Sedol

Sedol

etoposide

Manufacturer:

Venus Remedies

Distributor:

Cosma Medical

Marketer:

Cosma Medical
Full Prescribing Info
Contents
Etoposide.
Description
Each ml contains: Etoposide 20 mg, benzyl alcohol 30 mg, polysorbate 80 80 mg, alcohol base 30.5% v/v, citric acid 2 mg, polyethylene glycol 300, 650 mg.
Action
Pharmacology: Pharmacodynamics: Etoposide is a semi synthetic derivative of podophyllotoxin used in the treatment of certain neoplastic disease.
Mechanism of Action/Effect: The exact mechanism of Etoposide's antineoplastic effect is unknown. Etoposide is a topoisomerase II inhibitor. It seems to act at the premitotic stage of cell division to inhibit DNA synthesis; it is cell cycle dependent and phase specific, with maximum effect on the S and G 2 phase of division.
Pharmacokinetics:
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 to 11 hours. Total body clearance values range from 33 to 48 mL/min or 16 to 36mL/min/m2 and, like the terminal elimination half-life, are independent of dose over a range 100-600 mg/m2. Over the same dose range, the areas under the plasma concentration vs. time curves (AUC) and the maximum plasma concentration (Cmax) values increase linearly with dose. Etoposide dose not accumulate in the plasma following daily administration of 100 mg/m2 for 4 to 5 days.
The mean volumes of distribution at steady fall in the range of 18 to 29 liters or 7 to 17 L/m2. Etoposide enters the CSF poorly. Although it is detectable in CSF and intracerebral tumors, the concentrations are lower than in extracerebral tumors and in plasma. Etoposide concentrations are higher in normal lung than in lung metastases and are similar in primary tumors and normal tissues of the myometrium. In vitro, Etoposide is highly protein bound (97%) to human plasma proteins. An inverse relationship between plasma albumin levels and Etoposide renal clearance is found in children. In a study determining the effect of other therapeutic agents on the in vitro binding of carbon-14 labeled Etoposide to human serum proteins, only phenylbutazone, sodium salicylate, and aspirin displaced protein-bound Etoposide at concentrations achieved in vivo.
Etoposide binding ratio correlates directly with serum albumin in patients with cancer and in normal volunteers. The unbound fraction of Etoposide significantly correlated with bilirubin in a population of cancer patients. 2,3 Data have suggested a significant inverse correlation between serum albumin concentration and free fraction of Etoposide.
Metabolism and Excretion: There is no evidence of a first-pass effect for Etoposide. For example, no correlation exists between the absolute oral bioavailability of Etoposide capsules and non renal clearance. No evidence exists for any other differences in Etoposide metabolism and excretion after administration of oral capsules as compared to intravenous infusion.
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 to 10 mL/min/m2 or about 35% of the total body clearance over a dose range of 80 to 600 mg/m2. Etoposide, therefore, is cleared by both renal and non renal processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma Etoposide clearance is not known.
Indications/Uses
SEDOL (Etoposide Injection USP) is indicated in the management of the following neoplasms: Refractory Testicular Tumors: Etoposide For Injection in combination therapy with other approved chemotherapeutic agents in patients with refractory testicular tumors who have already received appropriate surgical, chemotherapeutic, and radio therapeutic therapy.
Small Cell Lung Cancer: Etoposide For Injection and/or Capsules in combination with other cancer. Etoposide is indicated in approved chemotherapeutic agents as first line treatment in patients with small cell lung cancer.
Dosage/Direction for Use
The usual dose of SEDOL in testicular cancer in combination with other approved chemotherapeutic agents ranges from 50 to 100 mg/m2/day on days 1 through 5 to 100 mg/m2/day on days 1, 3, and 5.
In small cell lung cancer, the SEDOL 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.
Mode of Administration: Administration Precautions: As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of SEDOL. Skin reactions associated with accidental exposure to SEDOL may occur. The use of gloves is recommended. If SEDOL solution contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water.
Dosage adjustment: The dosage of etoposide should be adjusted taking into account the myelosuppressive effects of other drugs in combination, or the effects of prior radiation or chemotherapy which may have compromised bone marrow reserve, clinical effect and patient tolerance.
Use in patient with renal impairment: In patients with impaired renal function, the following initial dose modification should be considered based on measured creatinine clearance: see Table.

