Etoposide-Teva, 20 mg/ml 10 ml

Pharmacotherapeutic group:antitumor agent, alkaloid.

ATX code: L01CB01

Pharmacological properties

Pharmacodynamics

The etoposide is a semi-synthetic derivative of podophyllotoxin. The mechanism of action is associated with inhibition of topoisomerase II. Etoposide has cytotoxic effect due to DNA damage. The drug blocks mitosis, causing cell death in the G₂ phase and the late S phase of the mitotic cycle. High concentrations of the drug cause cell lysis in the premitotic phase. Etoposide also inhibits nucleotide penetration through the plasma membrane, which prevents DNA synthesis and repair.

Pharmacokinetics

. After intravenous administration, the maximum plasma concentration (C_max) is 30 µg/mL and is reached after 1-2 hours. The drug is detected in pleural fluid, saliva, liver tissue, spleen, kidneys, brain tissue. Values of etoposide concentration in cerebrospinal fluid vary from undetectable values to 5% of blood plasma concentration. Etoposide penetrates through the blood-brain and placental barriers. Binding with blood plasma proteins is about 97%. Total clearance of the drug is 16-36 ml/min/m².

Atoposide is actively metabolized in the body. Excretion occurs in a biphasic manner. In adults with normal renal and hepatic function, the elimination half-life (T_1/2) averages 0.6-2 hours in the initial phase and 5.3-11 hours in the terminal phase. It is excreted by the kidneys – 40-60% unchanged and 15% as metabolites within 48-72 hours. 2-16% is excreted by the intestine within 72 hours.

Indications

Active ingredient

Composition

How to take, the dosage

The drug Etoposide-Teva should only be used under the close supervision of a physician experienced in cytotoxic drug therapy. Special Instructions

Etoposide should be given slowly slowly over 30-60 minutes intravenously, as you can get very hypotensive if given quickly.

The doses are 50-100 mg/m2 per day for 5 consecutive days, with cycles repeated at least 3-4 weeks later.

Or an administration regimen of 100-120 mg/m2 every other day on days 1, 3, and 5, with courses to be repeated at the earliest after 3-4 weeks.

The dose of etoposide should be adjusted for the myelosuppressive effects of other drugs used in combination or for the effects of prior radiation therapy/chemotherapy.

Elderly patients

Dose adjustment is not necessary.

Patients with impaired renal function

In patients with mild to moderate impaired renal function (creatinine clearance 15-50 ml/min), the dose of etoposide should be reduced by 25%. In creatinine clearance <15 ml/min the use of etoposide is contraindicated. Repeated courses are carried out only after normalization of peripheral blood parameters.

Patients with hepatic impairment

There are currently insufficient data on dosing regimen adjustment of the drug in patients with mild to moderate hepatic impairment. The drug should not be used in patients with severe hepatic impairment.

Preparation of solution for intravenous administration

Dilute Etoposide-Teva 20 mg/ml immediately before administration with 0.9% sodium chloride solution or 5% dextrose solution to a final concentration of 0.2-0.4 mg/ml.

Before use, the solution should be visually assessed for solids or color changes. The prepared solution should be clear and contain no undissolved particles. Do not allow in contact with buffered aqueous solutions with pH > 8 as insoluble precipitate may form.

When handling the drug, care should be taken to prevent etoposide contact with the skin and mucous membranes, in particular protective clothing (gown, cap, mask, glasses and disposable gloves). If etoposide comes into contact with the skin or mucous membranes, wash them thoroughly with soap and water.

Interaction

Atoposide must not be mixed with other drugs in the same solution.

Pharmaceutically incompatible with solutions having alkaline pH values.

Etoposide may potentiate the cytotoxic and myelosuppressive effects of other drugs (e.g., cyclosporine), radiation therapy.

The antitumor effects of etoposide are enhanced when used in combination with cisplatin (note that in patients who were previously treated with cisplatin excretion of etoposide may be impaired).

Concomitant use with cisplatin decreases etoposide clearance.

Concomitant use with phenytoin increases clearance of etoposide and decreases its effectiveness.

Etoposide may decrease the effectiveness of antiepileptic drugs when used concomitantly.

