Гидреа®

General characteristics. Structure:

Active ingredient: 500 mg of a hydroxycarbamide.

Excipients: citric acid, lactoses monohydrate, sodium hydrophosphate, magnesium stearate.

Structure of a cover of the capsule: gelatin, titanium dioxide, dye ferrous oxide red, dye ferrous oxide yellow, dye FD&C indigo carmine blue 2.

The structure blackened for a text: shellac, ferrous oxide black, N-butyl alcohol, the water purified propylene glycol, industrial metilirovanny alcohol, isopropyl alcohol.

Pharmacological properties:

Pharmacodynamics. Gidroksikarbamid is the fazospetsifichny cytostatic drug (an antimetabolite, according to some information — the alkylating action) operating in a phase S of a cellular cycle. Blocks growth of cells in G1-S interphase that is essential to the carried-out at the same time radiation therapy as synergy sensitivity of tumor cells in the phase G1 on radiation appears. Strengthening effect of RNA-reductase inhibitor — a ribonukleoziddifosfatreduktaza, causes DNA synthesis suppression. Drug does not influence synthesis of RNA and protein.

Pharmacokinetics. After intake it is quickly soaked up from digestive tract. The maximum concentration of drug in a blood plasma are reached within 2 hours after reception.

There are no data on influence of meal on absorbability of drug. It is quickly distributed on body tissues, gets through a blood-brain barrier. In cerebrospinal fluid 10–20%, in ascitic liquid — 15–50% of concentration in a blood plasma are defined. Gidroksikarbamid collects in leukocytes and erythrocytes. An elimination half-life — 3–4 hours. It is partially metabolized in a liver. 80% of hydroxurea within 12 hours are removed with urine, at the same time 50% in not changed look and in small amounts in the form of urea. Drug is also removed through respiratory tracts in the form of dioxide carbon. In 24 hours in plasma is not defined.

Patients with a renal failure. As hydroxurea is removed preferential through kidneys, such patients need a dose decline at purpose of drug.

Indications to use:

— Myelosis
— Osler's disease (erythremia)
— Essential trombotsitemiya
— Osteomyelofibrosis
— Melanoma
— Malignant tumors of the head and neck, except for lip cancer (in a combination with radiation therapy)
— Cancer of a neck of uterus (in a combination with radiation therapy)

Route of administration and doses:

At the choice of the mode and doses in each individual case it is necessary to be guided by data of special literature. Drug is used inside. At swallowing difficulty the capsule it is possible to open, pour out contents in a glass of water and to drink immediately. At the same time some water insoluble excipients can remain on the surface of solution. During treatment by drug it is necessary to accept rather large amount of liquid.

Resistant myelosis. Continuous therapy. From 20 to 30 mg/kg daily once a day. Assessment of efficiency of drug is carried out after 6 weeks of treatment. At the acceptable clinical answer treatment can be continued beyond all bounds long. Treatment should be suspended if the maintenance of leukocytes — less than 2500/mm3 or the maintenance of thrombocytes — less than 100000/mm3. In 3 days carry repeatedly out blood test. Treatment is resumed when the maintenance of leukocytes and erythrocytes increases to accepted (see above). Usually recovery of maintenance of leukocytes and erythrocytes happens quickly enough, otherwise at combined use of drug to radiation therapy, the last can be also suspended.

Development of anemia, even heavy, does not demand interruption of a course of treatment on condition of adequate therapy (a packed red cells transfusion).

Osler's disease. Treatment begin 15–20 mg/kg with a daily dose. The dose is established individually, aiming to support a hematocrit at the level of lower than 45%, and number of thrombocytes — below 400000/mkl. At most of patients it is possible to reach these indicators, constantly applying a hydroxycarbamide in a daily dose from 500 to 1000 mg.

Essential trombotsitemiya. Usually appoint the drug Gidrea® in an initial daily dose of 15 mg/kg; then select such dose which supports number of thrombocytes at the level below 600000/mkl, without leading at the same time to reduction of number of leukocytes is lower 4000/mkl.

Solid tumors, melanoma. Discontinuous therapy:
— 80 mg/kg once a day each three days (6–7 doses).

Continuous therapy:
— 20–30 mg/kg daily once a day within 3 weeks.

Carcinoma of the head and neck, carcinoma of a neck of uterus. 80 mg/kg once a day, each three days in a combination with radiation therapy. Treatment with drug is begun not less than in 7 days prior to radiation therapy and continued during radiation therapy. After radiation therapy drug continues to be accepted during unlimited time at strict observation of the patient and at absence at it unusual or heavy toxic reactions.

Patients with an abnormal liver function. Instructions on change of doses at this group of patients are absent. It is necessary to carry out careful monitoring of indicators of blood at patients with an abnormal liver function.

Patients with a renal failure. As hydroxurea is removed preferential through kidneys, such patients need a dose decline at purpose of drug.

The patient with a renal failure (clearance of creatinine less than 60 ml/min.) drug is usually appointed in a dose of 15 mg/kg. The patient in an end-stage of a renal failure drug is appointed in a dose of 15 mg/kg twice, at an interval of 7 days between receptions: the first time — upon termination of the 4-h-sentry of a session of a hemodialysis, the second time — before holding a session of a hemodialysis.

