Hydrea - instructions for use, doses, side effects, contraindications

composition of the capsule shell: gelatin 93.743 mg, titanium dioxide 2.016 mg, iron dye oxide red 0.115 mg, iron oxide dye yellow 0.110 mg, dye indigo carmine FD&C blue 2 0.017 mg;

ink composition for the inscription: shellac, iron oxide, black, N-butyl alcohol, purified water, propylene glycol, industrial methylated alcohol, isopropyl alcohol.

Description:

Capsules - hard gelatinous, opaque, with a size of 0. Cover: green matte. Case: pale pink matte. On the capsule there is an inscription of black color "BMS 303 ".The contents of the capsule: powder or compacted mass of white.

Pharmacotherapeutic group:Antitumor agent - antimetabolite

ATX: & nbsp

L.01.X.X.05 Hydroxycarbamide

Pharmacodynamics:

Hydroxycarbamide is a phase-specific cytostatic drug (antimetabolite, according to some data - the alkylating action), acting in phase S cell cycle. Blocks cell growth in interphase G1-S, which is essential for simultaneous radiotherapy, since synergistic sensitivity of tumor cells appears in the phase G1 for irradiation. Strengthening the action of the RNA reductase inhibitor, ribonucleoside diphosphate reductase, causes 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. Maximum plasma concentrations of the drug are reached within 2 hours after admission. Data on the effect of food intake on the absorption of the drug there. Quickly distributed to the tissues of the body, it penetrates the blood-brain barrier. In the cerebrospinal fluid is determined 10-20%, in the ascitic fluid - 15-50% of the concentration in the blood plasma. Hydroxycarbamide accumulates in leukocytes and erythrocytes. Half-life is 3-4 hours.Partially metabolized in the liver. 80% hydroxyurea for 12 hours is excreted in the urine, with 50% unchanged and in small amounts in the form of urea. The drug is also excreted through the respiratory tract as carbon dioxide. After 24 hours in the plasma is not determined.

Patients with impaired renal function

Since hydroxyurea is excreted primarily through the kidneys, a dose reduction in prescribing the drug to such patients is necessary.

Indications:

- Resistant chronic myelogenous leukemia;

- true polycythemia (erythremia) with a high risk of thromboembolic complications;

- essential thrombocythemia with a high risk of thromboembolic complications;

- osteomyelophybrosis;

- melanoma;

- malignant tumors of the head and neck (excluding lip cancer) in combination with radiotherapy;

- cervical cancer in combination with radiotherapy.

Contraindications:

- Hypersensitivity to hydroxycarbamide or any other auxiliary substance included in the preparation;

- pregnancy and the period of breastfeeding;

- leukopenia below 2500 / μL, thrombocytopenia below 100,000 / μL;

- children's age (safety and efficacy not established).

Carefully:

- Hepatic and / or renal insufficiency;

- severe anemia (should be compensated before treatment), patients after radiotherapy or chemotherapy (the possibility of myelosuppression, exacerbation of radiation erythema);

- deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

Pregnancy and lactation:

The drug should not be taken during pregnancy. During therapy, the patient should be warned about the need for reliable contraception. If the pregnancy occurred during treatment with the drug, it is necessary to warn the patient about the possibility of risk to the fetus.

The drug penetrates into breast milk. It is necessary to stop breastfeeding for the period of treatment or to cancel therapy, having previously estimated the importance of its carrying out for the mother.

Dosing and Administration:

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

The drug is used inside.

If swallowing is difficult, the capsule can be opened, pour the contents into a glass of water and immediately drink.In this case, some water-insoluble auxiliary substances can remain on the surface of the solution.

During treatment with the drug should take a fairly large amount of fluid.

Resistant chronic myelogenous leukemia

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

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 2.5 × 10⁹/ l or platelet count - less than 100x10⁹/ l. After 3 days, a blood test is repeated. Treatment is resumed when the white blood cells and erythrocytes are elevated to acceptable levels (see above). Usually, the recovery of white blood cells and red blood cells occurs quickly enough, otherwise, when the drug is used together with radiotherapy, the latter can also be suspended.

The development of anemia, even severe, does not require discontinuation of treatment, provided adequate therapy (transfusion of erythrocyte mass).

True polycythemia (erythremia) with a high risk of thromboembolic complications

Treatment begins with a daily dose of 15-20 mg / kg. The dose is set individually, seeking to maintain a hematocrit below 45%, and the number of platelets - below 400x10⁹/ l. In most patients, it is possible to achieve these parameters by constantly applying hydroxycarbamide in a daily dose of 500 to 1000 mg.

Treatment is continued until the ability to adequately control the number of platelets and / or leukocytes is maintained or until resistance or intolerance of the drug appears.

Essential thrombocythemia with a high risk of thromboembolic complications

Usually, the preparation Hydrea® is prescribed in the initial daily dose of 15 mg / kg; then select a dose that maintains a platelet count below 600x10⁹/ l, without leading to a decrease in the number of white blood cells below 4x10⁹/ l.

Treatment is continued until the ability to adequately control the number of platelets and / or leukocytes is maintained or until resistance or intolerance of the drug appears.

