Hydroxycarbamide

Package leaflet (information for patients)

Tradename
Hydroxycarbamide

Dosage form
Tablets 500 mg.

Description
Round, flat, beveled to the edge white tablets with an imprint in the form of the brand name "V" on one side.

Structure
Active ingredient: Hydroxycarbamide 500 mg.
Excipients: microcrystalline cellulose 102, calcium stearate, aerosil ® 200 (hydrophilic pyrogenic silicon dioxide).

Pharmacotherapeutic group
Antineoplastic agent, antimetabolite

Pharmacological properties
It is an S- phase-specific agent, inhibits ribonucleotide reductase, rapidly disrupting DNA synthesis, without affecting the synthesis of RNA and protein, which leads to a cytotoxic effect. Suppresses the activity of polymerases, as a result of which the process of DNA repair after potentially lethal damage by radiation or chemical agents is disrupted. This mechanism of action of hydroxycarbamide allows it to be used as a radiosensitizer.
An adequate period for assessing the antitumor efficacy of hydroxycarbamide is considered to be 6 weeks of therapy. The presence of the effect is indicated by a decrease in the size of the tumor or the cessation of tumor growth.
Significantly increases the effectiveness of radiation therapy for tumors of the cranial brain, cervical cancer.
Possible use in the treatment of psoriasis (mainly pustular forms), disease Sneddon - Wilkinson, gangrenous pyoderma, psoriasis erythrodermic, sickle-cell anemia.
Gene toxicity of hydroxycarbamide has been revealed in various test systems. Cases of secondary leukemia were observed in patients who received the drug for a long time in the treatment of myeloproliferative disorders (polycythemia vera, thrombocythemia).
In experiments on animals, teratogenic and carcinogenic effects have been revealed; affects fertility; it is shown that hydroxycarbamide passes through the placenta and has an embryotoxic effect. However, there have been no adequate and well-controlled studies in pregnant women. In in vitro experiments, hydroxycarbamide exerted a mutagenic effect on the cells of bacteria, fungi, protozoa and mammals; Clastogenicity of hydroxycarbamide was confirmed in in vitro experiments (on cells of hamsters and human lymphoblasts) and in vivo (test of exchange of sister chromatids in rodents, micronucleus test in mice).
After oral administration, it is well absorbed from the gastrointestinal tract and immediately penetrates into tissues, does not accumulate in the body. In the cerebrospinal fluid is 10-20%, in ascitic - 15-50% of the concentration in plasma. Bioavailability averages (108 ± 36)%. Passes through the BBB. Cmax is achieved 2 hours after administration and averages 22.9–65.6 mg / l. After 24 hours, the plasma content approaches zero. T1 / 2 - 3-4 hours Partially metabolized in the liver and kidneys. It is excreted mainly by the kidneys (when taken orally or intravenously from 7 to 30 mg / kg, 80% of the dose is excreted in the urine within 12 hours), 50% unchanged and in small amounts in the form of urea. It is also excreted through the respiratory tract in the form of carbon dioxide.
Undergoes elimination during dialysis.

Indications for use
Acute and chronic myelogenous leukemia,
osteomyelofibrosis,
erythremia,
Essential thrombocythemia,
thrombocytosis on the background of myeloproliferative syndrome,
lymphoma,
melanoma,
ovarian cancer,
horionepitelioma uterus,
tumors of the head (with the exception of the lips) and neck,
brain tumor,
acute lymphoblastic leukemia in children,
metastatic breast gland and stomach,
colon cancer,
prostate cancer,
lung cancer,
cervical cancer (to increase the effectiveness of radiation therapy).

