to check the functions of the bone marrow, kidneys and liver. Determination of hemoglobin, white blood cells and platelets should be carried out at least once a week throughout the entire period of treatment with the drug. If the white blood cell count is less than 2500/µL or platelets are less than 100,000/µL, treatment should be suspended until their content returns to normal.

Hydroxycarbamide has a cytotoxic effect, so caution should be exercised when opening capsules and avoid getting the capsule powder on the skin, mucous membranes, or inhaling the drug. If the capsule contents are accidentally spilled, the powder should be immediately collected with a tissue into a plastic bag, tied up and discarded.

Anemia is not a contraindication for treatment with the drug. Severe anemia before treatment with the drug should be compensated.

During treatment with the drug, myelosuppression may develop, mainly leukopenia. Thrombocytopenia and anemia develop less frequently and very rarely without preceding leukopenia. Anemia, even in severe form, is resolved without interrupting treatment. Myelosuppression is most likely in patients after recent prior intensive radiation therapy or chemotherapy with other drugs. After recently conducted intensive radiation therapy, the drug should be used with caution due to the possible exacerbation of post-radiation erythema and increased severity of side effects (bone marrow aplasia, dyspepsia and gastrointestinal ulceration).

In the early stages of treatment with the drug, moderate megaloblastic erythropoiesis is often observed. Morphological changes resemble pernicious anemia, but they are not associated with vitamin B₁₂ or folic acid deficiency.

The drug may reduce the clearance of iron from blood plasma and reduce the efficiency of iron utilization by erythrocytes, but it does not affect the lifespan of erythrocytes.

The use of hydroxycarbamide may provoke the generalization of infections (including those caused by the Herpes zoster virus (shingles, chickenpox).

During treatment, patients should consume a sufficient amount of fluid.

The drug should be used with caution in patients with impaired renal and liver function. A dose reduction of the drug may be required.

Use in pediatrics

The safety and efficacy of hydroxycarbamide use in children have not been established.

Effect on the ability to drive vehicles and mechanisms

During treatment with hydroxycarbamide (especially in high doses), caution must be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

When using the drug in doses several times higher than recommended, patients develop signs of acute dermatological toxicity: soreness, purple erythema, swelling followed by peeling of the palms of the hands and soles of the feet, intense generalized skin hyperpigmentation and severe acute stomatitis, and other side effects may also intensify.

A specific antidote is unknown. Treatment is symptomatic.

Drug Interactions

With simultaneous use of the drug with other myelosuppressive drugs or radiation therapy, the degree of bone marrow function suppression or the development of other side effects may increase.

The drug may increase the content of uric acid in the blood, so adjustment of the dose of drugs that increase the excretion of uric acid from the body may be required. Uricosuric agents increase the risk of nephropathy.

Hydroxycarbamide weakens the body’s immune system, so for the desired immune response, vaccination is recommended 3-12 months after the end of treatment.

Storage Conditions

List B. Store at a temperature not exceeding 25°C (77°F) in a dry place, out of reach of children.

Shelf Life

Shelf life – 5 years. Do not use after the expiration date indicated on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.