Osteomyelophybrosis

Usually, the preparation Hydrea® is prescribed in the initial daily dose of 15 mg / kg; then select a dose that supports the number of leukocytes not lower than 4х10⁹/ l and the number of platelets is not lower than 100x10⁹/ l.

Melanoma, solid tumors

Intermittent therapy:

- 80 mg / kg once a day every three days (6-7 doses)

Continuous therapy:

- 20-30 mg / kg daily once a day for 3 weeks.

Malignant tumors of the head and neck (with the exception of lip cancer) in combination with radiotherapy, cervical cancer in combination with radiotherapy

80 mg / kg once a day, every three days in combination with radiotherapy.

Treatment with the drug begins at least 7 days before the start of radiotherapy and continues during radiotherapy. After radiation therapy, the drug continues to be taken for an unlimited time, with strict observation of the patient and in the absence of unusual or severe toxic reactions.

Patients with impaired hepatic function

There are no instructions for changing the doses in this group of patients. It should be carefully monitored blood levels in patients with impaired liver function.

Patients with impaired renal function

Since hydroxyurea is excreted primarily through the kidneys, a dose reduction should be used when the drug is administered to such patients.

Patients with renal insufficiency (creatinine clearance less than 60 ml / min) the drug is usually given in a dose of 15 mg / kg.Patients in the terminal stage of renal failure receive the drug at a dose of 15 mg / kg twice, with an interval of 7 days between doses: the first time - after the 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 Hydrea® than in young patients, the recommended dose for patients in this group should not exceed 60 mg / kg per day.

Side effects:

Conventional signs of the occurrence of undesirable phenomena (AEs): "very often" (≥ 1/10), "often" (≥1 / 100, <1/10), "infrequently" (≥ 1/1000, <1/100), "rarely" (≥1 / 10000, <1/1000), "very rarely" (<1/10000), "frequency unknown" (the frequency of the EW can not be estimated using the available data).

Infections: frequency is unknown - gangrene.

From the hematopoiesis: frequency unknown - suppression of bone marrow function (leukopenia, anemia, thrombocytopenia).

From the side organs of digestion: frequency unknown - hepatotoxicity, 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 mucous membrane of the gastrointestinal tract; increased activity of "hepatic" enzymes and bilirubin concentration at plasma, cholestasis, hepatitis.

From the skin and skin appendages: frequency unknown - cutaneous vasculitis, maculopapular rashes, erythema of the face and peripheral erythema, ulceration of the skin, dermatomiozitopodobnye skin changes and skin exfoliation, hyperpigmentation, erythema, atrophy of the skin and nails, peeling, papules purple toxic dermal vasculitis (including vasculitis ulceration and gangrene); rarely - alopecia, skin cancer.

From the nervous system: frequency unknown - dizziness, drowsiness, disorientation; headache, hallucinations, convulsions, peripheral neuropathy (in HIV-infected patients who are simultaneously receiving antiretroviral therapy, in particular didanosine and stavudine), increased fatigue.

On the part of the respiratory system: frequency unknown - pulmonary fibrosis, diffuse pulmonary infiltration, dyspnea.

From the urinary system: frequency unknown - an increase in the content of uric acid in the blood serum, an increase in urea nitrogen and creatinine in the blood plasma, urinary retention, interstitial nephritis; rarely - dysuria.

Other: frequency unknown - chills, fever, general malaise, increased ESR, skin allergic reactions, asthenia, azoospermia, oligospermia, tumor lysis syndrome; rarely diffuse infiltration of the lungs, dyspnea.

Cases of pancreatitis and hepatotoxicity (with possible fatal outcome), as well as severe peripheral neuropathy, were noted in HIV patients who were taking hydroxycarbamide together with antiretroviral drugs, in particular didanosine in combination with stavudine or without it.

Side effects observed with simultaneous application of hydroxycarbamide and radiation therapy are the same as in monotherapy with the drug, mainly oppression of bone marrow function (leukopenia, anemia) and irritation of the gastric mucosa.

Taking hydroxycarbamide may increase some of the side effects that are observed with radiation therapy, such as stomach discomfort and mucositis.

Overdose:

Symptoms. When using the drug in doses several times higher than recommended, the 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. The specific antidote is not known. Treatment is symptomatic.

Interaction:

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

In studies in vitro It was noted that with the simultaneous use of the drug Hydrea® and cytarabine, the cytotoxic effect of the latter increases.

If severe dyspepsia, nausea, vomiting, or anorexia are noted during combination therapy, they can usually be quenched by interrupting the use of Hydrea®.

Soreness and discomfort of the mucous membranes at the site of irradiation (mucositis) can be facilitated by the use of local anesthetics and the intake of analgesic drugs inside. With severe mucositis therapy with Hydrea® is temporarily stopped; in very severe cases, also stop radiation therapy.

The drug can increase the content 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. Urikozuric drugs increase the risk of developing nephropathy. There have been cases of false positive 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).

An increased risk of developing vaccine-associated fatal infections is possible with the joint use of the Hydrea® preparation and live vaccines. The use of live vaccines is not recommended in patients with reduced immunity.

