Hydrea capsules 500mg, No. 20

- Chronic myeloid leukemia
- Polycythemia vera (erythremia)
- 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)

When choosing a regimen and doses in each individual case, one should be guided by the data of special literature.
The drug is administered orally.
If it is difficult to swallow, the capsule can be opened, pour the contents into a glass of water and drink immediately. However, some water-insoluble excipients may remain on the surface of the solution.
During treatment with the drug, a sufficiently large amount of liquid should be taken.
Resistant chronic myeloid leukemia
Continuous therapy. 20 to 30 mg / kg daily, once a day.
The evaluation of the effectiveness of the drug is carried out after 6 weeks of treatment. With an acceptable clinical response, treatment can be continued indefinitely. Treatment should be suspended if the white blood cell count is less than 2500 / mm3 or the platelet count is less than 100000 / mm3. After 3 days, a blood test is repeated. Treatment is resumed when the content of leukocytes and erythrocytes rises to an acceptable level (see above). Usually, the restoration of the content of leukocytes and erythrocytes occurs quickly enough, otherwise, when the drug is used together with radiation therapy, the latter can also be suspended.
The development of anemia, even severe, does not require interruption of the course of treatment, provided adequate therapy (red blood cell transfusion).
Polycythemia vera
Treatment begins with a daily dose of 15Ц20 mg / kg. The dose is set individually, aiming to maintain the hematocrit below 45% and the platelet count below 400,000 / ?l. In most patients, it is possible to achieve these indicators by constantly using hydroxycarbamide in a daily dose of 500 to 1000 mg.
Essential thrombocythemia
Usually, HydreaЃ is prescribed at an initial daily dose of 15 mg / kg; then select such a dose that maintains the number of platelets at a level below 600,000 / ?l, without leading to a decrease in the number of leukocytes below 4000 / ?l. Solid tumors, melanoma Intermittent therapy:
- 80 mg / kg once a day every three days (6-7 doses)
Continuous therapy:
- 20-30 mg / kg once a day for 3 weeks.
Carcinoma of the head and neck, carcinoma of the cervix
80 mg / kg once a day, every three days in combination with radiation therapy.
Treatment with the drug begins at least 7 days before the start of radiation therapy and continues during radiation therapy. After radiation therapy, the drug continues to be taken indefinitely under strict supervision of the patient and in the absence of unusual or severe toxic reactions.
Patients with impaired liver function There are no
indications for changing doses in this group of patients. Blood counts should be carefully monitored in patients with impaired liver function.
Patients with impaired renal function
Since hydroxyurea is excreted mainly through the kidneys, a dose reduction is necessary when prescribing the drug to such patients.
For patients with renal insufficiency (creatinine clearance less than 60 ml / min), the drug is usually prescribed at a dose of 15 mg / kg. For patients with terminal stage of renal failure, the drug is prescribed at a dose of 15 mg / kg twice, with an interval of 7 days between doses: the first time - at the end of a 4-hour hemodialysis session, the second time - before the hemodialysis session.
Elderly patients
Since elderly patients are more likely to develop side effects when using the drug HydreaЃ than in young patients, the recommended dose for patients in this group should not exceed 60 mg / kg per day.

One capsule contains:
active substance - hydroxycarbamide 500 mg;
excipients: citric acid 12.8 mg, lactose monohydrate 42.2 mg, sodium hydrogen phosphate 36.0 mg, magnesium stearate 9.0 mg;
composition of the capsule shell: gelatin 93.743 mg, titanium dioxide 2.016 mg, iron dye red oxide 0.115 mg, iron dye yellow oxide 0.110 mg, indigo carmine FD&C blue dye 0.017 mg.
The composition of the ink for the inscription: shellac, black iron oxide, N-butyl alcohol, purified water, propylene glycol, industrial methylated alcohol, isopropyl alcohol.

- Hypersensitivity to hydroxycarbamide or any other excipient included in the drug.
- Pregnancy and the period of breastfeeding.
- Leukopenia below 2500 / ?L, thrombocytopenia below 100,000 / ?L.
- Children's age (safety and efficacy have not been established).
With caution:
- hepatic and / or renal failure,
- severe anemia (must be compensated before starting treatment),
- patients after radiotherapy or chemotherapy (the possibility of myelosuppression, exacerbation of radiation erythema).
- lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Trade name of the drug:

HydreaЃ (HydreaЃ)

International non-proprietary name:

hydroxycarbamide

Dosage form:

capsules

Composition:

One capsule contains:
active substance - hydroxycarbamide 500 mg;
excipients: citric acid 12.8 mg, lactose monohydrate 42.2 mg, sodium hydrogen phosphate 36.0 mg, magnesium stearate 9.0 mg;
composition of the capsule shell: gelatin 93.743 mg, titanium dioxide 2.016 mg, iron dye red oxide 0.115 mg, iron dye yellow oxide 0.110 mg, indigo carmine FD&C blue dye 0.017 mg.
The composition of the ink for the inscription: shellac, black iron oxide, N-butyl alcohol, purified water, propylene glycol, industrial methylated alcohol, isopropyl alcohol.

