Hydroxyurea - instructions for use, dose, side effects, contraindications

gelatin capsule: housing - titanium dioxide 2.00%, iron dye oxide red 0.0425%, dye crimson [Ponso 4R] 0.0068%, gelatin up to 100.00%; cap - titanium dioxide 2.00%, indigocarmine 0.0193%, dye quinoline yellow 0.006%, gelatin to 100.00%.

Description:

Hard gelatin capsules No. 0-e1 of cylindrical shape with hemispherical ends. The case is light pink in color, the lid is light blue with a greenish shade of color. The contents of the capsules are white powder.

Pharmacotherapeutic group:Antitumor agent - antimetabolite

ATX: & nbsp

L.01.X.X.05 Hydroxycarbamide

Pharmacodynamics:

Hydroxycarbamide is an antimetabolite of a specific action, selectively acting on cells in Sphase of mitosis. Suppresses cell growth in G₁-S interphase, which causes an increase in the sensitivity of tumor cells in G₁-phase of mitosis to radioactive radiation.

The mechanism of action of the hydroxycarbamide is due to the suppression of the activity of ribonucleotide reductase, an enzyme that catalyzes the reaction of the conversion of ribonucleotides to deoxyribonucleotides, which leads to suppression of the synthesis of deoxyribonucleic acid (DNA) without affecting the ribonucleic acid and protein synthesis. Besides, hydroxycarbamide can damage directly the DNA.

Simultaneous use of hydroxycarbamide and cytosine-arabinoside in patients with resistant to therapy with lymphosarcoma leads to a clinical improvement in 43% of cases.

Pharmacokinetics:

Quickly absorbed in the gastrointestinal tract (GIT), does not accumulate in the body. The maximum concentration (C_m_Oh) in the blood plasma is achieved within 2 hours after administration. Oscillations C_m_Oh in blood plasma are from 22.9 mg / l to 65.6 mg / l. The concentration in the CSF is 10-20% of the plasma concentration, and the concentration in the ascitic fluid is 15-50%. The basic metabolism of hydroxycarbamide proceeds in the liver and kidneys.Half-life (T_1/2) is 3-4 hours. 80% hydroxycarbamide is excreted by the kidneys within 12 hours. 50% of the hydroxycarbamide is excreted unchanged and in small amounts in the form of urea. After 24 hours, plasma is not detected.

Indications:

- Chronic myeloproliferative syndromes: chronic myelogenous leukemia, true polycythemia with a high risk of thrombosis and thromboembolism, thrombocythemia, 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 other components of the drug;

- severe bone marrow suppression, leukopenia less than 2.5х10⁹/ l, thrombocytopenia less than 100x10⁹/ l or severe anemia;

- pregnancy or lactation period;

- age to 18 years.

Carefully:

Previous radio or chemotherapy in patients with renal carcinoma, especially with decreased renal or hepatic function; anemia (should be eliminated before starting treatment); viral (including chicken pox, shingles), fungal and bacterial infections, elderly patients.

Pregnancy and lactation:

It is proved that hydroxycarbamide has mutagenic and teratogenic effects. The use of the drug Hydroxyurea during pregnancy is contraindicated.

Hydroxycarbamide penetrates into breast milk. If you need to use the drug Hydroxyurea during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Inside, without chewing, drinking a glass of water.

Dosage depends on the disease, as well as on the actual or optimal body weight, if the actual body weight is too small.

With a decrease in the number of leukocytes less than 2.5x10⁹/ l or platelets less than 100x10⁹/ l treatment is discontinued.

After the withdrawal of the drug Hydroxyurea myelopoiesis is restored.

Malignant tumors of head and neck, cervical cancer

80 mg once a day every third day in combination with radiation therapy.

Treatment is started no earlier than 7 days before the start of radiotherapy and continues during radiotherapy. After radiation therapy, take for an unlimited time until the appearance of toxic reactions or progression of the disease.

Melanoma

At 20-30 mg / kg per day in a single dose or 60-80 mg / kg per day once every three days or in combination with radiotherapy.

Chronic myelogenous leukemia

The initial daily dose is 40 mg / kg. The dose reduction depends on the number of leukocytes in the blood plasma. The dose is reduced by 50% if the number of leukocytes is less than 20x10⁹/ l. In the case of leukopenia, the dose should be adjusted so as to maintain a leukocyte count of at least 5 × 10⁹/ l. With a decrease in the number of leukocytes less than 5x10⁹/ l dose should be reduced. Increase the dose can only after reaching a number of leukocytes at least 10x10⁹/ l.

Treatment is suspended if the number of white blood cells is less than 2.5x10⁹/ l or platelets less than 100x10⁹/ l. Renewal of treatment is possible after recovery of the number of leukocytes and platelets.

The evaluation period for the antitumor activity of the Hydroxiourea preparation is 6 weeks. If there is a significant deterioration in the course of the disease, treatment should be discontinued. With clinically meaningful improvement, treatment is extended indefinitely.

