Etoposide-Ebove - instructions for use, doses, side effects, contraindications

Etoposide is a semi-synthetic derivative of podophyllotoxin. Mechanism action is associated with the inhibition of topoisomerase II (an enzyme unwinding DNA). Etoposide has a cytotoxic effect due to DNA damage. The death of cells depends on the concentration of etoposide and the duration of its effect. Etoposide has a phase-specific effect with stopping the cell cycle in Sphase and at the beginning of the 02 phase, while it differs from other known preparations of podophyllotoxin, since it does not cause accumulation of cells in the metaphase, but prevents mitosis or causes the death of cells preparing for mitosis. High concentrations of the drug cause lysis of cells in the pre-pertussis phase. Etoposide also suppresses penetration of nucleotides through the plasma membrane, which prevents synthesis and restoration of DNA.

Pharmacokinetics:After intravenous administration meanings the maximum the concentration of etoposide in the blood plasma and the "concentration-time" curve are linearly dose dependent. The drug is found in pleural fluid, in saliva, liver, spleen, kidneys, myometrium, brain tissues. Etoposide permeates across blood-brain and placental barriers. The concentrations of etoposide in the cerebrospinal fluid range from undetectable values to 14.3% of the plasma concentration. It has been shown that the concentration of etoposide in healthy lung tissue is higher than in pulmonary metastases, and its values achieved in primary myometrium tumors are similar to those in healthy myometrium tissue.Data on the isolation of the drug with breast milk is absent. At the beginning of the application, the volume of distribution of etoposide is 27.8 liters, and at subsequent administrations - 18.4-25.2 liters. 97 % of etoposide binds to blood plasma proteins.

Etoposide is actively metabolized in the body. Excretion of etoposide is carried out two-phase way. In adults with normal renal and hepatic function, the half-life (T1_/2) in the initial phase averages 0.5-3 hours, the half-life in the final phase is 8 ± 4 hours.

In children with normal liver and kidney function T1/₂ on the average is 0.6-1.4 hours in the initial phase and 3.0-5.8 hours in the final phase. Plasma clearance is 47.1-50.7 ml / min, the renal clearance is about 1/3 of the plasma clearance (13.5-16.3 ml / min). Approximately 40-60 % of the dose etoposide is excreted by the kidneys in unchanged form and in the form of metabolites for 48-72 hours; less than 2-16% - through the intestine within 72 h.

In patients with impaired liver and / or kidney function the plasma clearance of etoposide slows down.

Indications:

The main indications for the use of etoposide-Ebewe are germ cell tumors of the testis and ovaries, lung cancer.

There are reports of the effectiveness of Etoposide-Ebene in the treatment of bladder cancer, lymphogranulomatosis, non-Hodgkin's lymphomas,acute monoblast and myeloblastic leukemia, Ewing's sarcoma, trophoblastic tumors, stomach cancer, Kaposi's sarcoma and neuroblastoma.

Contraindications:- increased sensitivity to etoposide or accessory substances of the preparation;

- severe myelosuppression (neutrophil count below 1500 cells / μl and / or platelets below 100,000 cells / μl);

- marked violations of the liver and kidneys;

- acute infections;

- vaccination with live vaccines, incl. yellow fever vaccine;

- pregnancy and the period of breastfeeding;

- children under 3 years.

Carefully:

Carefully used in patients from renal insufficiency of mild and moderate severity; impaired liver function of mild and moderate severity; alcoholism; epilepsy; diseases brain; children over 3 years and adolescents under 18 years (due to the presence of ethanol in the drug), elderly patients.

Pregnancy and lactation:

Controlled studies of the use of etoposide in pregnant women have not been conducted. Studies on animals have shown embryotoxic, teratogenic and mutagenic effects of etoposide.Therefore, pregnant women should not prescribe Etoposide-Ebove®. It is not known whether the etoposide in breast milk, so the use of the drug during lactation (breastfeeding) is contraindicated or to avoid the toxic effect of the drug Etoposide-Ebove® on the baby, during the period of treatment should stop breastfeeding.

Dosing and Administration:

Intravenously.