Elderly patients. As at elderly patients the probability of development of side effects at use of the drug Gidrea® is higher, than at patients of young age, the recommended dose for patients of this group should not exceed 60 mg/kg a day.

Features of use:

Pregnancy and feeding by a breast. Drug should not be accepted during pregnancy. During therapy it is necessary to warn the patient about need of reliable contraception. If pregnancy occurred during treatment by drug, it is necessary to warn the patient about a possibility of risk for a fruit.

Drug gets into breast milk. It is necessary to stop breastfeeding for treatment or to cancel therapy, previously having estimated importance of its carrying out for mother.

Treatment by drug should be carried out only under observation of the doctor having experience of use of antineoplastic therapy. Before each course and periodically during treatment by drug it is necessary to control functions of marrow, kidneys and a liver. Definition of hemoglobin, leukocytes and thrombocytes has to be carried out at least 1 time a week throughout the entire period of treatment by drug. Treatment is appointed only if the maintenance of leukocytes exceeds 2500/mkl, and thrombocytes — 100000/mkl. If during treatment it is revealed that the maintenance of leukocytes — less 2500/mkl or thrombocytes — less 100000/mkl, it is necessary to suspend treatment until contents they are not recovered to norm.

The severe form of anemia has to be compensated prior to treatment by drug. During treatment by drug the miyelosupressiya, mainly a leukopenia can develop. Thrombocytopenia and anemia develop less often and absolutely seldom — without the previous leukopenia. Miyelosupressiya is most probable at patients after the recent previous radiation therapy or chemotherapy with other drugs.

After recent beam or chemotherapy drug has to be used with care because of a possible aggravation of a post-radiation erythema and strengthening of expressiveness of side effects (a marrow aplasia, dyspepsia and an ultseration of digestive tract).

At emergence of heavy by-effects from digestive organs (such as nausea, vomiting, anorexia) usually stop therapy by the drug Gidrea®.

At pain and discomfort at development of a mukozit in the field of radiation usually appoint local anesthetics and analgetik for intake. In hard cases therapy by drug is temporarily stopped, and in very hard cases — temporarily cancel the accompanying radiation therapy.

At early stages of treatment drug often observes a moderate megaloblastichesky erythrogenesis. Morphological changes remind pernicious anemia, however, they are not connected with deficit of B12 vitamin or folic acid. Because the macrocytosis can mask deficit of folic acid, it is necessary to consider a question of preventive appointment to the patient of folic acid.

Gidroksikarbamid can also slow down clearance of iron of plasma and reduce iron utilization speed erythrocytes, however, it does not exert impact on time of life of erythrocytes.

Cases of development of pancreatitis and hepatotoxic (with possible death) are noted at HIV-positive patients who accepted a hydroxycarbamide together with anti-retrovirus drugs, in particular диданозин (with stavudiny and without it). In this regard it is necessary to avoid joint purpose of these drugs. Also cases of development of peripheral neuropathy, sometimes heavy, were noted at HIV-positive patients who accepted a hydroxycarbamide together with anti-retrovirus drugs, including диданозин (with stavudiny and without it).

During treatment patients have to use enough liquid. The drug dose decline at renal failures can be required.

Drug should be used with care at patients at an impaired renal function and a liver. During treatment drug at patients with myeloproliferative diseases observed skin toxic vasculites, including vaskulitny ulcerations and gangrene. It was most often reported about toxic vasculites at the patients who are receiving or receiving interferon in the past. When progressing vaskulitny ulcerations administration of drug should be stopped.

At prolonged use of the drug Gidrea® at patients with myeloproliferative diseases, such as Osler's disease and trombotsitemiya, cases of secondary leukoses are noted. At the same time it is unknown what is the reason of development of a secondary leukosis: reception of a hydroxycarbamide or a basic disease, At prolonged use of the drug Gidrea® were observed also cases of a carcinoma cutaneum. It is necessary to warn patients about need to protect skin from a sunlight and to carry out self-checking of a condition of skin. During planned visits of the doctor it is necessary to control a condition of integuments of the patient for the purpose of identification of possible malignant changes.

The drug Gidrea® possesses cytotoxic action therefore it is necessary to be careful when opening capsules and to avoid hit of powder of capsules on skin, mucous membranes or inhalations of drug. If contents of the capsule are accidentally scattered, it is necessary to collect immediately powder by a napkin in a plastic bag, to tie it and to throw out.

Use in pediatrics. Safety and efficiency of use for children is not established. As at elderly patients the probability of development of side effects at use of the drug Gidrea® is higher, than at patients of young age, use of drug in a reduced dose can be required.

Influence on ability to driving of motor transport and to control of mechanisms. Researches on studying of influence of drug on ability to driving of motor transport and control of mechanisms were not conducted. Because the hydroxycarbamide can cause dizziness and other undesirable phenomena from a nervous system, during treatment by drug ability to concentration of attention can worsen.

