Hydroxycarbamide-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HYDROXYCARBAMIDE-VISTA (HYDROXYCARBAMIDE-VISTA)

Composition:

Active substance: hydroxycarbamide;

1 capsule contains 500 mg of hydroxycarbamide;

Excipients: lactose monohydrate; anhydrous citric acid; anhydrous sodium hydrogen phosphate; magnesium stearate;

Capsule shell: gelatin, titanium dioxide (E 171), erythrosine (E 127), indigo carmine (E 132), quinoline yellow (E 104).

Pharmaceutical form. Capsules.

Main physicochemical characteristics: hard gelatin capsules size №0 with an opaque pink body and an opaque light-green cap, containing a homogeneous powder ranging from white to almost white.

Pharmacotherapeutic group. Other antineoplastic agents. ATC code L01X X05.

Pharmacological properties.

Pharmacodynamics.

Hydroxycarbamide is an oral antineoplastic agent. The exact mechanism of the antineoplastic action of the drug has not been fully elucidated, but it is believed to be related to the inhibition of DNA synthesis.

Pharmacokinetics.

After oral administration, hydroxycarbamide is well absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 2 hours after administration. After 24 hours, plasma concentration becomes zero. Approximately 80 % of an oral or intravenous dose of the drug ranging from 7 to 30 mg/kg may be excreted in the urine within 12 hours. Hydroxycarbamide crosses the blood-brain barrier. It is well distributed throughout the body. Hydroxycarbamide is genotoxic and is considered a probable multispecies carcinogen, implying a carcinogenic risk for humans.

Clinical characteristics.

Indications.

Treatment of patients with chronic myeloid leukemia (CML):

• as a treatment phase prior to tyrosine kinase inhibitors (TKIs) in cases of confirmed BCR-ABL fusion with an immediate need for therapy due to high leukocyte and platelet counts;
• as palliative therapy in patients in blast phase with leukocytosis and thrombocytosis.

Treatment of cervical cancer in combination with radiation therapy.

Contraindications.

Hypersensitivity to the active substance or to any other component of the medicinal product. Suppressed bone marrow function (leukocyte count less than 2.5 × 10^9/L, platelet count – less than 100 × 10^9/L) or presence of severe anemia.

Interaction with other medicinal products and other types of interactions.

Myelosuppressive activity may be enhanced by prior or concomitant radiotherapy or cytotoxic therapy. Pancreatitis, both fatal and non-fatal, has occurred in HIV-infected patients receiving hydroxycarbamide together with didanosine, with or without stavudine. During post-marketing surveillance of HIV-infected patients receiving hydroxycarbamide and other antiretroviral agents, cases of hepatotoxicity and liver failure leading to fatal outcomes have been reported. Fatal hepatic events have been most frequently reported in patients receiving the combination of hydroxycarbamide, didanosine, and stavudine; therefore, this combination should be avoided. Peripheral neuropathy, sometimes severe, has been reported in HIV-infected patients receiving hydroxycarbamide in combination with antiretroviral agents, including didanosine, with or without stavudine (see Special warnings and precautions for use). Analytical interference of hydroxycarbamide with enzymes (urease, uricase, and lactate dehydrogenase) used to measure urea, uric acid, and lactic acid has been demonstrated, leading to false-positive results in patients receiving hydroxycarbamide.

Vaccination.

There is an increased risk of severe, potentially fatal infections with concomitant administration of live vaccines. Live vaccines should not be administered to immunocompromised patients (see "Special warnings and precautions for use").

Special precautions for use.

Prior to initiating treatment and during therapy with the medicinal product, blood parameters should be monitored, including, if necessary, bone marrow examination, as well as kidney and liver function. Hydroxyurea-Vista treatment should not be initiated if bone marrow function is suppressed. Complete blood counts, including hemoglobin levels, total leukocyte count, and differential platelet count, should be performed regularly, including after establishing the individual optimal dose. The frequency of monitoring should be determined individually, but typically on a weekly basis. Treatment should be discontinued if leukocyte counts fall below 2.5 × 10^9/L or platelet counts fall below 100 × 10^9/L until levels return to normal.

Hydroxyurea may cause bone marrow suppression, most commonly manifesting as leukopenia, and less frequently as thrombocytopenia and anemia. Bone marrow suppression is more likely to occur in patients previously treated with radiation therapy or cytotoxic chemotherapy. Such patients should be treated with Hydroxyurea-Vista with caution. Recovery from myelosuppression after discontinuation of Hydroxyurea-Vista occurs rapidly. If anemia develops before or during treatment, red blood cell transfusions may be required. If anemia occurs during therapy, it should be managed without discontinuing Hydroxyurea-Vista treatment. Transient megaloblastic erythropoiesis is often observed at the beginning of hydroxyurea therapy. The morphological changes resemble pernicious anemia but are not associated with vitamin B12 or folic acid deficiency. Macrocytosis may mask the development of folic acid deficiency; therefore, regular measurement of serum folic acid levels is recommended. Hydroxyurea may also delay plasma iron clearance and reduce the rate of iron utilization by erythrocytes, but this does not appear to alter erythrocyte lifespan.

