DESCRIPTION:
ETOPOSIDE injection is a semisynthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases.

COMPOSITION:
Each ml contains:
Etoposide U.S.P 20 mg
Benzyl Alcohol U.S.N.F 30 mg
Ethanol U.S.P 30.5%v/v.
Citric Acid U.S.P q.s.
In a sterile non-aqueous vehicle.

CLINICAL PHARMACOLOGY :
ETOPOSIDE injection has been shown to cause metaphase arrest in chick fibroblasts. Its main effect, however appears to be at the G2 portion of the cell cycle in mammalian cells. Two different dose-dependent responses are seen . At high concentrations (10 mcg/ml or more) lysis of cells entering mitosis is observed. At low concentrations ( 0.3 to 10 mcg/ml ) cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of ETOPOSIDE injection appears to be DNA synthesis inhibition .

PHARMACOKINETICS :
On intravenous administration, the disposition of Etoposide is best described as a biphasic process with a distribution half-life of 1.5 hours and terminal elimination half-life between 4 to 11 hours. The total body clearance values range from 33 to 48 ml/min or 16 to 36 ml/min/m². ETOPOSIDE enters CSF poorly. ETOPOSIDE concentration has been found to be higher in normal lung than that in myometrium. In vitro ETOPOSIDE is highly protein bound(97%) with upto 35 % recovery 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.Biliary excretion appears to be a minor route of elimination (6%).

INDICATIONS:
Refractory Testicular Tumors
Small Cell Lung Cancer

CONTRAINDICATIONS:
History of previous hypersensitivity to ETOPOSIDE or any component of ETOPOSIDE.

WARNINGS:
Patients being treated with ETOPOSIDE injection must be frequently observed for myelosuppression both during and after therapy. Dose-limiting bone marrow suppression is the most significant toxicity associated with ETOPOSIDE injection therapy. Therefore, the following studies should be obtained at the start of the therapy and prior to each subsequent dose of ETOPOSIDE injection : platelet count, hemoglobin, white blood cell count and differential count. The occurrence of a platelet count below 50,000/ mm³ or an absolute neutrophil count below 500 mm³ is an indication to withhold therapy until the blood counts have sufficiently recovered.
There may be possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm. dyspnea, and hypotension. Treatment is symptomatic. The infusion should be terminated immediately, followed by administration of pressor agents, corticosteroids, antihistamines, or volume expanders.
For parental administration, ETOPOSIDE injection should be given only by slow intravenous infusion (usually over a 30 to 60 minutes period ) since hypotension has been reported as a possible side effect of rapid intravenous injection.

PRECAUTIONS :
General : Before initiation and while continuing therapy with ETOPOSIDE injection the need and usefulness of the drug against the risk of adverse reaction should be assessed. If severe reactions occur the dose should be reduced or drug should be discontinued and appropriate corrective measures should be taken.
Laboratory tests : Complete periodic blood counts should be done prior to the therapy and during the course of treatment with ETOPOSIDE injection.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity test with ETOPOSIDE injection have not been conducted in laboratory animals. In view of its mechanism of action it should be considered a possible carcinogen in humans. The mutagenic and genotoxic potential of ETOPOSIDE injection has been established in mammalian cells. ETOPOSIDE injection 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 crosslinks in mouse leukemia cells. ETOPOSIDE injection also caused a dose-related increase in sister chromatid exchanges in Chinese hamster ovary cells.
ETOPOSIDE injection is teratogenic and embryocidal in rats and mice at doses of 1 to 3% of the recommended clinical dose based on body surface area.
Pregnancy
ETOPOSIDE injection has been shown to be teratogenic in mice and rats. There are no adequate well controlled studies in pregnant woman. If this drug is used in pregnancy, or if the patient becomes pregnant while receiving this drug the patient should be appraised of the potential hazard to the fetus.
Nursing Mothers :
It is not known whether the drug is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants with ETOPOSIDE injection, a decision should be made whether to discontinue the drug taking into account the importance of the drug to the mother.

DRUG INTERACTIONS :
Combination chemotherapy with ETOPOSIDE injection and Cisplatin has a synergistic antineoplastic activity against testicular carcinomas, small cell carcinoma of the lung or non-small cell carcinoma of the lung. Limited data indicates that patients previously treated with Cisplatin may have impaired elimination of ETOPOSIDE. Phenylbutazone, sodium salicylate, and aspirin displace ETOPOSIDE from plasma protein binding sites and thus raise plasma levels of the free drug.

ADVERSE REACTIONS:
Hematologic Toxicity : Myelosuppression is dose related and dose limiting. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported.
The occurrence of acute leukemia with or without a preleukemic phase has been reported rarely in patients treated with ETOPOSIDE injection 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.
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. To prevent this rare occurrence, it is recommended that ETOPOSIDE be administered by slow intravenous infusion over a 30 to 60 minute period.
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. 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, urticaria, and /or pruritus have infrequently been reported at recommended doses. At investigational doses, a generalized pruritic erythematous maculopapular rash, consistent with pervasculitis, 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 infrequently reported; aftertaste, fever, pigmentation abdominal pain, constipation, dysphagia, transient cortical blindness, and optic neuritis.
Hepatic toxicity, generally in patients receiving higher doses of the drug than those recommended, has been reported with ETOPOSIDE injection. Metabolic acidosis has been reported in patients receiving higher doses.

OVERDOSAGE:
The anticipated complications of overdosage are secondary to bone marrow suppression. There is no known antidote for overdosage. Treatment consists of supportive care including blood products and antibiotics.

DOSAGE AND ADMINISTRATION :
Note : Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, butadiene, and styrene ) have been reported to crack and leak when used with undiluted ETOPOSIDE injection.
Testicular Cancer : 50 to 100 mg/m²/day on days 1 through 5 to 100mg/m²/day on days 1,3 and 5, in combination with other approved chemotherapeutic agents.
Small cell lung cancer : 35 mg/m³/day for 4 days to 50 mg/m²/day for 5 days in combination with other approved chemotherapeutic drugs.
Chemotherapy courses are repeated at 3 to 4 week intervals after adequate recovery from any toxicity.

HANDLING OF SOLUTION:
ETOPOSIDE injection should be handled and prepared cautiously. Skin reactions may occur with accidental exposure to ETOPOSIDE injection. The use of gloves is recommended . If the solution comes in contact with skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.
Observe all the necessary routine precautions in handling of cytotoxic drugs in respect of this formulation too.
Preparation for intravenous administration : ETOPOSIDE injection must be diluted prior to use with either 5% Dextrose injection or 0.9% Sodium Chloride injection, 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 ETOPOSIDE injection solution be administered over a 30 to 60 minute period. A longer duration of administration may be used if the volume of fluid to be infused is large. ETOPOSIDE injection should not be given by rapid intravenous injection.

STORAGE:
Store at 8° to 25°C. Do not Freeze. Protect from light. Unopened vials are stable for 2 years at room temperature (25°C). Vials diluted as recommended to a concentration of 0.2 or 0.4 mg/ml are stable for 96 and 24 hours, respectively, at room temperature (25°C) in glass containers.

SHELF LIFE:
2 years from date of manufacture.

PRESENTATION:
ETOPOSIDE injection U.S.P. is available as vial containing 100 mg / 5 ml and 200 mg / 10 ml.