Hydroxycarbamide, 500 mg capsules 100 pcs

Pharmacotherapeutic group

Antitumor drug – antimetabolite

ATX Code

L01XX05

Pharmacodynamics:

Hydroxycarbamide is a phase-specific cytostatic drug (an alkylating antimetabolite according to some reports) active in phase S of the cell cycle. It blocks cell growth in G1-S phase, which is essential for simultaneous radiation therapy, because there appears a synergistic sensitivity of tumor cells in G1 phase to radiation.

The potentiating effect of RNA reductase inhibitor – ribonucleotide reductase causes suppression of deoxyribonucleic acid (DNA) synthesis without affecting ribonucleic acid (RNA) and protein synthesis.

Pharmacokinetics:

Intake and distribution

It is rapidly absorbed in the gastrointestinal tract (GIT). Maximum plasma concentration of hydroxycarbamide (Cmax) is reached within 2 hours after ingestion. There are no data on the effect of food intake on absorption. It is rapidly distributed throughout the body tissues penetrates through the blood-brain barrier. Concentration of hydroxycarbamide in CSF is 10-20% of the plasma concentration, while the concentration in ascitic fluid is 15-50%. Hydroxycarbamide accumulates in leukocytes and erythrocytes.

Metabolism

Partially metabolized in the liver and kidneys.

Elimination

The elimination half-life (T1/2) is 3-4 hours. 80% of hydroxycarbamide is excreted by the kidneys within 12 hours. 50% of hydroxycarbamide is excreted unchanged and in small amounts as urea. The drug is also excreted through the respiratory tract as carbon dioxide. After 24 hours, hydroxycarbamide is undetectable in plasma.

Indications

– Resistant chronic myeloid leukemia.

– Polycythemia vera (erythremia) with a high risk of thromboembolic complications.

– Essential thrombocythemia with a high risk of thromboembolic complications.

– Osteomyelofibrosis.

– Melanoma.

– Malignant tumors of the head and neck (except lip cancer) in combination with radiation therapy.

– Cervical cancer (in combination with radiation therapy).

Pharmacological effect

Pharmacotherapeutic group

Antitumor agent – antimetabolite

ATX code

L01XX05

Pharmacodynamics:

Hydroxycarbamide is a phase-specific cytostatic drug (an antimetabolite, according to some sources, with an alkylating effect) acting in the S phase of the cell cycle. It blocks the growth of cells in G1-S, which is essential for concurrent radiation therapy since there is a synergistic sensitivity of tumor cells in the G1 phase to radiation.

By enhancing the effect of an RNA reductase inhibitor, ribonucleotide reductase, it suppresses the synthesis of deoxyribonucleic acid (DNA) without affecting the synthesis of ribonucleic acid (RNA) and protein synthesis.

Pharmacokinetics:

Suction and distribution

Rapidly absorbed from the gastrointestinal tract (GIT). The maximum concentration of hydroxycarbamide (Cmax) in the blood plasma is achieved within 2 hours after administration. There are no data on the effect of food intake on absorption. It is quickly distributed throughout the tissues of the body and penetrates the blood-brain barrier. The concentration of hydroxycarbamide in the cerebrospinal fluid is 10-20% of the plasma concentration, and the concentration in ascitic fluid is 15-50%. Hydroxycarbamide accumulates in leukocytes and erythrocytes.

Metabolism

Partially metabolized in the liver and kidneys.

Removal

The half-life (T1/2) is 3-4 hours. 80% of hydroxyurea is excreted by the kidneys within 12 hours. 50% of hydroxyurea is excreted unchanged and in small quantities in the form of urea. The drug is also excreted through the respiratory tract in the form of carbon dioxide. After 24 hours, hydroxycarbamide is not detected in plasma.

Special instructions

Treatment with the drug should be carried out under the supervision of a physician experienced in the use of antitumor therapy.

Before each course and periodically during treatment, it is necessary to monitor the functions of the bone marrow of the liver and kidneys. Determination of hemoglobin of leukocytes and platelets should be carried out at least once a week throughout the entire period of treatment with the drug. Treatment is prescribed only if the leukocyte count exceeds 2500/μl and the platelet count exceeds 100,000/μl. If during treatment it is revealed that the leukocyte count is less than 2500/μl or platelet count is less than 100,000/μl, treatment should be suspended until their content is restored to normal.

Severe anemia must be compensated before starting treatment with the drug.

During treatment with the drug, myelosuppression, mainly leukopenia, may develop. Thrombocytopenia and anemia develop less frequently and very rarely without previous leukopenia. Myelosuppression is most likely in patients who have had recent prior radiation therapy or chemotherapy with other drugs.

After recent radiation or chemotherapy, the drug should be used with caution due to a possible exacerbation of post-radiation erythema and increased severity of side effects (bone marrow aplasia, dyspepsia and ulceration of the gastrointestinal tract).