Description
Capsules - hard gelatinous, opaque, size No. 0. Cap: green matte. Case: pale pink matt. The capsule has a black lettering 'BMS 303'. Capsule content: white powder or solid mass.

Pharmacotherapeutic group:

Antineoplastic agent, antimetabolite.

Pharmacological properties

Pharmacodynamics
Hydroxycarbamide is a phase-specific cytostatic drug (antimetabolite, according to some sources - alkylating action), acting in the S phase of the cell cycle. Blocks the growth of cells in the G1-S interphase, which is essential for simultaneous radiation therapy, since there is a synergistic sensitivity of tumor cells in the G1 phase to irradiation. Strengthening the action of the inhibitor of RNA reductase - ribonucleoside diphosphate reductase, causes the suppression of DNA synthesis. The drug does not affect the synthesis of RNA and protein.
Pharmacokinetics
After oral administration, it is rapidly absorbed from the gastrointestinal tract. The maximum concentration of the drug in blood plasma is reached within 2 hours after administration.
There are no data on the effect of food intake on the absorption of the drug. It is quickly distributed throughout the tissues of the body, penetrates the blood-brain barrier. In the cerebrospinal fluid, 10Ц20% is determined, in the ascitic fluid - 15Ц50% of the concentration in the blood plasma. Hydroxycarbamide accumulates in leukocytes and erythrocytes. The half-life is 3-4 hours. Partially metabolized in the liver. 80% of hydroxyurea is excreted in the urine within 12 hours, while 50% is unchanged and in small amounts in the form of urea. The drug is also excreted through the respiratory tract in the form of carbon dioxide. After 24 hours, it is not detected in plasma.
Patients with impaired renal function
Since hydroxyurea is excreted mainly through the kidneys, a dose reduction is necessary when prescribing the drug to such patients.

Indications for use

- Chronic myeloid leukemia
- Polycythemia vera (erythremia)
- 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)

Contraindications

- Hypersensitivity to hydroxycarbamide or any other excipient included in the drug.
- Pregnancy and the period of breastfeeding.
- Leukopenia below 2500 / ?L, thrombocytopenia below 100,000 / ?L.
- Children's age (safety and efficacy have not been established).
With caution:
- hepatic and / or renal failure,
- severe anemia (must be compensated before starting treatment),
- patients after radiotherapy or chemotherapy (the possibility of myelosuppression, exacerbation of radiation erythema).
- lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Pregnancy and breastfeeding

The drug should not be taken during pregnancy. During therapy, the patient should be warned about the need for reliable contraception. If pregnancy occurs during treatment with the drug, it is necessary to warn the patient about the possible risk to the fetus.
The drug passes into breast milk. Breastfeeding should be stopped for the period of treatment or therapy should be discontinued, having previously assessed the importance of its implementation for the mother.