Exacerbation of post-radiation erythema may occur in patients who have previously undergone radiation therapy.

Hydroxyurea should be used with caution in patients with severe renal dysfunction.

Hydroxyurea is not intended for concomitant use with antiretroviral agents in HIV-infected patients, as this may lead to treatment failure and toxicity (in some cases, fatal) in HIV patients (see "Interaction with other medicinal products and other forms of interaction").

Patients undergoing long-term hydroxyurea treatment for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, may develop secondary leukemia. It remains unclear to what extent this is related to the underlying disease or to hydroxyurea therapy.

Skin cancer has been reported in patients receiving long-term hydroxyurea therapy. Patients should be advised to protect their skin from sun exposure. Additionally, patients should perform regular skin self-examinations during and after hydroxyurea therapy and undergo routine screening for secondary malignancies during follow-up visits.

Skin toxicities, including vasculitic ulcers and gangrene, have been observed during hydroxyurea therapy in patients with myeloproliferative disorders. The risk of toxic vasculitis is increased in patients currently or previously treated with interferon. Digital localization of these vasculitic ulcers and progressive clinical course of peripheral vascular insufficiency, leading to digital infarction or gangrene, clearly distinguishes them from typical skin ulcers usually described with hydroxyurea use. Due to the potentially serious clinical consequences of skin vasculitic ulcers in patients with myeloproliferative disorders, hydroxyurea therapy should be discontinued and alternative cytoreductive agents initiated if vasculitic ulcers develop.

Patients receiving hydroxyurea, particularly in combination with other cytotoxic agents, should be informed about the potential for increased serum uric acid levels, which may lead to gout or, in severe cases, gouty nephropathy. Therefore, regular monitoring of uric acid levels and maintaining high fluid intake during treatment are essential.

Hydroxyurea-Vista contains lactose; therefore, patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Vaccination.

Concomitant use of hydroxyurea with live viral vaccines may potentiate replication of the vaccine virus and/or intensify certain adverse reactions from the vaccine virus, as normal defense mechanisms may be suppressed by hydroxyurea. Vaccination with live vaccines in patients taking Hydroxyurea-Vista may result in severe infection. The patient's humoral immune response to the vaccine may be diminished. The use of live vaccines should be avoided during treatment and for at least 6 months after completion of therapy (see "Interaction with other medicinal products and other forms of interaction").

Respiratory disorders.

Interstitial lung disease, including pulmonary fibrosis, lung infiltration, pneumonitis, and alveolitis/allergic alveolitis, has been reported in patients receiving treatment for myeloproliferative neoplasms, which may be associated with fatal outcomes. A patient experiencing fever, cough, dyspnea, or other respiratory symptoms should be carefully monitored, evaluated, and treated. Discontinuation of hydroxyurea therapy and treatment with corticosteroids usually lead to resolution of pulmonary manifestations (see "Undesirable effects").

Cases of hemolytic anemia have been reported in patients receiving hydroxyurea for the treatment of myeloproliferative disorders. Patients who develop severe anemia should undergo laboratory testing to assess for hemolysis. If hemolytic anemia is diagnosed, hydroxyurea therapy should be discontinued.

Use during pregnancy or breastfeeding.

Pregnancy.

Hydroxyurea may be a potent mutagenic agent. The physician must carefully consider the possibility of hydroxyurea therapy before prescribing this medicinal product to men or women planning conception. Hydroxyurea should not be administered during pregnancy except when the potential benefit justifies the potential risk to the fetus. Men and women of reproductive potential must use effective contraception during treatment with Hydroxyurea-Vista and for some time after the last dose.

Since hydroxyurea is a cytotoxic agent, teratogenic effects have been observed in certain animal species.

Lactation (breastfeeding).

Hydroxyurea is excreted in breast milk. Due to the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue breastfeeding or to discontinue the medicinal product, taking into account the importance of the therapy to the mother.

Fertility.

In rats and dogs, high doses of hydroxyurea suppressed sperm production.

Ability to influence reaction speed when driving or operating machinery.

Hydroxyurea may cause somnolence. Patients should refrain from driving or operating machinery unless it has been established that the medicinal product does not affect their physical or mental abilities.

Administration and Dosage

Treatment regimens may be continuous or intermittent. The continuous regimen is more suitable for the treatment of chronic myeloid leukemia, whereas the intermittent regimen, with reduced bone marrow suppression, is more appropriate for the treatment of cervical cancer.

Treatment with hydroxycarbamide should begin 7 days prior to the initiation of radiation therapy. If hydroxycarbamide is administered concurrently with radiotherapy, dose adjustments of radiation are generally not required.

