Etoposide Teva

Etoposide.

Each ml contains: Etoposide 20 mg.

Pharmacology: Pharmacodynamics: Action: Etoposide is a semisynthetic podophyllotoxin-derivative antineoplastic agent.
Etoposide has cytostatic action which prevents the cells from entering mitosis or destroys them in the premitotic phase. The exact mechanism of action of etoposide is not known, but the drug appears to produce its cytotoxic effects by damaging DNA and thereby inhibiting or altering DNA synthesis. Etoposide appears to be cell-cycle dependent and cycle-phase specific, inducing G2-phase arrest and preferentially killing cells in the G2 and late S phases.
Pharmacokinetics: Absorption and Distribution: On intravenous administration, the disposition of etoposide is best described as a biphasic process with a distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4-11 hours. Total body clearance values range from 33-48 ml/min or 16-36 ml/min and, like the terminal elimination half-life, are independent of dose over a range 100-600 mg/m². Etoposide is distributed minimally into pleural fluid and has been detected in the saliva, liver, spleen, kidney, myometrium, healthy brain tissue, and brain tumor tissue. Limited data suggest that distribution of the drug into bile is minimal. It is not known if etoposide is distributed into milk. The drug apparently crosses the placenta in animals. Etoposide apparently does not readily penetrate the CNS (although CSF etoposide concentrations generally range from undetectable to less than 5% of concurrent plasma concentrations during the initial 24 hours after IV administration of the drug, even after administration of very high doses). In vitro, etoposide is highly protein bound (97%) to human plasma proteins.
Metabolism and Excretion: The metabolic fate of etoposide has not been completely determined. Etoposide appears to be metabolized principally to produce the resulting hydroxy acid; this metabolite appears to be pharmacologically inactive. Other metabolites include glucuronide and sulfate conjugates. In vitro, they have minimal cytotoxic activity. Etoposide is cleared by both renal and nonrenal processes, i.e. metabolism and biliary excretion. The effect of renal disease on plasma etoposide clearance is not known. Biliary excretion appears to be a minor route of etoposide elimination. Only 6% or less of an intravenous dose is recovered in the bile as etoposide. Metabolism accounts for most of the nonrenal clearance of etoposide. The major urinary metabolite of etoposide in adults and children is the hydroxy acid. Glucuronide and/or sulfate conjugates of etoposide are excreted in urine and represent 5-22% of the dose. In adults, the total body clearance of etoposide is correlated with creatinine clearance, serum albumin concentration and nonrenal clearance. In children, elevated serum SGPT levels are associated with reduced total body clearance of the drug. Prior use of cisplatin may also result in a decrease of etoposide total body clearance in children. In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7-10 ml/min/m² or about 35% of the total body clearance over a dose range of 80 to 600 mg/m².

Etoposide is indicated in the management of: Refractory Testicular Tumors: Etoposide for Injection Concentrate may be used as combination therapy with other approved chemotherapeutic agents in patients with refractory testicular tumors who have already received appropriate surgical, chemotherapeutic and radiotherapeutic therapy.
Small Cell Lung Cancer: Etoposide for Injection Concentrate may be used in combination with other approved chemotherapeutic agents as first-line treatment in patients with small cell lung cancer.
Hodgkin's Disease: Malignant (non-Hodgkin's) lymphomas, especially of the histiocytic variety, acute non-lymphocytic leukemia.

Parenteral drug products should be inspected visually for particulate matter and discoloration, prior to administration, whenever solution and container permit. Etoposide should be given only by slow intravenous infusion (usually over a 30- to 60-minute period), since hypotension has been reported as a possible side effect of rapid intravenous injection. The dosage should be modified to take into account the myelosuppressive effects of other drugs in combined drug therapy, or the effects of prior x-ray therapy.
Refractory Testicular Tumors, Hodgkin's Disease, Malignant (non-Hodgkin's) Lymphomas Especially of the Histiocytic Variety, Acute Non-Lymphocytic Leukemia: The usual dose of Etoposide for Injection Concentrate in combination with other approved chemotherapeutic agents, ranges from 50-1 00 mg/m²/day on days 1 through 5 to 100 mg/m²/day on days 1, 3 and 5.
Small Cell Lung Cancer: The dose of Etoposide for Injection Concentrate, in combination with other approved chemotherapeutic drugs, ranges from 35 mg/m²/day for 4 days to 50 mg/m²/day for 5 days. Chemotherapy courses are repeated at 3- to 4-week intervals after adequate recovery from any toxicity.
Use in Pediatrics: Safety and efficacy for use in children have not been established.

Manifestations: Acute complications related to etoposide's hematotoxicity.
Treatment: There is no known antidote and therefore symptomatic measures should be taken to sustain the patient through any period of toxicity that might occur. Patient's renal and hepatic functions should be monitored for 3-4 weeks in case of delayed toxicity.

Etoposide is contraindicated in: Patients who have demonstrated a previous hypersensitivity to the preparation; Patients who show evidence of severe hepatic dysfunction.
Etoposide must not be administered by intra-cavitary injection.