Atoposide increases the effect of indirect anticoagulants (increases the International Normalized Ratio (INR)).

Phenylbutazone, sodium salicylate and salicylic acid may affect the binding of etoposide to plasma proteins. Cross-resistance between anthracyclines and etoposide may develop.

Because of the immunosuppressive effect of the drug and the possibility of severe infection, live vaccines should not be used during chemotherapy (see section “Contraindications”). The use of yellow fever vaccine increases the risk of systemic post-vaccination complications with lethal outcome. Vaccination should be performed 3 months after completion of therapy.

The occurrence of acute leukemia has been reported in patients receiving etoposide in combination with other anticancer drugs (bleomycin, cisplatin, ifosfamide, methotrexate).

Special Instructions

The drug Etoposide-Teva should only be used under the constant supervision of a physician experienced in cytotoxic drug therapy. Before using the drug, the physician should evaluate the benefit/risk ratio for each patient and the risk of side effects. Most adverse reactions are reversible if detected early. If severe reactions occur, the dose of the drug should be reduced or its use should be discontinued and appropriate treatment should be started. Resumption of therapy with the drug should be done with caution and under close medical supervision for possible recurrence of toxicity.

The rules for handling cytotoxic drugs should be followed when handling etoposide-Teva. If contact with skin or mucous membranes is made, the affected areas should be washed immediately with soap and water.

Myelosuppression

The use of the drug may lead to severe myelosuppression (sometimes with lethal outcome) and, consequently, to infection or bleeding.

The suppression of bone marrow function is a dose-limiting effect of etoposide-Teva. Routine gross clinical blood counts should be performed before starting treatment, at intervals and before each subsequent course of the drug. If radiotherapy and/or chemotherapy have been given prior to starting Etoposide-Teva therapy, a sufficient interval between these two treatments should be observed to ensure recovery of bone marrow function. The choice of dosing regimen should be made taking into account the severity of bone marrow function inhibition.

In case of platelet count decreasing below 100000 cells/μL and/or absolute neutrophil count below 1500 cells/μL (except for myelosuppression due to cancer) the therapy with etoposide should be stopped until complete recovery of blood parameters.

In case of severe hematological toxicity (decrease of neutrophil count below 500/mm3 for more than 5 days or in combination with fever/infection, decrease of platelet count below 25000/mm3), other manifestations of grade III and IV toxicity, further doses of the drug should be adjusted if CK < 50 ml/min decrease.

Secondary leukemia

The occurrence of acute leukemia, which may occur with or without myelodysplastic syndrome, has been described in patients treated with etoposide chemotherapy. To date, neither the cumulative risk nor the predisposing factors associated with the development of secondary leukemia are known. The total dose of etoposide and chemotherapy regimens have been suggested as one risk factor and have not been clearly defined. Patients with emerging secondary leukemia who received epipodophyllotoxins were found to have 11q23 chromosomal abnormalities. These chromosomal abnormalities were also detected in patients with secondary leukemia after chemotherapy not containing epipodophyllotoxins and in leukemia occurring de novo. The average period of leukemia occurrence after chemotherapy is about 32 months.

Hypersensitivity

Possible anaphylactic reaction (chills, fever, tachycardia, bronchospasm, shortness of breath, arterial hypotension) that can be fatal.

In case of anaphylactic reactions the use of Etoposide-Teva should be discontinued and treatment with vasopressor drugs, glucocorticosteroids and/or antihistamines should be started.

Arterial hypotension

Atoposide should be administered intravenously slowly (usually within 30 to 60 minutes) because severe arterial hypotension may develop if given rapidly.

Low serum albumin concentration

Patients with low serum albumin concentration have an increased risk of etoposide-related toxicity.

Reactions at the site of administration

Caution should be exercised regarding possible extravasation of the drug as it has a marked local irritant effect and in some cases may lead to necrosis of the surrounding tissue.

In the event of signs of extravasation (burning sensation), the Etoposide-Teva infusion should be stopped immediately. The remaining drug should be injected into another vein. Subcutaneous injections of hydrocortisone are given around the affected area and 1% hydrocortisone ointment is applied under a dry dressing (until skin hyperemia has disappeared – usually for 24 hours).