Method of administration and dosage
Inside, in the treatment of head and neck cancer, ovarian cancer, melanoma is prescribed intermittently according to the scheme: for 3 weeks every 3 days at a dose of 80 mg / kg (3200 mg / sq. M) or daily at 20-30 mg / kg (800-1200 mg / sq. M / day).
In the treatment of chronic myeloid leukemia, a daily intake regimen is used: the daily dose is 20-30 mg / kg (up to 1600 mg / sq. M) at a time (often in combination with allopurinol 300 mg / day).
Essential thrombocythemia - usually prescribed at an initial daily dose of 15 mg / kg; then a dose is selected that maintains the number of platelets at a level below 600 thousand / μl, without leading to a decrease in the number of leukocytes below 4 thousand / μl.
Recommended prescription regimens for long- term administration: with myelosis and thrombocytosis - an initial dose of 20-40 mg / kg / day, then 10-30 mg / kg, with an exacerbation - 25-60 mg / kg; with myelofibrosis - the initial dose is 20 mg / kg, the maintenance dose is 10 mg / kg; with erythremia: exacerbation - 15-20 mg / kg, maintenance dose - 10 mg / kg; cancer and melanocarcinoma - 20-30 mg / kg / day.
With a decrease in leukocytes below 20 thousand / μl, the dose is reduced to 600 mg / sq. m, below 5 thousand / μl - cancel. Doses are calculated based on actual or appropriate body weight, whichever is the smaller. Older patients may be more sensitive to hydroxycarbamide. The period during which the effectiveness of treatment can be assessed is 6 weeks. If, after 4 weeks of therapy, pronounced progression of the disease continues to be observed, treatment is stopped. With sufficient effectiveness, treatment is carried out for an unlimited time. The average maintenance dose is 0.5-2 g / day. The development of anemia does not require interruption of the course of treatment, provided that adequate therapy is carried out (transfusion of erythrocyte mass).

Side effects
From the side of hematopoiesis: leukopenia, anemia, thrombocytopenia.
On the part of the digestive system: stomatitis, anorexia, nausea, vomiting, diarrhea or constipation, ulceration of the gastrointestinal tract mucosa, increased activity of "liver" enzymes.
On the part of the skin and skin appendages: maculopapular rashes, flushing of the skin (including facial skin), dermatomyositis skin changes. In some cases, as a result of daily use of the drug for several years - hyperpigmentation, erythematous rash, skin atrophy and nails, skin peeling, purple papules, cutaneous toxicity vasculitis (in incl. Vasculitic ulcerations and gangrene). Rarely - alopecia, skin cancer.
From the nervous system: headache, dizziness, increased fatigue, drowsiness, disorientation; rarely - hallucinations and convulsions.
From the urinary system: an increase in the content of uric acid, urea and creatinine in plasma, urinary retention, interstitial nephritis. In rare cases, dysuria is noted.
Others: chills, general malaise, increased ESR, skin allergic reactions. Rarely - acute pulmonary reactions: diffuse lung infiltration, fever and shortness of breath.

Contraindication
Hypersensitivity, leukopenia below 2.5-3 thousand / μl, thrombocytopenia below 100 thousand / μl, lactation period.
Carefully. Hepatic and / or renal failure, anemia (must be eliminated before starting treatment); pregnancy.
Category of action on the fetus. D

Overdose
Symptoms: when prescribing high doses of the drug (higher than 60 mg / kg / day), undesirable effects may increase, incl. with severe bone marrow dysfunctions.
Treatment: symptomatic, prophylactic anti-infectious therapy, transfusion of blood components according to indications. The specific antidote is unknown.