The preparation Etoposide-Ebove® can It can be used both in monotherapy and in combination with other antitumor drugs. Dose and Scheme applications preparation is selected individually (with combination therapy when choosing doses preparation Etoposide-Ebene ® should take into account the myelosuppressive effect of other drugs, and act previous radiation therapy and chemotherapy).

Preparation of the solution for intravenous administration

Before intravenous administration, the drug Etoposide-Ebene ® diluted with 250 ml of 0.9% sodium chloride solution or 5% dextrose solution to a final concentration of 0.2-0.4 mg / ml. Do not allow contact with buffered aqueous solutions with pH above 8, since it is possible to form an insoluble precipitate.The prepared drug solution should be clear and should not contain undissolved particles. A solution with signs of precipitation is subject to destruction. To prepare the drug solution Only recommended solvents should be used. Do not apply the drug undiluted!

Etoposide-Ebene ® is administered by intravenous infusion for 30-60 minutes.

Adults and children over 3 years old A drug Etoposide-Ebene ® apply in a dose of 50-100 mg / m² per day for 5 consecutive days. Repeat the cycle no earlier than 3-4 weeks. Or, the preparation Etoposide-Ebove® is applied at 120-150 mg / m for 1, 3 and 5 days.

Repeated courses are held only after the normalization of peripheral blood.

Recommendations for dose adjustment of etoposide

Dose etoposide should be correct from account for myelosuppressive action of other drugs used in combination, or taking into account the effects of preliminary ray therapy / chemotherapy, which can reduce the reserve of bone marrow. With hematological disorders (neutrophil count <1500 cells / μl and / or platelet count <100,000 cells / μl), except for myelosuppression, caused by oncological disease, the next course is postponed until the laboratory indicators are restored.

Elderly patients Correction of the dose is not required.

Patients with impaired renal function

In patients with mild and moderate renal dysfunction (with creatinine clearance (CK) of 15-50 ml / minute), but with preserved liver function dose preparation Etoposide-Ebweve® is recommended to reduce on 25%. With SC less than 15 ml / min, application etoposide contraindicated (due to lack of clinical data).

Patients with impaired hepatic function

Currently, there is insufficient data to develop recommendations for dose adjustment for patients with impaired liver function of the lung or moderate severity. Do not use Etoposide-Ebove® for patients with severe liver dysfunction.

Side effects:

According to the World Health Organization (WHO) undesirable phenomena are classified according to their frequency of development as follows: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1/10000, <1/1000) and very rarely (<1/10000), including individual messages, the frequency is unknown (can not be calculated from available data).

On the part of the blood and lymphatic system Often: myelosuppression (with possible development of lethal outcome), leukopenia, thrombocytopenia, neutropenia, anemia.

The maximum decrease in the number of granulocytes and thrombocytes (nadir) is usually observed on 10-14 days after intravenous administration of the drug. Recovery of peripheral blood values occurs usually on the 20th day after the administration of the standard dose.

From the nervous system often: dizziness; infrequently: peripheral Neuropathy; rarely: convulsions, inflammation optic nerve, transient cortical blindness, neurotoxicity (including drowsiness, increased fatigue, depression of consciousness), hyperkinesia, akinesia.

From the side of the cardiovascular system

often: in 1-2% of patients there is a temporary decrease in blood pressure (BP) due to rapid intravenous administration of the drug, not associated with cardiotoxicity and changes on electrocardiogram, which It is restored at the termination of introduction of a preparation and introduction of a liquid or other supporting therapy.

Renewal infusion recommended at a lower speed. Violation of the rhythm of the heart (arrhythmia), myocardial infarction; rarely: increase of arterial pressure, "tides" of blood to the face, phlebitis.

From the respiratory system rarely: cough, bronchospasm, laryngospasm, cyanosis, apnea, interstitial pneumonitis, pulmonary fibrosis, pneumonia.

From the digestive system

Often: nausea, vomiting occur in about 30-40 % patients, are of moderate nature and usually do not require withdrawal of the drug (to control these side effects it is recommended to apply antiemetics drugs), anorexia, pain in the abdomen; often: mucositis (including stomatitis (inflammation of the oral mucosa), esophagitis (inflammation of the mucosa of the esophagus), diarrhea; rarely: dysphagia (difficulty swallowing), dysgeusia (perversion taste), constipation, hepatotoxicity, increased activity of "hepatic" tranaminases, alkaline phosphatase, a violation of liver function.