Thrombocythemia

The initial daily dose is 15 mg / kg, then the dose is selected so as to maintain a platelet count of at least 600x10⁹/ l, and leukocytes not less than 4х10⁹/ l.

True polycythemia

The initial daily dose is 15-20 mg / kg.The dose is set individually so that the hematocrit is less than 45%, and the platelet count is at least 400x10⁹/ l.

The majority of patients manage to reach this index, constantly applying hydroxycarbamide in a daily dose from 500 mg / day to 1000 mg / day.

If the hematocrit and platelet count are stabilized, the treatment should be continued indefinitely.

Osteomyelophybrosis

The initial daily dose is from 5 to 20 mg / kg. The maintenance daily dose is 10 mg / kg.

Elderly patients may be more sensitive to treatment with Hydroxyurea, so a dose reduction may be required.

In patients with impaired renal and hepatic function a dose reduction may be required.

Side effects:

The incidence of side effects is classified according to the recommendations of the World Health Organization: very often at least 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely - less than 0.01%, including isolated cases.

From the side of the blood and lymphatic system: often - suppression of hematopoiesis, leukopenia, an increase in the number of megaloblasts in the blood; infrequently - thrombocytopenia, anemia.

During therapy with hydroxycarbamide, megablastosis, resistant to folic acid and vitamin B, can develop.

From the nervous system: rarely - headache, dizziness, convulsions, impaired orientation, blurred vision, hallucinations, increased fatigue, drowsiness, disorientation.

From the digestive tract: often - constipation, diarrhea; infrequently - nausea, vomiting, stomatitis, bleeding gums, anorexia, ulceration of the gastrointestinal mucosa.

Severe disorders of the gastrointestinal tract (nausea, vomiting, anorexia) caused by the simultaneous use of hydroxycarbamide and radiation therapy, usually disappear after the elimination of hydroxycarbamide.

From the liver and bile ducts: infrequently - increased activity of "hepatic" enzymes and bilirubin concentration in blood plasma.

From the urinary system: infrequently - transient disorders of renal tubular function with an increase in the concentration of uric acid, urea and creatinine in the blood plasma; rarely - weakened and painful urination, urinary retention; very rarely - renal failure, interstitial nephritis.

From the respiratory system, organs of the thorax and mediastinum: rarely - acute pulmonary reactions (diffuse infiltrates in the lungs, fever, dyspnea), allergic alveolitis.

Allergic reactions: infrequently - maculopapular rash, skin itch, drug fever; rarely - hypersensitivity reactions.

From the skin and subcutaneous tissues: infrequently - erythema of facial skin, palms and soles; rarely - hair loss; single cases with long-term treatment - dermatomyositis, skin hyperpigmentation, nail pigmentation, skin and nail atrophy, skin ulceration (especially on the lower extremities), actinic keratosis, skin peeling, purple papule formation, skin cancer (squamous cell carcinoma, basaloma).

Other: infrequently - chills, malaise, general weakness; rarely - tumor disintegration syndrome, impaired fertility (amenorrhea, azoospermia); very rarely - an increase in the rate of erythrocyte sedimentation.

Overdose:

In patients receiving hydroxycarbamide in doses several times exceeding the recommended, severe reactions from the skin and mucous membranes develop.

Symptoms: pain, purple erythema, edema of the palms and feet, hyperkeratosis of the hands and feet, intense hyperpigmentation of the entire skin, stomatitis.

Treatment: gastric lavage, symptomatic therapy, monitoring of the hemopoiesis system. Hemodialysis is effective.

Interaction:

The use of drugs that increase the excretion of uric acid during treatment with hydroxycarbamide is not recommended because of the risk of nephropathy caused by uric acid. If such a combination is necessary, then one should simultaneously apply allopurinol.

Hydroxycarbamide should not be included in combination with antiviral agents in patients with acquired immune deficiency syndrome. In patients infected with the human immunodeficiency virus, therapy with hydroxycarbamide and didanosine (in combination with stavudine or without it) leads to the development of acute pancreatitis, sometimes fatal.

Simultaneous use of antiviral agents and hydroxycarbamide leads to liver damage and liver failure, including fatal.

The suppressive effect of hydroxycarbamide on the bone marrow is enhanced by the simultaneous use of drugs or other treatments with myelosuppressive action.

Particular caution should be exercised in relation to patients receiving hydroxycarbamide simultaneously after another antitumor treatment or radiotherapy, as in such cases, unwanted reactions develop more often and are more severe than with the separate application of hydroxycarbamide, antitumor agents and radiation therapy.

Hydroxycarbamide increases the effect of cytarabine, weakens - fluorouracil and methotrexate.

When used simultaneously with uricosuric medicines, the risk of developing nephropathy increases.

With simultaneous use with antidepressants, antihistamines, sedatives and hypnotics, preparations for general anesthesia, and also with ethanol, an inhibitory effect on the central nervous system is enhanced.

Special instructions:

Treatment with Hydroxyurea should be under the supervision of a doctor.