If severe side effects from the digestive system (such as nausea, vomiting, anorexia) occur, drug therapy is usually suspended.

For pain and discomfort due to the development of mucositis in the area of ​​radiation, local anesthetics and analgesics are usually prescribed for oral administration. In severe cases, drug therapy is temporarily suspended, and in very severe cases, concomitant radiation therapy is temporarily discontinued.

In the early stages of treatment with the drug, moderate megaloblastic erythropoiesis is often observed. Morphological changes resemble pernicious anemia; however, they are not associated with vitamin B12 or folic acid deficiency. Due to the fact that macrocytosis may mask folic acid deficiency, regular determination of serum folic acid is recommended.

Hydroxyurea may also slow the clearance of plasma iron and reduce the rate of iron utilization by red blood cells; however, this does not affect the lifespan of red blood cells.

Cases of pancreatitis and hepatotoxicity (possibly fatal) have been reported in HIV-infected patients who took hydroxyurea in combination with antiretroviral drugs, particularly didanosine (with or without stavudine). In this regard, co-administration of these drugs should be avoided. Also, cases of the development of peripheral neuropathy, sometimes severe, have been observed in HIV-infected patients who took hydroxyurea in conjunction with antiretroviral drugs including didanosine (in combination with or without stavudine).

During treatment, patients should drink sufficient fluids. It may be necessary to reduce the dose of the drug if renal function is impaired. The drug should be used with caution in patients with impaired renal and liver function.

During treatment with the drug, cutaneous toxic vasculitis, including vasculitic ulcerations and gangrene, was observed in patients with myeloproliferative diseases. Toxic vasculitis was most often reported in patients receiving or who have previously received interferon. If vasculitic ulcerations progress, use of the drug should be discontinued.

With long-term use of the drug in patients with myeloproliferative diseases such as polycythemia vera and thrombocytopenia, cases of secondary leukemia have been reported. However, it is unknown what causes the development of secondary leukemia: the use of hydroxycarbamide or the underlying disease.

Cases of skin cancer have also been observed with long-term use of hydroxyurea. Patients should be warned about the need to protect their skin from sunlight and self-monitor their skin condition. During routine visits to the doctor, the condition of the patient’s skin should be monitored to identify possible malignant changes.

Azoospermia or oligospermia, sometimes reversible, has been observed in male patients. In this regard, patients should be informed about the possibility of sperm conservation before starting therapy.

Due to the possible genotoxicity of hydroxyurea, male patients taking the drug should be informed of the need for reliable contraception during treatment and for at least one year after the end of therapy.

When vaccinated with live viral vaccines simultaneously with hydroxyurea therapy, it is possible to activate the replication of the vaccine virus and/or increase the development of adverse reactions due to the suppression of the body’s defense mechanisms caused by the use of hydroxyurea. Vaccination with live vaccines while using hydroxyurea can lead to the development of severe infections. It is also possible that the immune response to vaccines may be reduced.

You should avoid administering live vaccines during drug therapy and consult a specialist.

Hydroxycarbamide has a cytotoxic effect, so care should be taken when opening capsules and avoid getting powder from capsules on the skin, mucous membranes or inhaling the drug. If the contents of the capsule are accidentally spilled, you should immediately collect the powder with a napkin in a plastic bag, tie it and throw it away.

Use in pediatrics

The safety and effectiveness of hydroxyurea in children has not been established.

Use in elderly patients

Since elderly patients are more likely to develop side effects when using hydroxycarbamide than younger patients, it may be necessary to use the drug in a reduced dose.

Impact on the ability to drive vehicles. Wed and fur.:

No studies have been conducted to study the effect of hydroxyurea on the ability to drive vehicles and operate machinery. If adverse reactions from the nervous system (dizziness, etc.) develop when using the drug, you should refrain from driving vehicles and machinery, as well as from engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Active ingredient

Hydroxyurea

Composition

For one capsule:

Active ingredient: hydroxyurea – 500.00 mg.

Excipients: lactose monohydrate (milk sugar) – 42.20 mg; sodium hydrogen phosphate dihydrate – 36.00 mg; citric acid monohydrate – 12.8 mg; magnesium stearate – 9.00 mg.

Composition of the capsule body: titanium dioxide – 2.0000%; gelatin – up to 100%.

Composition of the capsule cap: titanium dioxide – 2.0000%; gelatin – up to 100%.

Pregnancy

It has been proven that hydroxyurea has mutagenic and teratogenic effects. The use of hydroxycarbamide during pregnancy is contraindicated. During therapy, the patient should be warned about the need for reliable contraception. If pregnancy occurs during treatment with hydroxyurea, the patient must be warned about the possible risk to the fetus.

Hydroxycarbamide passes into breast milk. If it is necessary to use hydroxyurea during breastfeeding, breastfeeding should be discontinued.

Contraindications

– Hypersensitivity to hydroxyurea or other components of the drug.