From the genitourinary system is very rare: impaired renal function, hypomenorrhea, amenorrhoea, anovulatory menstrual cycle, decreased fertility.

From the skin and skin appendages

Often: reversible alopecia (occurs in 66% of cases), sometimes complete baldness, skin pigmentation; often: rash, itchy skin, hives, swelling of the face, tongue, increased sweating; rarely: malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), relapse of radiation dermatitis.

Allergic reactions often: Anaphylactic reactions (chills, "tides" of blood to the face, tachycardia, dyspnea, bronchospasm, lowering of blood pressure), with possible

development of lethal outcome. These reactions usually occur during or immediately after the administration of etoposide. It is necessary to immediately stop the infusion of the drug, start carrying out anti-shock and symptomatic therapy (administration of glucocorticosteroids, antihistamines). Dysfunction at the injection site often: extravasation (including local toxic effect on soft tissues, edema, pain, cellulitis (inflammation of subcutaneous fat), necrosis of surrounding tissues), phlebitis.

Other

often: acute leukemia. rarely: fever, sepsis, metabolic acidosis, hyperuricemia;

rarely: syndrome of tumor disintegration (sometimes leading to death).

Overdose:

Intravenous injection of the drug in a total dose of 2.4-3.5 g / m2 for 3 days led to the development of severe mucositis and myelotoxicity. Also reported about development of metabolic acidosis and hepatotoxicity when doses are applied preparation higher recommended.

Treatment: held symptomatic therapy. The specific antidote is not known. It is necessary to monitor vital body functions.

Interaction:

Etoposide can potentiate cytotoxic and myelosuppressive effects of other drugs (eg, cyclosporine), radiation therapy. Antineoplastic act etoposide increases with simultaneous use with cisplatin, however, it should be borne in mind that in patients, before who received treatment with cisplatin, excretion of etoposide may be impaired. At simultaneous application with cisplatin decreases the clearance of etoposide.

When used simultaneously with phenytoin, the clearance of etoposide increases and its efficiency.

Enhances action of indirect anticoagulants (the International Normalized Ratio (INR) is increasing).

Phenylbutazone, sodium salicylate and salicylic acid may affect the binding of etoposide to plasma proteins.

It is possible to develop cross-resistance between anthracyclines and etoposide.

Pharmaceutically incompatible with solutions having alkaline values pH (more than 8).

In connection with the immunosuppressive effect of the drug and the possibility of developing a serious infection, in rare cases with the development of a lethal outcome, it is contraindicated during chemotherapy to apply live vaccines. Vaccination should be carried out 3 months after the completion of therapy.

Special instructions:

Application preparation Etoposide-Ebene ® must be implemented under observation qualified doctor, experienced work with antineoplastic chemotherapeutic preparations. A drug Etoposide-Ebewe ® can be used both in monotherapy, and in combination with other antineoplastic preparations. The dose and scheme of the drug is selected individually. AT the case combination therapy should be considered cumulative myelosuppressive effect of all drugs included in the treatment regimen. Before applying preparation Etoposide-Ebene ®, the physician should assess the benefit / risk ratio for each patient, the risk of side effects. Most adverse reactions are reversible in the early detection. When occurrence of severe reactions, the dose of the drug should be reduced or discontinued and appropriate treatment initiated. Renewal of therapy with Etoposide-Ebove ® must be conducted with caution and under close supervision of the physician regarding the possible recurrence of toxicity.

A drug Etoposide-Ebene ® Concentrate for solution for infusion should be administered intravenously slowly (Usually within 30 to 60 minutes), since the rapid introduction may develop severe hypotension.

When working with the drug Etoposide-Ebove ® care must be taken. Dilution preparation should be handled by trained personnel in aseptic conditions in a specially designated room. It is necessary to take all measures to prevent contact with skin etoposide solution and mucous membranes, in particular the use of protective clothing (gown, cap, mask, goggles and disposable gloves). Etoposide After contact with skin or mucous membranes should be carefully washed with soap and water or (eyes) with plenty of water.