Before and during (at least once a week) treatment with the drug Hydroxyurea, it is necessary to monitor the clinical blood test. With a decrease in the number of leukocytes less than 2.5 × 10⁹/ l and platelets less than 100x10⁹/ l treatment is interrupted until the normalization of hematological indicators.

The appearance of symptoms of suppression of bone marrow function (bleeding,hemorrhage, blood in urine or feces, black stool, petechial rash) requires immediate medical attention.

During treatment, you should avoid accidental cuts with sharp objects (safety razor, scissors), avoid contact sports or other situations in which you can get injuries and hemorrhages.

If possible, dental interventions should be completed before the start of therapy or postponed until normalization of the blood test (possibly increasing the risk of infectious and inflammatory diseases, slowing the healing process, bleeding). During treatment, care should be taken when using toothbrushes, threads or toothpicks.

It is necessary to monitor the condition of patients who developed leukopenia. If signs of an infectious-inflammatory disease are detected, antibiotic treatment is performed. Patients with neutropenia with increasing body temperature, broad-spectrum antibiotics are used empirically to obtain the results of bacteriological studies and appropriate diagnostic tests.

Long-term patients receiving treatment with hydroxyurea for myeloproliferative diseases, such as true polycythemia or thrombocytosis, may develop secondary leukemia. The relationship of this phenomenon with the primary disease or with the intake of hydroxycarbamide to the end has not been studied.

During the period of treatment, it is not recommended to vaccinate patients with "live" viral vaccines, including "live" polio vaccine, contact with people vaccinated with poliomyelitis vaccine should be avoided, with sick bacterial infections. Use "live" viral vaccines in patients with leukemia in the remission phase should not be at least 3 months after the last course of chemotherapy. Vaccination with an oral vaccine against poliomyelitis of people in close contact with such patients, especially members of their family, should be postponed.

Severe anemia should be corrected by blood transfusion before starting therapy or during therapy with Hydroxyurea.

Disorders of erythropoiesis (megaloblastic erythropoiesis) may appear at the beginning of the course of treatment with the drug Hydroxyurea.Morphological changes resemble pernicious anemia, but are not associated with deficiency of folic acid or vitamin AT₁₂. Against the background of treatment with hydroxyurea, plasma clearance of iron and iron utilization by red blood cells can decrease, while the lifespan of erythrocytes does not change.

A regular dynamic control of the concentration of uric acid, creatinine, the activity of transaminases in the blood plasma is necessary.

During treatment with the drug Hydroxyurea, the concentration of uric acid in the blood plasma may increase (in these cases it is recommended to prescribe allopurinol, increase the volume of circulating blood or urine alkalinization). In the course of treatment, it is important to consume enough fluids and then increase diuresis to ensure the excretion of uric acid.

At the initial stage of treatment of leukemia and lymphoma there can be a rapid increase in the concentration of uric acid in the blood plasma.

It is necessary to regularly do scrapings of the skin because of the rare possibility of developing scaly-cell cancer.

Treatment with Hydroxyurea can cause painful ulceration of the skin of the lower limbs,which are difficult to treat and require discontinuation of therapy. Abolition of the drug Hydroxyurea leads to the healing of ulcers within two weeks.

The use of hydroxyurea after radiotherapy can cause worsening of the course of erythema.

Simultaneous use of the drug Hydroxyurea with nucleoside reverse transcriptase inhibitors increases the risk and severity of the course of side effects of this group of drugs (pancreatitis, hepatic insufficiency, neuropathy).

Men and women of childbearing age should use effective methods of contraception before starting therapy with Hydroxyurea, during and within 3 months after its termination. Since the drug Hydroxyurea has a genotoxic effect, genetic counseling is recommended for patients planning a pregnancy after completion of therapy.

If the patient has no clinical effect after 6 weeks of treatment, the drug hydroxyurea should be discontinued; In the case of the effectiveness of therapy, the administration of Hydroxyurea can be continued indefinitely.

Care must be taken with combination therapy and take each drug at the appointed time.

Combination with radiotherapy can lead to an increase in the severity of side effects (bone marrow aplasia, dyspepsia and development of peptic ulceration of the gastrointestinal tract).

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

During treatment it is recommended to refrain from driving vehicles and controlling mechanisms due to the fact that side reactions may develop: dizziness, disorientation, clouding of consciousness, affecting the ability to concentrate attention and the speed of psychomotor reactions.

Form release / dosage:Capsules, 500 mg.

Packaging:

100 capsules in a plastic bag. The package is sealed and, together with the instruction for use and the adsorbent, is placed in a metal jar closed by an aluminum membrane and a lid.

100 capsules together with the adsorbent in a polyethylene opaque bottle of white color with a polypropylene lid. The bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N012318 / 01

Date of registration:10.01.2012

Expiration Date:Unlimited

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

TEVA Czech Industries, s.r.o. Czech Republic

Representation: & nbspTeva Teva Israel

Information update date: & nbsp15.04.2017

Illustrated instructions

Instructions

Hydroxyurea (Hydroxyurea)