– Pregnancy and breastfeeding period.

– Leukopenia below 2500/μl thrombocytopenia below 100,000/μl.

– Age under 18 years (safety and effectiveness of use have not been established).

With caution:

– Liver and/or kidney failure.

– Severe anemia (must be corrected before starting treatment).

– Patients after undergoing radiotherapy or chemotherapy (possibility of myelosuppression of exacerbation of radiation erythema).

– Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Side Effects

The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems. The incidence of adverse reactions is estimated as follows: very common – ≥ 10%; often – ≥ 1% and <10%; uncommon - ≥01% and <1%; rarely - ≥001% and <01%; very rare - <001% including individual messages; frequency unknown—frequency cannot be estimated from available data.

Infectious and parasitic diseases:

frequency unknown – gangrene.

Blood and lymphatic system disorders:

frequency unknown – suppression of bone marrow function (leukopenia, anemia, thrombocytopenia):

Gastrointestinal disorders:

frequency is unknown – pancreatitis is sometimes fatal (in HIV-infected patients simultaneously receiving antiretroviral therapy, in particular didanosine and stavudine); stomatitis anorexia nausea vomiting diarrhea constipation mucositis dyspepsia irritation of the gastric mucosa ulceration of the gastrointestinal mucosa.

Disorders of the liver and biliary tract:

frequency unknown – hepatotoxicity, increased activity of liver enzymes and bilirubin concentration in the blood plasma, cholestasis, hepatitis.

Disorders of the skin and subcutaneous tissues:

rarely – alopecia, skin cancer; frequency unknown – cutaneous vasculitis macular-papular rashes facial erythema and peripheral erythema ulcerations on the skin dermatomyositis-like skin changes skin exfoliation hyperpigmentation atrophy of the skin and nails peeling purple papules skin toxic vasculitis (including vasculitic ulcerations and gangrene) skin allergic reactions.

Nervous system disorders:

frequency unknown – dizziness drowsiness disorientation headache hallucinations seizures peripheral neuropathy (in HIV-infected patients simultaneously receiving antiretroviral therapy, in particular didanosine and stavudine) increased fatigue.

Disorders of the respiratory system of the chest and mediastinum:

rarely – diffuse infiltration of the lungs; shortness of breath; frequency unknown – pulmonary fibrosis.

Renal and urinary tract disorders:

rarely – dysuria; frequency unknown – increased uric acid in the blood serum, increased urea nitrogen and creatinine in the blood plasma, urinary retention, interstitial nephritis.

General disorders and disorders at the injection site:

frequency unknown – chills, fever, general malaise, increased ESR, asthenia, azoospermia, oligospermia, tumor lysis syndrome.

Cases of pancreatitis and hepatotoxicity (possibly fatal) as well as severe peripheral neuropathy have been reported in patients with HIV who took hydroxyurea in combination with antiretroviral drugs, particularly didanosine, with or without stavudine.

The side effects observed with the simultaneous use of hydroxycarbamide and radiation therapy are the same as with monotherapy with the drug, mainly suppression of bone marrow function (leukopenia anemia) and irritation of the gastric mucosa.

The use of hydroxyurea may increase some of the side effects that are observed with radiation therapy, such as gastric discomfort and mucositis.

Interaction

When hydroxyurea is used concomitantly with other myelosuppressive drugs or radiation therapy, the degree of bone marrow suppression or the development of other side effects may increase.

In vitro studies have shown that the simultaneous use of hydroxycarbamide and cytarabine increases the cytotoxic effect of the latter.

If severe depression, nausea, vomiting or anorexia occur during combination therapy, they can usually be relieved by interrupting the use of hydroxycarbamide.

Soreness and discomfort of the mucous membranes at the radiation site (mucositis) can be relieved by the use of local anesthetics and the use of oral analgesics. For severe mucositis, hydroxyurea therapy is temporarily discontinued; and in very severe cases, radiation therapy is also suspended.

The drug may increase the level of uric acid in the blood serum, so it may be necessary to adjust the dose of drugs that increase the excretion of uric acid from the body. Uricosuric drugs increase the risk of developing nephropathy. There have been cases of false positive test results when determining urea, uric acid and lactic acid as a result of the interaction of hydroxycarbamide and enzymes (urease uricase lactate dehydrogenase).

An increased risk of developing fatal vaccine-associated infections is possible with the combined use of hydroxyurea and live vaccines. The use of live vaccines is not recommended in immunocompromised patients.

Overdose

Symptoms: when using hydroxycarbamide in doses several times higher than recommended, patients developed signs of acute dermatological toxicity: pain, purple erythema, swelling followed by peeling of the skin of the palms and feet, intense generalized hyperpigmentation of the skin and stomatitis.

Treatment: specific antidote is not known; treatment is symptomatic.

Storage conditions

At a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf life

3 years.

Do not use the drug after the expiration date.

Manufacturer

Ozon, Russia