Click on icon to see table/diagram/image

Subsequent SEDOL dosing should be based on patient tolerance and clinical effect.
Data are not available in patients with creatinine clearances <15 mL/min and further dose reduction should be considered in these patients.
Preparation for Intravenous Administration: SEDOL For Injection must be diluted prior to use with either 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, to give a final concentration of 0.2 to 0.4 mg/mL. If solutions are prepared at concentrations above 0.4 mg/mL, precipitation may occur.
Hypotension following rapid intravenous administration has been reported, hence, it is recommended that the SEDOL solution be administered over a 30- to 60-minute period.
Overdosage
No proven antidotes have been established for Etoposide over dosage.
Contraindications
SEDOL (Etoposide Injection USP) is contraindicated in patients who have demonstrated a previous hypersensitivity to Etoposide or any component of the formulation.
Special Precautions
Patients being treated with SEDOL must be frequently observed for myelosuppression both during and after therapy. Myelosuppression resulting in death has been reported.
Dose-limiting bone marrow suppression is the most significant toxicity associated with SEDOL therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent cycle of SEDOL: Platelet count, hemoglobin, white blood cell count, therapy should be suspended if the platelet count is less than 50,000 mm3 or the absolute neutrophil count is less than 500 mm3.
Physicians should be aware of the possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension.
SEDOL (Etoposide Injection USP) is contraindicated in severe bone marrow failure not due to malignant disease and severe hepatic dysfunction.
Sedol may cause severe harm, it should only be administered under the supervision of qualified physician.
SEDOL contains benzyl alcohol therefore it is prohibited in children below 2 years old.
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. Etoposide can cause fetal harm when administered to a pregnant woman. Etoposide has been shown to be teratogenic in mice and rats. Women of childbearing potential should be advised to avoid becoming pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be warned of the potential hazard to the fetus. Patients with low serum albumin may be at high/increased risk for Etoposide associated toxicities.
Use in Children: Safety and effectiveness in pediatric patients have not been established.
Etoposide For Injection contains polysorbate 80. In premature infants, a life-threatening syndrome consisting of liver and renal failure, pulmonary deterioration, thrombocytopenia, and ascites has been associated with an injectable vitamin E product containing polysorbate 80. Anaphylactic reactions have been reported in pediatric patients.
Use In Pregnancy & Lactation
Pregnancy: Etoposide can have genotoxic effects and impair the development of embryos. Etoposide has been shown to be teratogenic in animals, and has mutagenic properties. Etoposide should not be given to patients who are pregnant. If it is considered clinically essential to treat a pregnant patient she should be informed about the risk of damage to the foetus connected with the treatment. Women of child-bearing potential should avoid pregnancy during treatment with Etoposide.
Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Sedol (Etoposide). A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Side Effects
The following data on adverse reactions are based on both oral and intravenous administration of Etoposide as single agent, using several different dose schedules for treatment of a wide variety of malignancies.
Hematologic Toxicity: Myelosuppression is dose related and dose limiting, with granulocyte nadirs occurring 7 to 14 days after drug administration and platelet nadirs occurring 9 to 16 days after drug administration. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported. Fever and infection have also been reported in patients with neutropenia. Death associated with myelosuppression has been reported.
The occurrence of acute leukemia with or without a preleukemic phase has been reported rarely in patients treated with Etoposide in association with other antineoplastic agents.
Gastrointestinal Toxicity: 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. Mild to severe mucositis/esophagitis may occur. Gastrointestinal toxicities are slightly more frequent after oral administration than after intravenous infusion.
Hypotension: 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 rate should be used.
Allergic Reactions: Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnea, and/or hypotension have been reported to occur in 0.7% to 2% of patients receiving intravenous Etoposide and in less than 1% of the patients treated with the oral capsules. These reactions have usually responded promptly to the cessation of the infusion and administration of pressor agents, corticosteroids, antihistamines, or volume expanders as appropriate; however, the reactions can be fatal. Hypertension and/or flushing have also been reported. Blood pressure usually normalizes within a few hours after cessation of the infusion. Anaphylactic-like reactions have occurred during the initial infusion of Sedol.
Facial/tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat, laryngospasm, back pain, and/or loss of consciousness have sometimes occurred in association with the above reactions. In addition, an apparent hypersensitivity-associated apnea has been reported rarely. Rash, urticarial, and/or pruritus have infrequently been reported at recommended doses. At investigational doses, a generalized pruritic erythematous maculopapular rash, consistent with perivasculitis, has been reported.
Alopecia: Reversible alopecia, sometimes progressing to total baldness, was observed in up to 66% of patients.
Other Toxicities: The following adverse reactions have been infrequently reported: Abdominal pain, aftertaste, constipation, dysphagia, asthenia, fatigue, malaise, somnolence, transient cortical blindness, optic neuritis, interstitial pneumonitis/pulmonary fibrosis, fever, seizure (occasionally associated with allergic reactions), Stevens-Johnson syndrome, and toxic epidermal necrolysis, pigmentation, and a single report of radiation recall dermatitis.
Hepatic toxicity, generally in patients receiving higher doses of the drug than those recommended, has been reported with Etoposide. Metabolic acidosis has also been reported in patients receiving higher doses.
Reports of extravasation with swelling have been received postmarketing. Rarely extravasation has been associated with necrosis and venous induration.
The incidences of adverse reactions in the table that follows are derived from multiple data bases from studies in 2,081 patients when Etoposide was used either orally or by injection as a single agent.
Drug Interactions
High-dose cyclosporine resulting in concentrations above 2000 mg/mL administered with oral etoposide has led to an 80% increase in etoposide exposure with a 38% decrease in total body clearance of etoposide compared to etoposide alone.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Bone marrow depressants, other or radiation therapy: (Additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively).
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 side/adverse effects of the vaccine virus and/or may decrease the patient antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patients hematologic status and only with the knowledge and consent of the physician managing the etoposide therapy).
Concomitant warfarin therapy may result in international normalized ratio (INR). Close monitoring of INR is recommended.
Storage
Store below 30°C. Do not freeze. It is recommended that the vial should remain in carton until the time of use.
ATC Classification
L01CB01 - etoposide ; Belongs to the class of plant alkaloids and other natural products, podophyllotoxin derivatives. Used in the treatment of cancer.
Presentation/Packing
Inj (vial) 100 mg/5 mL (sterile, clear or slightly yellowish solution, free from visible extraneous particulate matter) x 1's.
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