Etoposide should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Severe myelosuppression with resulting infection or bleeding may occur; therefore, patients being treated with etoposide must be frequently observed for myelosuppression both during and after therapy. Dose-limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy. Therefore, the following laboratory studies should be obtained at the start of therapy and prior to each subsequent dose of etoposide: platelet count, hemoglobin and differential white blood cell count. The occurrence of a platelet count below 50,000/mm³ or an absolute neutrophil count below 500/mm³ is an indication to withhold further therapy until blood counts have sufficiently recovered. Etoposide should be given only by slow intravenous infusion (usually over a 30- to 60-minute period), since hypotension has been reported as a possible side effect of rapid intravenous injection. Anaphylaxis manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension may occur (see Adverse Reactions). Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of presser agents, corticosteroids, antihistamines or volume expanders, at the discretion of the physician.
Mutagenicity: The mutagenic and genotoxic potential of etoposide have been established in mammalian cells. Etoposide caused aberrations in chromosome number and structure in embryonic murine cells and human hematopoietic cells; gene mutations in Chinese hamster ovary cells and DNA damage by strand breakage and DNA-protein cross-links in mouse leukemia cells.
Carcinogenicity: Carcinogenicity tests with etoposide have not been conducted in laboratory animals. Etoposide should be considered a potential carcinogen in humans.
Teratogenicity: Etoposide is teratogenic and embryotoxic in rats and mice at doses of 1% to 3% of the recommended clinical dose based on body surface area.

Etoposide should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents.
Preparation for Intravenous Administration: Etoposide for Injection Concentrate may be diluted with either 5% Dextrose Injection, or 0.9% Sodium Chloride Injection, to give a final concentration of 0.2 mg/ml. The dilutions of Etoposide For Injection Concentrate in 5% Dextrose Injection, or 0.9% Sodium Chloride Injection are stable for 120 hours.
Notes: Etoposide should not be given by rapid intravenous injection.
Etoposide should not be physically mixed with any other drug.
Any solution showing signs of precipitation should be discarded.
Myelosuppression: Patients being treated with Etoposide must be frequently observed for myelosuppression, both during and after therapy. Dose-limiting bone-marrow suppression is the most significant toxicity associated with Etoposide therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent dose of Etoposide: platelet count, hemoglobin, white blood cell count and differential. The occurrence of a platelet count below 50,000/mm³ or an absolute neutrophil count below 500/mm³ is an indication to withhold further therapy until blood counts have sufficiently recovered.
Anaphylaxis: Anaphylaxis manifested by chills, fever, tachycardia, bronchospasm, dyspnea and hypotension may occur (0.7-2%). The reactions usually respond to cessation of infusion and institution of appropriate therapy. Refer to Management of Acute Hypersensitivity Reactions.
Effects on Mental Alertness: Etoposide injection has no effect on the ability to drive or use machines.

Use in Pregnancy: Etoposide can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus. Women of childbearing potential should not be started on etoposide until pregnancy has been ruled out and should be fully counseled on the serious risk to the fetus should they become pregnant while undergoing treatment.
Use in Breastfeeding: It is not known whether this drug is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.