Care should be taken with regard to possible extravasation of the drug Etoposide-Ebene ®, because it has a pronounced local irritant effect and in some cases may lead to necrosis of surrounding tissues. In the case of extravasation or when it is suspected (burning sensation), the drug should be stopped immediately, around the place of extravasation, subcutaneously enter hydrocortisone and apply 1% hydrocortisone ointment (until the redness disappeared) under the dry bandage for 24 hours. The remaining portion of the drug should be injected into another vein. Around the affected area, subcutaneous injections hydrocortisone.

When using the drug Etoposide-Ebene ® the development of severe myelosuppression (sometimes with the development of a lethal outcome) and, as a consequence, the occurrence of infection or bleeding. Suppression of bone marrow function is a dose-limiting action preparation Etoposide-Ebene.

It is necessary to conduct a regularly deployed clinical blood test before treatment, in breaks and before each subsequent course of the drug Etoposide-Ebene ®. If before the start therapy with Etoposide- Ebewe ® radiotherapy and / or chemotherapy, it follows that observe a sufficient interval between these two types of treatment, to ensure recovery functions of the bone marrow. When decrease in the number of platelets below 100,000 cells / μl and / or absolute number of neutrophils to 1500 cells / μl (excluding myelosuppression caused by oncological disease), therapy with Etoposide-Ebene ® is necessary stop before full restoration of clinical blood counts.

In the case of severe phenomena hematological toxicity (a decrease in the number of neutrophils less than 500 / mm3 for more than 5 days or in combination with fever / infection, platelets less than 25,000 / mm3), other manifestations toxicity levels III and IV, in case of a decrease in SC <50 ml / min should further adjust dose of the drug.

The emergence of acute leukemia, which can occur with or without mild asthma with indrama, has been described in patients who underwent chemotherapy etoposide. To date, neither total risk nor predisposing factors, associated with the development of secondary leukemia. As a risk factor, a total dose of etoposide and chemotherapy regimens were proposed that were not clearly defined.

In patients with secondary leukemia, who received epipodophyllotaboutxins, were identified 11q23 chromosomal abnormalities. Also data chromosomal abnormalities were detected in patients with secondary leukemia after chemotherapy that did not contain epipodophyllotoxins, and with leukemia occurring de novo.

The average period of leukemia after chemotherapy is about 32 months. Patients with low serum albumin concentrations have an increased risk of etoposide-related toxicity.

In patients with impaired liver and kidney function it is necessary to regularly monitor it because of the increased risk of accumulation of the drug. Care must be taken when using the drug in patients with hepatic or renal insufficiency. Bacterial infections should be treated before starting therapy with the drug Etoposide-Ebene ®.

When emergence of anaphylactic reaction Etoposide-Ebene ® it is necessary to stop and start treatment with glucocorticosteroids and / or antihistamine preparations.

Men's and women reproductive age during therapy with Etoposide-Ebove ® and at least 6 months after the end of treatment should use reliable methods of contraception. Since in the process of treatment possible the development of irreversible infertility, men should consider the possibility of preserving sperm in the bank before starting treatment.

Before use, a visual assessment of the solution should be carried out to identify solids or discoloration. A drug Etoposide-Ebene ® Concentrate for solution for infusion as a solvent contains 260.6 mg / ml of ethyl alcohol, which can be a risk factor for patients with liver disease, alcoholism, epilepsy, and also for children.

Safety and efficacy of Etoposide-Ebewe ® children have not been studied.

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

Because of the likelihood of side effects, such as dizziness, drowsiness, oppression of consciousness, transient cortical blindness, and taking into account the content in the preparation of ethanol, one should refrain from engaging in potentially dangerous activities, requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:Solution in vials.

Packaging:

The solution in brown glass vials at 50 mg / 2.5 ml, 100 mg / 5 ml, 200 mg / 10 ml and 400 mg / 20 ml. 1 bottle per pack together with instructions for use.

Storage conditions:Store in a dark place at a temperature of 15 ° to 25 ° C. Keep out of the reach of children.

Shelf life:

3 years. The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015174 / 01

Date of registration:09.06.2008

The owner of the registration certificate:Ebewe Pharma Gesmb.b. Nfg. KGEbewe Pharma Gesmb.b. Nfg. KG Austria

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp11.10.2015

Illustrated instructions

Instructions

Etoposide-Ebove® (Etoposid-Ebewe®)