Hydroxycarbamide, 500 mg capsules 100 pcs

Pharmacotherapeutic group

Antitumor drug – antimetabolite

ATX Code

L01XX05

Pharmacodynamics:

Hydroxycarbamide is a phase-specific cytostatic drug (an alkylating antimetabolite according to some reports) active in phase S of the cell cycle. It blocks cell growth in G1-S phase, which is essential for simultaneous radiation therapy, because there appears a synergistic sensitivity of tumor cells in G1 phase to radiation.

The potentiating effect of RNA reductase inhibitor – ribonucleotide reductase causes suppression of deoxyribonucleic acid (DNA) synthesis without affecting ribonucleic acid (RNA) and protein synthesis.

Pharmacokinetics:

Intake and distribution

It is rapidly absorbed in the gastrointestinal tract (GIT). Maximum plasma concentration of hydroxycarbamide (Cmax) is reached within 2 hours after ingestion. There are no data on the effect of food intake on absorption. It is rapidly distributed throughout the body tissues penetrates through the blood-brain barrier. Concentration of hydroxycarbamide in CSF is 10-20% of the plasma concentration, while the concentration in ascitic fluid is 15-50%. Hydroxycarbamide accumulates in leukocytes and erythrocytes.

Metabolism

Partially metabolized in the liver and kidneys.

Elimination

The elimination half-life (T1/2) is 3-4 hours. 80% of hydroxycarbamide is excreted by the kidneys within 12 hours. 50% of hydroxycarbamide is excreted unchanged and in small amounts as urea. The drug is also excreted through the respiratory tract as carbon dioxide. After 24 hours, hydroxycarbamide is undetectable in plasma.

Indications

– Resistant chronic myeloleukemia.

– True polycythemia (erythraemia) with high risk of thromboembolic complications.

– Essential thrombocythemia with high risk of thromboembolic complications.

– Osteomyelofibrosis.

– Melanoma.

– Malignant tumors of the head and neck (except lip cancer) in combination with radiotherapy.

– Cervical cancer (in combination with radiation therapy).

Active ingredient

Composition

In one capsule:

The active ingredient: hydroxycarbamide – 500.00 mg.

Excipients: lactose monohydrate (milk sugar) – 42.20 mg; sodium hydrophosphate dihydrate – 36.00 mg; citric acid monohydrate – 12.8 mg; magnesium stearate – 9.00 mg.

Capsule body composition: titanium dioxide – 2.0000%; gelatin – up to 100%.

Capsule cap composition: titanium dioxide – 2.0000%; gelatin – up to 100%.

How to take, the dosage

The choice of therapy regimen and dosages in each individual case should be guided by data from the literature.

The drug is used orally.

In case of difficulty in swallowing, the capsule may be opened and the contents poured into a glass of water and drunk immediately. Some water-soluble excipients may remain on the surface of the solution.

A considerable amount of fluid should be taken during treatment with the drug.

Resistant chronic myeloleukemia

Continuous therapy. 20 to 30 mg/kg daily once daily.

The efficacy of the drug is evaluated after 6 weeks of treatment. If there is an acceptable clinical response, treatment can be continued indefinitely.

The treatment should be stopped if the white blood cell count is less than 25 x 109/l or the platelet count is less than 100 x 109/l. The blood test is repeated after 3 days. Treatment is resumed when the leukocyte and erythrocyte counts increase to an acceptable level. Usually the leukocyte and erythrocyte content is restored rather quickly; otherwise, if the drug is used together with radiotherapy the latter may also be suspended.

The development of anemia, even severe, does not require discontinuation of therapy if adequate therapy (transfusion of red blood cells) is provided.

True polycythemia (erythraemia) with high risk of thromboembolic complications

The treatment is started with a daily dose of 15-20 mg/kg. The dose is adjusted individually, aiming to keep hematocrit below 45% and platelet count below 400 x 109/l.

In most patients it is possible to achieve these values with continuous use of hydroxycarbamide at a daily dose of 500 mg/day to 1000 mg/day.