Kidney and hepatic impairment

Patients with mild to moderate hepatic and renal impairment should use the drug with caution, dosing regimens should be adjusted and hepatic and renal function should be monitored regularly.

Tumor Lysis Syndrome

Tumor lysis syndrome (sometimes fatal) has been reported when etoposide is used in combination with other chemotherapeutic agents.

Influence on fertility

Males and women of childbearing age should use reliable contraception during treatment with etoposide-Teva and for at least 6 months after treatment ends. Because the drug may decrease fertility in men, sperm preservation should be considered before starting treatment.

Ethyl alcohol

. Etoposide-Teva solution for intravenous administration contains ethyl alcohol as an excipient, which may be a risk factor for patients with liver disease, alcoholism and epilepsy, as well as for children. The drug contains polysorbate-80. In premature infants, the use of injectable vitamin E containing polysorbate-80 has been reported to result in hepatic and renal failure, impaired lung function, thrombocytopenia, and ascites.

Influence on ability to drive vehicles, mechanisms

. Because of the possibility of side effects such as dizziness, weakness, somnolence, nausea, vomiting, transient cortical blindness, hypotension, and also due to the ethanol content of the drug, patients should not participate in potentially dangerous activities which require high concentration and quick psychomotor reactions.

Synopsis

Contraindications

Side effects

The incidence of adverse reactions is rated as follows: very common (≥1/10), common (≥1/100 to ˂1/10), infrequent (≥1/1000 to ˂1/100), rare (≥1/10000 to ˂1/1000), very rare (˂1/10000), frequency unknown (cannot be estimated from available data).

Infections and invasions: frequently, infections.

Benign and malignant neoplasms: frequently, acute leukemia; frequency unknown, acute promyelocytic leukemia.

Anemia, leukopenia, neutropenia, thrombocytopenia, myelosuppression (with possible lethal outcome).

Intrinsic system disorders: frequent – anaphylactic reactions; frequency unknown – angioedema, bronchospasm.

Metabolic disorders: frequency unknown – tumor lysis syndrome; rarely – metabolic acidosis, hyperuricemia.

Nervous system disorders: frequent – dizziness; infrequent – peripheral neuropathy; rare – transient cortical blindness, neurotoxicity (including drowsiness and increased fatigue), optic neuritis, seizures.

Cardiac side: frequent – arrhythmia, myocardial infarction.

vascular disorders: frequent – increase in blood pressure, transient decrease in blood pressure due to rapid intravenous infusion of the drug; infrequent – hemorrhages; rarely – flushing of the face.

In the respiratory system: frequently – interstitial pneumonitis, laryngospasm, cyanosis, apnea, pulmonary fibrosis; frequency unknown – bronchospasm.

Digestive system disorders: very common – abdominal pain, anorexia, constipation, nausea, vomiting; common – diarrhea, mucositis (including stomatitis and esophagitis); rare – dysphagia (difficulty swallowing), dysgeusia (perversion of taste).

Hepatic and biliary tract disorders: very often – increased liver transaminases activity, bilirubin, hepatotoxicity.

Skin and subcutaneous tissue: very common – alopecia, pigmentation; common – rash, pruritus, urticaria; rarely – Stevens-Johnson syndrome, toxic epidermal necrolysis, relapse of radiation dermatitis.

Urogenital system disorders: frequency unknown – decreased fertility.

General disorders:very common – asthenia, weakness; common – phlebitis, extravasation; rare – fever.

Overdose

Pregnancy use

Women of childbearing potential/ contraception in men and women

Women of childbearing potential should use appropriate contraception to avoid pregnancy while using etoposide. Men and women of childbearing age should use reliable contraceptive methods during treatment with etoposide-Teva and for at least 6 months after treatment ends.

Pregnancy

There have been no controlled studies of etoposide in pregnant women. Animal studies have shown embryotoxic, teratogenic and mutagenic effects of etoposide. Therefore, pregnant women should not be prescribed the drug.

Breastfeeding

Atoposide penetrates into breast milk.

Hence the use of the drug during breastfeeding is contraindicated or to avoid toxic effects of the drug on the infant, breastfeeding should be stopped during the treatment period.

Fertility

Because the drug may decrease fertility in men, sperm preservation should be considered before starting treatment.