Hydroxycarbamide-LENS - instructions for use, dose, side effects, contraindications

Excipients: to obtain a mass of the contents of the capsule 600 mg: citric acid 12.8 mg, sodium hydrogen phosphate 36.0 mg, lactose monohydrate (milk sugar) 42.2 mg, magnesium stearate 9.0 mg.

Hard gelatin capsules:

For the lid green: coloring diamond E 133 0.13%, dye quinoline yellow E 104 0.19%, titanium dioxide E 171 2.1%, gelatin up to 100%.

For pink case: dye azorubin 0.05%, dye quinoline yellow E 104 0.002%, titanium dioxide E 171 1.0%, gelatin up to 100%.

Description:

Hard gelatin capsules number 0, the lid is green, the body is pink. The contents of the capsules are white powder.

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 Gl-S, which is essential for simultaneous radiotherapy, since synergistic sensitivity of tumor cells appears in the phase G1 for irradiation. Strengthening the action of 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. The maximum concentrations of the drug in the blood plasma are reached after 2 hours after administration. 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, with the exception of 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;

- a leukopenia below 2,5х10⁹/ l, thrombocytopenia below 100x10⁹/ l;

- 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; (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, dissolved in a glass of water and immediately drunk. 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 myeloid 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 platelets are elevated to acceptable levels (see above). Usually, the recovery of white blood cells and platelets 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 platelet count is lower 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 prescribed drug Hydroxycarbamide-LENS 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 leukocytes below 4x10⁹/ l, Treatment is continued as long as the ability to adequately control the number of platelets and / or leukocytes is maintained or until the drug is resistant or intolerant.

Osteomyelophybrosis

Usually prescribed drug Hydroxycarbamide-LENS in the initial daily dose of 15 mg / kg; then select a safe dose, which maintains a white blood cell count of at least 4x10⁹/ l, and the number of platelets is not lower 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 head and neck, with the exception of lip cancer (in combination with radiotherapy), cervical cancer uterus (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 in prescribing the drug to such patients is necessary.

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 - at the end of 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 the drug Hydroxycarbamide-LENS than in young patients, the recommended dose for patients of this group should not exceed 60 mg / kg per day.

Side effects:

Conventional signs of 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 is 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).

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), cholestasis, hepatitis; stomatitis, anorexia, nausea, vomiting, diarrhea, constipation, mucositis, dyspepsia, irritation of the gastric mucosa, ulceration of the gastrointestinal mucosa, abdominal pain, melena; increased activity of "hepatic" enzymes and bilirubin concentration in plasma.

From the skin and skin appendages: frequency is unknown - cutaneous vasculitis, maculopapular eruptions, erythema of the face and peripheral erythema, ulceration of the skin, dermatomyositis-like skin changes, skin exfoliation, hyperpigmentation, erythema, skin and nail atrophy, peeling, violet papules, skin toxic vasculitis (including vasculitic 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, pulmonary edema, 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.

From the side of the reproductive system: frequency unknown - azoospermia, oligospermia.

Other: frequency unknown - chills, fever, general malaise, increased ESR, skin allergic reactions, asthenia.

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 greater than recommended, patients developed signs of acute dermatological toxicity: soreness, purple erythema, edema followed by peeling 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.

Hydroxycarbamide may enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors (NRTIs), such as didanosine and stavudine. Hydroxycarbamide inhibits the synthesis of DNA and the replication of the human immunodeficiency virus by reducing the intracellular deoxynucleotide. Hydroxycarbamide can also increase the side effects of this group of drugs, such as pancreatitis and peripheral neuropathy.

In studies in vitro It was noted that with the simultaneous use of the drug hydroxycarbamide 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 intake of the hydroxycarbamide preparation.

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 a hydroxycarbamide drug 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 combined use of hydroxycarbamide 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 in the event that the content of leukocytes exceeds 2,5х10⁹/ l, and thrombocytes - 100x10⁹/ l. If during treatment it is revealed that the white blood cell count is less than 2.5 × 10⁹/ l, or platelets - less than 100x10⁹/ l, treatment should be suspended until the content of them 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).

In the event of serious side effects on the part of the digestive organs (such as nausea, vomiting, anorexia), it is usual to stop the drug therapy hydroxycarbamide.

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, but they are not associated with vitamin B deficiency₁₂ or folic acid. Due to the fact that macrocytosis can mask the deficiency of folic acid, consideration should be given to the prophylactic appointment of folic acid to the patient.

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 (with possible fatal outcome) were noted 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 the hydroxycarbamide drug in patients with myeloproliferative diseases, such as true polycythemia and thrombocythemia, cases of secondary leukemia are noted. It is not known what causes secondary leukemia: taking hydroxycarbamide or the underlying disease.

With prolonged use of the drug hydroxycarbamide, skin cancer cases were also observed. Patients should be warned about the need to protect the skin from sunlight and carry out 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.

The drug hydroxycarbamide has a cytotoxic effect, so you should be careful 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.

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. In connection with the possible genotoxicity of hydroxycarbamide, male patients 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 concomitantly with therapy hydroxycarbamide, 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 intake of the hydroxycarbamide is possible. Vaccination with live vaccines during the intake of hydroxycarbamide may lead to the development of severe infections. It is also possible to reduce the immune response to the administration of vaccines. It is not recommended to administer live vaccines during the period of therapy with hydroxycarbamide, consult a specialist.

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

Because the the elderly patients The likelihood of developing side effects when using the drug hydroxy carbamide 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, during the period of drug treatment, the ability to concentrate attention can deteriorate. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

Capsules, 500 mg.

Packaging:

10 capsules per contour cell packaging from a three-layer polymer film consisting of a polyvinyl chloride / polyethylene / polyvinyl dichloride composition and an aluminum-lacquered aluminum foil.

For 50 or 100 capsules in a bottle of dark glass with a screw cap polymer with a gasket that provides control of the first opening,or in a jar of polypropylene or low pressure polyethylene with a lid with a control of the first opening of high pressure polyethylene.

Each vial or jar, or 5 or 10 contour squares, together with the instruction for use, is placed in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002984

Date of registration:29.04.2015 / 29.07.2016

Expiration Date:29.04.2020

Date of cancellation:2020-04-29

The owner of the registration certificate:VEROPHARM SA VEROPHARM SA Russia

Manufacturer: & nbsp

VEROPHARM SA Russia

Representation: & nbspVEROPHARM, AO VEROPHARM, AO Russia

Information update date: & nbsp15.04.2017

Illustrated instructions

Instructions

Hydroxycarbamide-LENS (HYDROXYCARBAMIDE-LANS)