Precautions
The use of hydroxycarbamide is carried out under strict medical supervision.
It is prescribed with caution to the elderly and children (dose reduction is required), patients who have previously received radiation or chemotherapy, patients with kidney tumors, with renal and hepatic insufficiency. Before starting treatment, correction of profound anemia (transfusion of whole blood preparations) is indicated. Before and during treatment (at least once a week), a regular blood test is required ; with a decrease in the number of leukocytes below 2.5 • 109 / l and platelets below 100 • 109 / l, the course of treatment is interrupted until a clear tendency towards the normalization of hematological parameters appears. It is also recommended to dynamically monitor the level of uric acid, creatinine, transaminases ; with a decrease in Cl creatinine less than 10 ml / min, the dose is halved.
Dental interventions should, if possible, be completed before the start of therapy or postponed until the blood count normalizes (there may be an increase in the risk of microbial infections, delayed healing processes, bleeding gums). During treatment, be careful when using toothbrushes, floss, or toothpicks.
During the period of treatment, vaccination of viral vaccines is not recommended; contact with people who have received the polio vaccine, with patients with bacterial infections should be avoided. Live viral vaccines should not be used in patients with leukemia in remission for at least 3 months after the last course of chemotherapy. Immunization with oral poliomyelitis vaccine in people with close contact with such a patient, especially family members, should be delayed.
Symptoms of bone marrow suppression, unusual bleeding or hemorrhage, black tarry stools, blood in the urine or stool, or pinpoint red spots on the skin require immediate medical attention.
Take care to avoid accidental cuts with sharp objects (safety razor, scissors), avoid contact sports or other situations in which hemorrhage or injury may occur.
During treatment, it is important to consume a sufficient amount of fluid and the subsequent increase in diuresis to ensure the excretion of uric acid.
Use caution with combination therapy; each drug must be taken at the appointed time.
If the patient has no clinical effect after 6 weeks of treatment, the drug should be discontinued; if therapy is effective, taking the drug can be continued indefinitely.
Patients with advanced leukopenia should be closely monitored for signs of infection, and antibiotics should be prescribed if necessary. Patients with neutropenia with an increase in body temperature are prescribed broad-spectrum antibiotics empirically until the results of bacteriological studies and appropriate diagnostic tests are obtained.
In patients with thrombocytopenia that has developed as a result of the use of hydroxycarbamide, it is recommended to observe special precautions (limiting the frequency of venipuncture, refusal of intramuscular injections, regular examination of intravenous injection sites, skin and mucous membranes, refusal to use acetylsalicylic acid, etc..).
During treatment, it is not recommended to drive a vehicle and perform work associated with increased concentration.
The combination with radiation therapy can lead to an increase in the severity of side effects (aplasia of the bone marrow, dyspepsia and the development of gastrointestinal ulcers).
During the treatment period, the use of contraceptives is recommended.

Interaction with other medicinal products
Against the background of uricosuric drugs, the risk of developing nephropathy increases. Drugs that cause pathological changes in the blood increase leukopenia and / or thrombocytopenia if these drugs have the same effect as hydroxycarbamide on leukocytes and platelets. Other drugs that inhibit bone marrow function or radiation therapy potentiate the effect and additively inhibit bone marrow function. With the introduction of live viral vaccines, there may be an increase in side effects or a decrease in antibody production; inactivated vaccines - a decrease in the production of antiviral antibodies.

Special instructions
Therapy should be carried out under close medical supervision. The combin ation with radiation therapy can lead to an increase in the severity of side effects (aplasia of the bone marrow, dyspepsia and ulceration of the gastrointestinal mucosa). Nausea, vomiting and loss of appetite, especially common with such treatment, may disappear as a result of temporary withdrawal of hydroxycarbamide. Before and during treatment, the state of hematopoiesis (clinical blood test, bone marrow examination), as well as the functions of the kidneys and liver, should be determined. The blood test is repeated at least 1 time per week. With a decrease in the number of leukocytes less than 2.5 thousand / μl, and platelets - less than 100 thousand / μl, treatment should be discontinued (until the normal blood count is restored). During treatment, patients should consume a sufficient amount of fluids.
In the treatment of myeloproliferative diseases, toxic vasculitis has been observed, most often in patients receiving or receiving interferon. With the progression of vasculitis ulceration, the drug should be discontinued.

Pregnancy and elbowing
Contraindicated for use during pregnancy and lactation (breastfeeding). If necessary, use during lactation should stop breastfeeding.

Influence on the ability to drive vehicles and work with mechanisms
Does not affect

Storage conditions
Store in a dry, dark place at a temperature not exceeding 25 ° C, out of the reach of children.

Shelf life
3 years. Do not use after the expiration date printed on the package.

Vacation conditions
On prescription.

Packaging
Hydroxycarbamide 500 mg Tablets. There are 15 tablets in a blister. 2 blisters are packed in a cardboard box together with an enclosed leaflet.