The treatment is continued as long as platelet and/or leukocyte counts can be adequately controlled or until resistance or intolerance to the drug develops.

Essential thrombocythemia at high risk of thromboembolic complications

The initial daily dose of hydroxycarbamide is 15 mg/kg then the dose is adjusted to maintain platelet counts below 600 x 109/L without causing a decrease in white blood cell count below 4 x 109/L.

The treatment is continued as long as platelet and/or leukocyte counts can be adequately controlled or until resistance or intolerance to the drug occurs.

Osteomyelofibrosis

The initial daily dose is 15 mg/kg. Then the dose is adjusted to maintain a white blood cell count of at least 4 x 109/l and a platelet count of at least 100 x 109/l.

Melanoma solid tumors

Intermittent therapy: 80 mg/kg once daily every three days (6-7 doses).

Continuous therapy: 20-30 hmg/kg daily once daily for 3 weeks.

Malignant head and neck tumors (except lip cancer) in combination with radiation therapy cervical cancer in combination with radiation therapy

80 mg/kg once daily every three days in combination with radiation therapy.

The treatment with the drug starts at least 7 days before the start of radiotherapy and continues during radiotherapy. After radiation therapy, the drug is continued indefinitely with strict patient monitoring and in the absence of unusual or severe toxic reactions.

Patients with impaired liver function

There is no indication to change doses in this group of patients. Blood values should be monitored closely in patients with impaired liver function.

Patients with impaired renal function

Because hydroxycarbamide is primarily excreted through the kidneys, the dose should be reduced when using the drug in patients with impaired renal function. In patients with renal impairment (creatinine clearance less than 60 ml/min) the drug is usually prescribed in a dose of 15 mg/kg.

In patients with end-stage renal failure the drug is prescribed in a dose of 15 mg/kg twice with an interval of 7 days between doses: first time at the end of a 4-hour hemodialysis session and second time before the hemodialysis session.

Patients in the elderly and elderly

Because elderly patients are more likely to have side effects when using the drug, the recommended dose for this group of patients should not exceed 60 mg/kg/day.

Interaction

In concomitant use of hydroxycarbamide with other myelosuppressive drugs or radiation therapy, the degree of suppression of bone marrow function or the development of other side effects may increase.

In in vitro studies it has been noted that concomitant use of hydroxycarbamide and cytarabine increases the cytotoxic effect of the latter.

If severe depression, nausea, vomiting or anorexia are noted during combination therapy, they can usually be managed by interrupting the use of hydroxycarbamide.

Pain and discomfort of the mucous membranes at the site of exposure (mucositis) can be relieved with local anesthetics and oral analgesics. In severe mucositis, hydroxycarbamide therapy is temporarily stopped; and in very severe cases, radiation therapy is also stopped.

The drug may increase serum uric acid content; therefore, it may be necessary to adjust the dose of drugs that increase excretion of uric acid from the body. Uricosuric drugs increase the risk of nephropathy. There have been cases of false-positive test results in the determination of uric acid and lactic acid as a result of interaction between hydroxycarbamide and enzymes (urease ureicase lactate dehydrogenase).

A higher risk of vaccine-associated infections with fatal outcome is possible when hydroxycarbamide and live vaccines are used together. The use of live vaccines is not recommended in immunocompromised patients.

Special Instructions

Treatment with this drug should be done under the supervision of a physician experienced in the use of antitumor therapy.

Bone marrow liver and kidney function should be monitored before each course and periodically during treatment. Hemoglobin leukocyte and platelet counts should be determined at least once a week for the duration of treatment with the drug. The treatment is prescribed only if the leukocyte count exceeds 2500/μl and the thrombocyte count is 100000/μl. If the leucocyte count is found to be below 2500/µl or the platelet count is below 100,000/µl, the treatment should be suspended until its normal values are restored.

Severe anemia should be compensated for before treatment with the drug.

Myelosuppression may develop during treatment with the drug, mainly leukopenia. Thrombocytopenia and anemia develop less frequently and very rarely without preceding leukopenia. Myelosuppression is most likely in patients after recent prior radiation therapy or chemotherapy with other drugs.