Special instructions:

Treatment with the drug should be carried out only under the supervision of a doctor who has experience in the use of antitumor therapy.

Before each course and periodically during treatment with the drug, it is necessary to monitor the functions of the bone marrow, kidney and liver. The determination of hemoglobin, leukocytes and platelets should be carried out at least once a week during the entire period of treatment with the drug.Treatment is prescribed only if the white blood cell count exceeds 2500 / μL, and the platelet count is 100,000 / μL. If, during treatment, it is found that the white blood cell count is less than 2500 / μL or platelets - less than 100,000 / μl, treatment should be stopped until the content is restored to normal.

Severe form of anemia should be compensated before starting treatment with the drug.

During treatment with the drug, myelosuppression may develop, mainly leukopenia. Thrombocytopenia and anemia develop less frequently and very rarely without previous 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 the post-radiation erythema and increased severity of side effects (bone marrow aplasia, dyspepsia and ulceration of the gastrointestinal tract).

If serious side effects occur on the part of the digestive organs (such as nausea, vomiting, anorexia) usually stop the therapy with Hydrea®.

With pain and discomfort in 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, temporary concomitant radiation therapy is canceled.

In the early stages of drug treatment, a moderate megaloblastic erythropoiesis is often observed.

Morphological changes resemble pernicious anemia, however, they are not associated with vitamin B deficiency₁₂ or folic acid. Due to the fact that macrocytosis can mask the deficiency of folic acid, regular determination of folic acid in serum is recommended.

Hydroxycarbamide can also slow down the iron clearance of the plasma and reduce the rate of iron utilization by red blood cells, but this does not affect the lifetime of red blood cells.

Cases of pancreatitis and hepatotoxicity (possibly fatal) were observed in HIV-infected patients who were taking hydroxycarbamide together with antiretroviral drugs, in particular didanosine (with and without stavudine). In connection with this, joint use of these drugs should be avoided.Also, cases of development of peripheral neuropathy, sometimes severe, were noted in HIV-infected patients who were taking hydroxycarbamide together with antiretroviral drugs, including didanosine (with and without stavudine).

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

It may be necessary to reduce the dose of the drug for violations of kidney function. The drug should be used with caution in patients with impaired renal and hepatic function.

During treatment with the drug, skin toxic toxic vasculitis, including vasculitic ulceration and gangrene, was observed in patients with myeloproliferative diseases. The most frequently reported toxic vasculitis in patients who received or received interferon in the past. With progression of vasculitis ulcerations, the drug should be discontinued.

With prolonged use of Hydrea® in patients with myeloproliferative diseases, such as true polycythemia and thrombocythemia, cases of secondary leukemia. It is not known what causes secondary leukemia: taking hydroxycarbamide or the underlying disease.

With prolonged use of the drug Hydrea® there were also cases of skin cancer. Patients should be warned about the need to protect the skin from sunlight and conduct self-monitoring of skin condition. During planned visits to the doctor, the skin condition of the patient should be monitored in order to identify possible malignant changes.

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

AT connection with possible genotoxicity of the Hydrea® drug, male patients taking Hydrea® should be informed of the need for reliable contraception during treatment and at least 1 year after the end of therapy.

When vaccinated with live viral vaccines simultaneously with the therapy with Hydrea®, activation of replication of the vaccine virus and / or an increase in the development of adverse reactions due to the suppression of the protective mechanisms of the body caused by the preparation of Hydrea® is possible. Vaccination with live vaccines while taking Hydrea® can lead to the development of severe infections.It is also possible to reduce the immune response to the administration of vaccines. It is necessary to avoid the introduction of live vaccines during the period of therapy with Hydrea ® and consult with a specialist.

The Hydrea® preparation has a cytotoxic effect, so take care when opening the capsules and avoid getting capsule powder on the skin, mucous membranes or inhaling the drug. If the contents of the capsule accidentally scattered, you should immediately collect the powder with a tissue in a plastic bag, tie it and discard it.

Application in pediatrics. Safety and effectiveness of use in children is not established.

Because the in elderly patients the likelihood of developing side effects with the use of the Hydrea® preparation is higher than in young patients, it may be necessary to use the drug in a reduced dose.

Effect on the ability to drive transp. cf. and fur:

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

Form release / dosage:

Capsules, 500 mg.

Packaging:

10 capsules per blister of aluminum foil / PVC / PVDC.

2 blisters together with instructions for use in a cardboard box.

Storage conditions:

At a temperature of 15-25 ° C, in a place protected from light.

Keep out of the reach of children.

Shelf life:

2 years.

Terms of leave from pharmacies:On prescription

Registration number:P N 015766/01

Date of registration:09.06.2009 / 19.10.2016

Expiration Date:Unlimited

The owner of the registration certificate:Bristol-Myers SquibbBristol-Myers Squibb France

Manufacturer: & nbsp

CORDEN PHARMA LATINA, S.p.A Italy

Representation: & nbspBRISTOL-Majers SKVIBB, LLCBRISTOL-Majers SKVIBB, LLCRussia

Information update date: & nbsp03.04.2017

Illustrated instructions

Instructions

Hydrea® (Hydrea®)