An adequate period to achieve an antineoplastic effect is 6 weeks. If a favorable therapeutic response is observed, treatment should continue indefinitely, provided the patient remains under appropriate monitoring and no adverse reactions occur. If the leukocyte count falls below 2.5 × 10⁹/L or the platelet count drops below 100 × 10⁹/L, therapy should be discontinued (see "Contraindications"). In such cases, blood tests should be repeated after 3 days, and hydroxycarbamide treatment should be resumed once normal blood parameters are restored. Bone marrow function recovery is usually rapid. If this does not occur during concomitant therapy with hydroxycarbamide and radiation, radiotherapy may be interrupted. Treatment of severe anemia may be managed without discontinuing hydroxycarbamide therapy.

Severe gastrointestinal adverse reactions, such as nausea, vomiting, and anorexia, occurring as a result of combination therapy, can generally be controlled by temporarily interrupting the administration of Hydroxycarbamide-Vista.

Pain or discomfort due to mucosal inflammation (mucositis) in the irradiated area is usually managed with local anesthetics and oral analgesics. If the reaction is pronounced, therapy with Hydroxycarbamide-Vista may be temporarily interrupted. If the reaction is extremely severe, radiotherapy may be postponed.

Continuous Therapy

Hydroxycarbamide is generally administered at a dose of 20–30 mg/kg body weight per day. Dosing should be based on the patient's actual or ideal body weight, whichever is lower.

Intermittent Therapy

Hydroxycarbamide-Vista should be administered at a single dose of 80 mg/kg every three days. With intermittent dosing regimens, the likelihood of leukopenia is reduced; however, if leukocyte levels do decrease, one or more doses of Hydroxycarbamide-Vista should be omitted.

Concomitant use of Hydroxycarbamide-Vista with other myelosuppressive agents may necessitate dose adjustments.

Children. As these conditions are rare in children, the dosing regimen in pediatric patients has not been studied.

Elderly Patients. Elderly patients may be more sensitive to the effects of hydroxycarbamide and may require dose reduction.

Patients with Renal or Hepatic Impairment. Since renal excretion is the primary route of elimination of the drug, dose reduction should be considered in this patient population.

Children.

The safety and efficacy of treatment with this medicinal product in this patient group have not been established.

Overdose.

Immediate management includes gastric lavage followed by supportive therapy and monitoring of the hematopoietic system.

In patients who have taken doses several times higher than the usual recommended doses, acute skin and mucosal disorders have been observed, including irritation, purple erythema, swelling of the palms and soles followed by desquamation of the skin on hands and feet, intense generalized skin hyperpigmentation, and stomatitis.

Adverse reactions.

Bone marrow suppression is the dose-limiting factor of toxicity. Cutaneous toxic vasculitis, including vasculitic ulcers and gangrene, has been observed in patients with myeloproliferative disorders during hydroxyurea therapy. The risk of developing toxic vasculitis is increased in patients who have received prior or concomitant therapy with interferon.

Hyperpigmentation, skin and nail atrophy, desquamation, purple papules, and alopecia have been observed in some patients after several years of continuous daily maintenance therapy with hydroxyurea.

Cases of pancreatitis, hepatotoxicity, and severe peripheral neuropathy, including fatal outcomes, have been observed in HIV patients receiving hydroxyurea concurrently with antiretroviral agents, particularly didanosine plus stavudine. In patients receiving hydroxyurea in combination with didanosine, stavudine, and indinavir, a mean decrease in CD4 cell count to approximately 100/mm³ was observed (see "Special precautions" and "Interaction with other medicinal products and other forms of interactions").

Adverse reactions observed during combined therapy with Hydroxyurea-Vista and radiation therapy were similar to those reported with hydroxyurea alone, primarily suppression of bone marrow function (leukopenia and anemia) and gastrointestinal irritation.

Leukopenia develops in nearly all patients receiving an adequate course of combined therapy with Hydroxyurea-Vista and radiation. Thrombocytopenia (<100,000/mm³) occurs rarely and usually only in the presence of marked leukopenia.

Hydroxyurea-Vista may potentiate certain adverse reactions typically observed with radiation alone, such as gastrointestinal disturbances and mucositis. Adverse reactions are categorized by frequency of occurrence as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

1Cases of pancreatitis and hepatotoxicity (sometimes with fatal outcome), as well as severe peripheral neuropathy, have been reported in HIV-infected patients receiving hydroxycarbamide in combination with antiretroviral agents, particularly didanosine in combination with stavudine.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is important. This allows continued monitoring of the benefit-risk balance of the medicinal product. Reports of adverse reactions from healthcare professionals are submitted in accordance with the current legislation on medicinal products circulation in Ukraine.

Shelf life. 3 years.

Storage conditions. Store in a place protected from light and inaccessible to children, at a temperature not exceeding 25 °C.

Packaging. 10 capsules in blisters made of aluminum foil and PVC film; 10 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Deva Holding A.Ş.

Manufacturer's address and site of manufacturing activity.

Cerkezkoy Organize Sanayi Bolgesi, Karagac Mahallesi, Fatih Blv. No:26, Kapakli/Tekirdag/Turkey.