The drug should be used with caution after recent radiation or chemotherapy because of possible exacerbation of postradiation erythema and increased severity of side effects (bone marrow aplasia dyspepsia and gastrointestinal ulcerations).

In case of severe digestive side effects (such as nausea, vomiting, anorexia), the drug therapy is usually stopped.

In case of pain and discomfort when mucositis develops in the radiation area, local anesthetics and analgesics are usually prescribed for oral administration. In severe cases, therapy with the drug is temporarily suspended, and in very severe cases the accompanying radiation therapy is temporarily withdrawn.

In the early stages of treatment with the drug, moderate megaloblastic erythropoiesis is often observed. The morphological changes resemble pernicious anemia but are not associated with vitamin B12 or folic acid deficiency. Because macrocytosis may mask folic acid deficiency, regular determination of serum folic acid is recommended.

Hydroxycarbamide may also slow plasma iron clearance and decrease erythrocyte iron utilization rate; however, this has no effect on erythrocyte lifetime.

In cases of pancreatitis and hepatotoxicity (with possible death) have been reported in HIV-infected patients who have taken hydroxycarbamide together with antiretroviral drugs, particularly with didanosine (in combination with or without stavudine). Therefore, coadministration of these drugs should be avoided. Also cases of peripheral neuropathy sometimes severe have been reported in HIV-infected patients who have taken hydroxycarbamide together with antiretroviral drugs including didanosine (in combination with or without stavudine).

Patients should drink plenty of fluids during treatment. It may be necessary to reduce the dose of the drug in case of impaired renal function. The drug should be used with caution in patients with impaired renal and hepatic function.

During treatment with the drug, cutaneous toxic vasculitis including vasculitic ulceration and gangrene have been observed in patients with myeloproliferative diseases. Toxic vasculitis has been most commonly reported in patients receiving or having received interferon in the past. If vasculitic ulcers progress, the drug should be discontinued.

In long-term use of the drug in patients with myeloproliferative diseases such as true polycythemia and thrombocytopenia there have been cases of secondary leukemia. At the same time it is unknown what is the cause of secondary leukemia: the use of hydroxycarbamide or the underlying disease.

In long-term use of hydroxycarbamide, there have also been cases of skin cancer. Patients should be warned to protect their skin from sunlight and to self-monitor their skin. Patients’ skin conditions should be monitored during routine medical visits to look for possible malignant changes.

Azoospermia or oligospermia has occasionally been observed in male patients. Therefore, patients should be informed about the possibility of sperm preservation before starting therapy.

Because of the possible genotoxicity of hydroxycarbamide, male patients taking the drug should be informed about the need for reliable contraception during treatment and for at least one year after the end of therapy.

Vaccination with live virus vaccines concomitantly with hydroxycarbamide therapy may activate vaccine virus replication and/or increase adverse reactions due to the suppression of the body’s defense mechanisms caused by hydroxycarbamide use. Vaccination with live vaccines while using hydroxycarbamide can lead to severe infections. There may also be a decreased immune response to vaccine administration.

The administration of live vaccines during therapy with the drug should be avoided and a specialist should be consulted.

Hydroxycarbamide is cytotoxic, so care should be taken when opening the capsules and avoid getting powder from the capsules on the skin, mucous membranes or inhaling the drug. If the capsule contents are accidentally scattered, immediately gather the powder into a plastic bag, tie it up, and discard it.

Pediatric use

The safety and effectiveness of hydroxycarbamide in children has not been established.

The use in elderly patients

Because elderly patients are more likely to have side effects when using hydroxycarbamide than younger patients, a reduced dose may be required.

There have been no studies on the effect of hydroxycarbamide on the ability to drive vehicles and mechanisms. In case of adverse reactions from the nervous system (dizziness, etc.) while using the drug one should refrain from driving vehicles and operating machinery as well as from carrying out other potentially dangerous activities requiring high concentration and quick psychomotor reactions.

Contraindications

– Hypersensitivity to hydroxycarbamide or other components of the drug.