Method of administration and dosage

When choosing a regimen and doses in each individual case, one should be guided by the data of special literature.
The drug is administered orally.
If it is difficult to swallow, the capsule can be opened, pour the contents into a glass of water and drink immediately. However, some water-insoluble excipients may remain on the surface of the solution.
During treatment with the drug, a sufficiently large amount of liquid should be taken.
Resistant chronic myeloid leukemia
Continuous therapy. 20 to 30 mg / kg daily, once a day.
The evaluation of the effectiveness of the drug is carried out after 6 weeks of treatment. With an acceptable clinical response, treatment can be continued indefinitely. Treatment should be suspended if the white blood cell count is less than 2500 / mm3 or the platelet count is less than 100000 / mm3. After 3 days, a blood test is repeated. Treatment is resumed when the content of leukocytes and erythrocytes rises to an acceptable level (see above). Usually, the restoration of the content of leukocytes and erythrocytes occurs quickly enough, otherwise, when the drug is used together with radiation therapy, the latter can also be suspended.
The development of anemia, even severe, does not require interruption of the course of treatment, provided adequate therapy (red blood cell transfusion).
Polycythemia vera
Treatment begins with a daily dose of 15Ц20 mg / kg. The dose is set individually, aiming to maintain the hematocrit below 45% and the platelet count below 400,000 / ?l. In most patients, it is possible to achieve these indicators by constantly using hydroxycarbamide in a daily dose of 500 to 1000 mg.
Essential thrombocythemia
Usually, HydreaЃ is prescribed at an initial daily dose of 15 mg / kg; then select such a dose that maintains the number of platelets at a level below 600,000 / ?l, without leading to a decrease in the number of leukocytes below 4000 / ?l. Solid tumors, melanoma Intermittent therapy:
- 80 mg / kg once a day every three days (6-7 doses)
Continuous therapy:
- 20-30 mg / kg once a day for 3 weeks.
Carcinoma of the head and neck, carcinoma of the cervix
80 mg / kg once a day, every three days in combination with radiation therapy.
Treatment with the drug begins at least 7 days before the start of radiation therapy and continues during radiation therapy. After radiation therapy, the drug continues to be taken indefinitely under strict supervision of the patient and in the absence of unusual or severe toxic reactions.
Patients with impaired liver function There are no
indications for changing doses in this group of patients. Blood counts should be carefully monitored in patients with impaired liver function.
Patients with impaired renal function
Since hydroxyurea is excreted mainly through the kidneys, a dose reduction is necessary when prescribing the drug to such patients.
For patients with renal insufficiency (creatinine clearance less than 60 ml / min), the drug is usually prescribed at a dose of 15 mg / kg. For patients with terminal stage of renal failure, the drug is prescribed at a dose of 15 mg / kg twice, with an interval of 7 days between doses: the first time - at the end of a 4-hour hemodialysis session, the second time - before the hemodialysis session.
Elderly patients
Since elderly patients are more likely to develop side effects when using the drug HydreaЃ than in young patients, the recommended dose for patients in this group should not exceed 60 mg / kg per day.

Side effect

Legend for the occurrence of adverse events (AE):
'very often' (? 1/10), 'often' (? 1/100,

Infections: frequency unknown - gangrene;
From the side of hematopoietic organs: the frequency is unknown - suppression of bone marrow function (leukopenia, anemia, thrombocytopenia).
On the part of the digestive system: the frequency is unknown - hepatotoxicity, and pancreatitis, sometimes fatal (in HIV-infected patients who are 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 tract mucosa; increased activity of 'liver' enzymes and the concentration of bilirubin in plasma;
On the part of the skin and cutaneous appendages:frequency unknown - cutaneous vasculitis, macular-papular rash, facial erythema and peripheral erythema, skin ulceration, dermatomyositis-like skin changes, skin exfoliation, hyperpigmentation, erythema, skin and nail atrophy, desquamation, purple papules, cutaneous toxic vasculitis (including and gangrene); rarely - alopecia, skin cancer.
From the side of the nervous system: the frequency is unknown - dizziness, drowsiness, disorientation; headache, hallucinations, seizures, peripheral neuropathy (in HIV-infected patients who are simultaneously receiving antiretroviral therapy, in particular, didanosine and stavudine), increased fatigue;
From the respiratory system: the frequency is unknown - pulmonary fibrosis, diffuse lung infiltration, shortness of breath.
From the urinary system: the frequency is unknown - an increase in the content of uric acid in the blood serum, an increase in the content of urea nitrogen and creatinine in the blood plasma, urinary retention, interstitial nephritis, rarely - dysuria.
Others: the frequency is unknown - chills, fever, general malaise, increased ESR, allergic skin reactions, asthenia, rarely - diffuse infiltration of the lungs, shortness of breath. Cases of the development of pancreatitis and hepatotoxicity (with a possible fatal outcome), as well as severe peripheral neuropathy, were noted in HIV patients who took hydroxycarbamide in conjunction with antiretroviral drugs, in particular didanosine in combination with stavudine or without it.
Side effects observed with the simultaneous use of hydroxycarbamide and radiation therapy are the same as with monotherapy with the drug, mainly inhibition of bone marrow function (leukopenia, anemia) and irritation of the gastric mucosa. Taking hydroxycarbamide can increase some of the side effects seen with radiation therapy, such as stomach discomfort and mucositis.

Overdose

Symptoms: When using the drug in doses several times higher than recommended, patients developed signs of acute dermatological toxicity: soreness, purple erythema, edema followed by desquamation of the palms of the hands and feet, intense generalized hyperpigmentation of the skin and stomatitis.
Treatment: No specific antidote known. Treatment is symptomatic.