Most adverse reactions are reversible if detected early. If severe reactions occur, dosage should be reduced or discontinued and corrective measures should be instituted (see Precautions).
Hematopoietic System: Severe myelosuppression with resulting infection or bleeding may occur; therefore, patients being treated with etoposide must be frequently observed for myelosuppression both during and after therapy. Dose-limiting bone-marrow suppression is the most significant toxicity associated with etoposide therapy. Therefore, the following laboratory studies should be obtained at the start of therapy and prior to each subsequent dose of etoposide: platelet count, hemoglobin and differential white blood cell count. The occurrence of a platelet count below 50,000/mm³ or an absolute neutrophil count below 500/mm³ is an indication to withhold further therapy until blood counts have sufficiently recovered.
Myelosuppression is dose-related and dose-limiting with granulocyte nadirs occurring 7-14 days after drug administration and platelet nadirs occurring 9-16 days after drug administration. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported. The frequency of hematopoietic system toxicities is as follows: Leukopenia: < 4,000 WBC/mm³ (60-91%), < 1,000 WBC/mm³ (3-17%).
Thrombocytopenia: < 100,000 platelets/mm³ (22-41%), < 50,000 platelets/mm³ (1-20%).
Anemia: (< 33%).
The occurrence of acute leukaemia, which can occur with or without a preleukemic phase, has been reported rarely in patients treated with etoposide in association with other antineoplastic drugs such as bleomycin, cisplatin, ifosfamide and methotrexate.
Hypotension: Etoposide should be given only by slow intravenous infusion (usually over a 30- to 60-minute period), since hypotension has been reported as a possible side effect of rapid intravenous injection.
Gastrointestinal System: Nausea and vomiting are the major gastrointestinal toxicities. The severity of such nausea and vomiting is generally mild to moderate, with treatment discontinuation required in 1% of patients. Nausea and vomiting can usually be controlled with standard antiemetic therapy. The frequency of gastrointestinal toxicities is as follows: nausea/vomiting (31-43%), anorexia (10-13%), diarrhea (1-13%), abdominal pain (<2%), stomatitis (1-6%), hepatic toxicity (<3%), dysphagia, constipation.
Cardiovascular System: Transient hypotension following rapid intravenous administration has been reported in 1% to 2% of patients. It has not been associated with cardiac toxicity or electrocardiographic changes. No delayed hypotension has been noted. To prevent this rare occurrence, it is recommended that etoposide be administered by slow intravenous infusion over a 30- to 60-minute period. If hypotension occurs, it usually responds to cessation of the infusion and administration of fluids or other supportive therapy as appropriate. When restarting the infusion, a slower administration rate should be used.
Hypersensitivity Reactions (see Warnings): Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnea and hypotension have been reported to occur in 0.7% to 2% of patients receiving intravenous etoposide. These reactions have usually responded promptly to the cessation of the infusion and administration of presser agents, corticosteroids, antihistamines or volume expanders as appropriate. One fatal acute reaction associated with bronchospasm has been reported. Hypertension and flushing have also been reported. Blood pressure usually normalizes within a few hours after cessation of the infusion.
Skin: Reversible alopecia, sometimes progressing to total baldness was observed in up to 66% of patients.
Dental Effects: The bone marrow depressant effects of etoposide may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Etoposide may also cause stomatitis, which may be associated with considerable discomfort.
Other Adverse Reactions: The following adverse reactions have been infrequently reported: aftertaste, rash, fever, abnormal pigmentation, pruritus, abdominal pain, constipation, dysphagia, transient cortical blindness and a single report of radiation recall dermatitis. There are reports of hepatic toxicity in patients receiving higher doses of etoposide than those recommended. Metabolic acidosis also has been reported in patients receiving these higher doses.

The occurrence of acute leukaemia, which can occur with or without a preleukemic phase, has been reported rarely in patients treated with etoposide in association with other antineoplastic drugs such as bleomycin, cisplatin, ifosfamide and methotrexate.
Note: The ready-for-use IV solution should not be physically mixed with any other drug.
Etoposide/Vaccines, killed virus: Because normal defense mechanisms may be suppressed by etoposide therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year.
Etoposide/Vaccines, live virus: Because normal defense mechanisms may be suppressed by etoposide therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the etoposide therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus until at least 3 months after their last chemotherapy. In addition, immunization with oral polio-virus vaccine should be postponed in persons in close contact with the patient, especially family members.

Pharmaceutical Precautions: Incompatibilities: The ready-for-use IV solution should not be physically mixed with any other drug.
Dilution of Etoposide for Injection Concentrate: Etoposide for Injection Concentrate may be diluted with either 5% Dextrose Injection, or 0.9% Sodium Chloride Injection, to give a final concentration of 0.2 mg/ml. The dilutions of Etoposide For Injection Concentrate in 5% Dextrose Injection, or 0.9% Sodium Chloride Injection are stable for 120 hours. Etoposide should not be physically mixed with any other drug. Any solution showing signs of precipitation should be discarded. (See also Dosage & Administration.)
Handling and Disposal: As with all cytotoxic preparations, special precautions should be taken for safe handling and disposal.
1. Only trained personnel should handle the drug. Pregnant women should not be involved in the handling process.
2. Handling should be performed in a designated area, ideally in a vertical laminar flow hood (Biological Safety Cabinet - Class II). The work surface should be covered with disposable plastic-backed absorbent paper.
3. Adequate protective clothing should be worn, i.e. PVC gloves, safety glasses, disposable gowns and masks. In the event of contact with the eyes, wash with copious amounts of water or saline.
4. Luer-Lock fittings should be used on all syringes and sets. The possible formation of aerosols may be reduced by using large bore needles and venting needles.
5. AII unused material, needles, syringes, vials and other items which have come into contact with cytotoxic drugs, should be segregated, placed in double sealed polyethylene bags and incinerated at 1000°c or more. Excreta should be similarly treated. Liquid waste may be flushed away with copious amounts of water.

The drug should be stored at room temperature, protected from light.
Etoposide for Injection concentrate 20 mg/ml is stable for at least 48 hours at room temperature following piercing of the rubber stopper. It is therefore suitable for multidose use. Etoposide for Injection Concentrate may be diluted with either 5% Dextrose Injection, or 0.9% Sodium Chloride Injection, to give a final concentration of 0.2 mg/ml. The dilutions of Etoposide For Injection Concentrate 20 mg/ml in 5% Dextrose Injection, or 0.9% Sodium Chloride Injection are stable for 120 hours at room temperature, protected from light.

Cytotoxic Chemotherapy

L01CB01 - etoposide ; Belongs to the class of plant alkaloids and other natural products, podophyllotoxin derivatives. Used in the treatment of cancer.

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