– Pregnancy and breastfeeding.

– Leukopenia below 2500/μL Thrombocytopenia below 100000/μL.

– Age under 18 years (safety and efficacy of use have not been established).

– Hepatic and/or renal insufficiency.

– Severe anemia (must be compensated before starting treatment).

– Patients after undergoing radiotherapy or chemotherapy (possibility of myelosuppression of exacerbation of radiation erythema).

– Lactase deficiency lactose intolerance glucose-galactose malabsorption.

Side effects

The adverse reactions presented below are listed according to organ and system involvement. The incidence of adverse reactions is estimated as follows: occurring very frequently, ≥10%; frequent, ≥1% and <10%; infrequent, ≥01% and <1%; rare, ≥001% and <01%; very rare, <001% including individual reports; frequency unknown – frequency cannot be estimated with the available data.

Infectious and parasitic diseases:

frequency unknown – gangrene.

Disorders of the blood and lymphatic system:

frequency unknown – suppression of bone marrow function (leukopenia anemia thrombocytopenia):

Gastrointestinal tract disorders:

frequency unknown – pancreatitis sometimes fatal (in HIV-infected patients simultaneously receiving antiretroviral therapy in particular didanosine and stavudine); stomatitis anorexia nausea vomiting diarrhea constipation mucositis dyspepsia gastrointestinal mucosa irritation ulceration of the gastrointestinal tract mucosa.

Hepatic and biliary tract disorders:

frequency unknown – hepatotoxicity increased “liver” enzyme activity and plasma bilirubin concentration cholestasis hepatitis.

Dermal and subcutaneous tissue disorders:

rarely – alopecia skin cancer; frequency unknown – cutaneous vasculitis maculopapular rash erythema facial and peripheral erythema skin ulcerations dermatomyositis-like skin changes skin exfoliation hyperpigmentation skin and nail atrophy peeling purple papules skin toxic vasculitis (including vasculitic ulcerations and gangrene) skin allergic reactions.

Nervous system disorders:

frequency unknown – dizziness somnolence disorientation headache hallucinations seizures peripheral neuropathy (in HIV-infected patients simultaneously receiving antiretroviral therapy in particular didanosine and stavudine) increased fatigue.

Disorders of the respiratory system of the chest and mediastinum:

Rarely, diffuse pulmonary infiltration dyspnea; frequency unknown, pulmonary fibrosis.

Renal and urinary tract disorders:

rarely – dysuria; frequency unknown – increased serum uric acid, increased serum urea nitrogen and creatinine levels in plasma urine retention interstitial nephritis.

General disorders and disorders at the site of administration:

frequency unknown – chills fever general malaise increased sed rate asthenia azoospermia oligospermia tumor lysis syndrome.

In cases of pancreatitis and hepatotoxicity (possibly fatal) and severe peripheral neuropathy have been reported in patients with HIV who have taken hydroxycarbamide with antiretrovirals such as didanosine in combination with or without stavudine.

The side effects observed with concomitant use of hydroxycarbamide and radiotherapy are the same as with monotherapy of the drug mainly suppression of bone marrow function (leukopenia anemia) and gastric mucosal irritation.

The use of hydroxycarbamide may exacerbate some side effects that are seen with radiation therapy such as gastric discomfort and mucositis.

Overdose

Symptoms: when using hydroxycarbamide in doses several times higher than recommended, patients developed signs of acute dermatological toxicity: soreness purple erythema edema with subsequent peeling of the palms and feet intense generalized skin hyperpigmentation and stomatitis.

Treatment: no specific antidote is known treatment is symptomatic.

Pregnancy use

Hydroxycarbamide has been proven to have mutagenic and teratogenic effects. The use of hydroxycarbamide during pregnancy is contraindicated. During therapy, the patient should be warned about the need for reliable contraception. If pregnancy occurs during treatment with hydroxycarbamide it is necessary to warn the patient about the possibility of risk to the fetus.

Hydroxycarbamide penetrates into breast milk. If hydroxycarbamide must be used during breastfeeding, breastfeeding should be stopped.

Similarities