Interaction with other drugs
With the simultaneous use of the drug with other myelosuppressive drugs or radiation therapy, the degree of suppression of bone marrow function or the development of other side effects may increase.
In in vitro studies, it was noted that with the simultaneous use of HydreaЃ and cytarabine, the cytotoxic effect of the latter increases.
If severe dyspepsia, nausea, vomiting or anorexia occur during combination therapy, they can usually be stopped by interrupting the use of HydreaЃ.
Soreness and discomfort of the mucous membranes at the radiation site (mucositis) can be alleviated by the use of local anesthetics and oral analgesics. In severe mucositis, therapy with HydreaЃ is temporarily stopped; in very severe cases, radiation therapy is also stopped.
The drug can increase the serum uric acid level, so a dose adjustment of drugs that increase the excretion of uric acid from the body may be required. Uricosuric drugs increase the risk of developing nephropathy.
There have been cases of false positive test results in the determination of urea, uric acid and lactic acid as a result of the interaction of hydroxycarbamide and enzymes (urease, uricase, lactate dehydrogenase).

special instructions

Treatment with the drug should be carried out only under the supervision of a physician experienced in the use of anticancer therapy.
Before each course and periodically during treatment with the drug, it is necessary to monitor the functions of the bone marrow, kidneys and liver. Determination of hemoglobin, leukocytes and platelets should be carried out at least 1 time per week throughout the entire period of drug treatment. Treatment is prescribed only if the leukocyte count exceeds 2500 / ?l, and the platelet count is 100,000 / ?l. If during treatment it is revealed that the content of leukocytes is less than 2500 / ?l or platelets - less than 100,000 / ?l, the treatment should be suspended until their content is restored to normal.
Severe anemia should be compensated for 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 prior leukopenia. Myelosuppression is most likely in patients after recent previous radiation therapy or chemotherapy with other drugs.
After recent radiation or chemotherapy, the drug should be used with caution because of the possible exacerbation of post-radiation erythema and increased severity of side effects (bone marrow aplasia, dyspepsia and ulceration of the gastrointestinal tract).
In the event of severe side effects from the digestive system (such as nausea, vomiting, anorexia), therapy with HydreaЃ is usually stopped.
For pain and discomfort during the development of mucositis in the area of ??radiation, local anesthetics and analgesics for oral administration are usually prescribed. In severe cases, drug therapy is temporarily suspended, and in very severe cases, concomitant radiation therapy is temporarily canceled.
In the early stages of drug treatment, moderate megaloblastic erythropoiesis is often observed. Morphological changes resemble pernicious anemia, however, they are not associated with a deficiency of vitamin B12 or folic acid. Since macrocytosis can mask folate deficiency, prophylactic folic acid supplementation should be considered.
Hydroxycarbamide can also slow down plasma iron clearance and reduce the rate of iron utilization by red blood cells, however, this does not affect the life of red blood cells.
Cases of pancreatitis and hepatotoxicity (with a possible fatal outcome) were noted in HIV-infected patients who took hydroxycarbamide in conjunction with antiretroviral drugs, in particular didanosine (with and without stavudine). In this regard, co-administration of these drugs should be avoided. Also, cases of peripheral neuropathy, sometimes severe, were observed in HIV-infected patients who took hydroxycarbamide in conjunction with antiretroviral drugs, including didanosine (with and without stavudine).
During treatment, patients should consume a sufficient amount of fluids.
It may be necessary to reduce the dose of the drug in case of impaired renal function.
The drug should be used with caution in patients with impaired renal and liver function.
During treatment with the drug, in patients with myeloproliferative diseases, cutaneous toxic vasculitis, including vasculitic ulceration and gangrene, were observed. The most frequently reported toxic vasculitis in patients receiving or receiving interferon in the past. With the progression of vasculitis ulceration, the drug should be discontinued.
With prolonged use of the drug HydreaЃ in patients with myeloproliferative diseases, such as polycythemia vera and thrombocythemia, cases of secondary leukemia have been reported. At the same time, it is not known what is the cause of the development of secondary leukemia: the intake of hydroxycarbamide or the underlying disease.Cases of skin cancer have also been observed with prolonged use of HydreaЃ. Patients should be warned about the need to protect the skin from sunlight and self-monitor the condition of the skin. During routine visits to the doctor, the condition of the patient's skin should be monitored in order to identify possible malignant changes.
The drug HydreaЃ has a cytotoxic effect, therefore, you should be careful when opening the capsules and avoid getting the capsule powder 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 up and discard.
Use in pediatrics The
safety and efficacy of use in children has not been established.
Since elderly patients are more likely to develop side effects when using the drug HydreaЃ than in young patients, it may be necessary to use the drug in a reduced dose.

Influence on the ability to drive vehicles and control mechanisms
Studies to study the effect of the drug on the ability to drive vehicles and control mechanisms have not been conducted.
Due to the fact that hydroxycarbamide can cause dizziness and other undesirable phenomena from the nervous system, during the period of drug treatment, the ability to concentrate may deteriorate.

Release form

Capsules 500 mg.
10 capsules in a blister made of aluminum foil / PVC / PVDC. 2 blisters with instructions for use in a cardboard box.

Storage conditions:

At a temperature of 15-25 ? C in a dark place.
Keep out of the reach of children.