Side effects:

Symbols of occurrence of the undesirable phenomena (UP): "it is very frequent" (≥1/10), is "frequent" (≥1/100, <1/10), "infrequently" (≥1/1000, <1/100), is "rare" (≥1/10000, <1/1000), "it is very rare" (<1/10000), "frequency is unknown" (frequency of NYa cannot be estimated by means of the available data).

Infections: frequency is unknown — gangrene.

From bodies of a hemopoiesis: frequency is unknown — suppression of function of marrow (a leukopenia, anemia, thrombocytopenia).

From digestive organs: frequency is unknown — a hepatotoxic, and pancreatitis, sometimes with a lethal outcome (at the HIV-positive patients who are at the same time receiving anti-retrovirus therapy, in particular, диданозин and ставудин); stomatitis, anorexia, nausea, vomiting, diarrhea, a lock, mukozit, dyspepsia, irritation of a mucous membrane of a stomach, an ulceration of a mucous membrane of digestive tract; increase in activity of "hepatic" enzymes and concentration of bilirubin in plasma.

From skin and skin appendages: frequency is unknown — a skin vasculitis, makulezno-papular rashes, an erythema of the person and a peripheral erythema, ulcerations on skin, dermatomiozitopodobny changes of skin, skin exfoliation, a hyperpegmentation, an erythema, an atrophy of skin and nails, a peeling, papules of violet color, skin toxic vasculites (including vaskulitny ulcerations and gangrene); seldom — an alopecia, a carcinoma cutaneum.

From a nervous system: frequency is unknown — dizziness, drowsiness, a disorientation; a headache, hallucinations, spasms, peripheral neuropathy (at the HIV-positive patients who are at the same time receiving anti-retrovirus therapy, in particular, диданозин and ставудин), increased fatigue.

From respiratory system: frequency is unknown — a pneumosclerosis, diffusion infiltration of lungs, an asthma.

From an urinary system: frequency is unknown — increase in content of uric acid in blood serum, increase in maintenance of an urea nitrogen and creatinine in a blood plasma, an ischuria, intersticial nephrite, is rare — a dysuria.

Others: frequency is unknown — a fever, fever, a febricula, increase in SOE, skin allergic reactions, an adynamy, is rare — diffusion infiltration of lungs, an asthma.

Cases of development of pancreatitis and hepatotoxic (with possible death), and also heavy peripheral neuropathy are noted at sick HIV which accepted a hydroxycarbamide together with anti-retrovirus drugs, in particular диданозин in a combination with stavudiny or without it.
The by-effects observed at simultaneous use of a hydroxycarbamide and radiation therapy same, as well as at monotherapy by drug, mainly oppression of function of marrow (a leukopenia, anemia) and irritation of a mucous membrane of a stomach. Reception of a hydroxycarbamide can strengthen some side effects which are observed at radiation therapy, such as discomfort in a stomach and mukozit.

Interaction with other medicines:

At simultaneous use of drug with other myelosuppressive drugs or radiation therapy extent of suppression of function of marrow or development of other side effects can increase.

In the researches in vitro it is noted that at simultaneous use of the drug Gidrea® and Cytarabinum the cytotoxic effect of the last increases.

If during a combination therapy heavy dyspepsia, nausea, vomiting or anorexia are noted, they can usually be stopped interruption of administration of drug of Gidrea®.

Morbidity and discomfort of mucous membranes in the place of radiation (mukozit) it is possible to facilitate use of local anesthetics and reception of analgeziruyushchy drugs inside. At a heavy mukozit therapy by the drug Gidrea® is temporarily stopped; in very hard cases stop also radiation therapy.

Drug can increase the content of uric acid in blood serum therefore correction of a dose of the drugs increasing removal of uric acid from an organism can be required. Uricosuric means increase risk of development of a nephropathy.

Cases of emergence of false positive results of analyses when determining urea, uric acid and lactic acid as a result of interaction of a hydroxycarbamide and enzymes are noted (ureases, uricases, lactate dehydrogenases).

Contraindications:

— Hypersensitivity to the hydroxycarbamide or any other excipient which is a part of drug.
— Pregnancy and period of breastfeeding.
— The leukopenia is lower 2500/mkl, thrombocytopenia is lower 100000/mkl.
— Children's age (safety and efficiency of use is not established).

With care:
— liver and/or renal failure,
— heavy anemia (it has to be compensated before an initiation of treatment),
— patients after the postponed radiotheraphy or chemotherapy (a possibility of a miyelosupressiya, an aggravation of a beam erythema).
— deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption.

Overdose:

Symptoms: At use of drug in the doses several times exceeding recommended at patients signs of acute dermatological toxicity developed: morbidity, a violet erythema, hypostasis with the subsequent peeling of palms of hands and feet of legs, an intensive generalized hyperpegmentation of skin and stomatitis.

Treatment: The specific antidote is not known. Symptomatic treatment.

Storage conditions:

At a temperature of 15-25 °C in the place protected from light. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules of 500 mg. On 10 capsules in the blister from an aluminum foil / PVC / PVDH. On 2 blisters together with the application instruction in a cardboard pack.