Fytosid

Etoposide.

Each mL contains Etoposide 20.0 mg in a sterile non aqueous vehicle.
FYTOSID (Etoposide) is a semisynthetic derivative of podophyllotoxin used in the treatment of wide variety of neoplasms. Etoposide is a white crystalline powder. It is sparingly soluble in methanol and chloroform, slightly soluble in ethanol and very slightly soluble in water or ethyl ether.
Chemical name is 4-demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-β-D-glu-copyranoside].
Chemical formula is C₂₉H₃₂O₁₃.
Molecular weight: 588.6.
Excipients/Inactive Ingredients: This product contains polysorbate 80 and benzyl alcohol (see Use in Children under Precautions).

Pharmacology: Pharmacodynamics: Mechanism of Action: Etoposide is a semisynthetic derivative of the podophyllotoxins, an epipodophyllotoxin. It inhibits DNA topoisomerase II, thereby inhibiting DNA synthesis. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases.
Pharmacokinetics: Absorption after oral doses is variable, but on average about 50% of the dose of etoposide is absorbed. The pharmacokinetics of etoposide are subject to considerable interindividual variation. It is rapidly distributed, and concentrations in plasma fall in a biphasic manner, with a terminal half-life of 4 to 11 hours.
Etoposide is about 94% bound to plasma protein. It is metabolised by the cytochrome P450 isoenzyme CYP3A4. Etoposide is excreted in urine and faeces as unchanged drug and metabolites: about 45% of a dose is reported to be excreted in urine over 72 hours. It crosses the blood brain barrier poorly; concentrations in CSF are 1 to 10% of those in plasma. It is distributed into breast milk.

Etoposide has demonstrated highly significant clinical activity against several human neoplasms including small cell lung cancer, testicular cancers and bladder cancer. Etoposide is also active in malignant lymphomas of both Hodgkins & non Hodgkins type and acute Leukaemias. In addition, it is extremely active in gestational trophoblastic tumours and paediatric especially Ewing's sarcoma when used in combination.

RECOMMENDED DOSE: The recommended dose of Etoposide is: Refractory Testicular Tumors: 50 to 100 mg/m² per day administered intravenously over 30 to 60 minutes on days 1 through 5 of each 21-day (or 28-day cycle), or 100 mg/m² administered intravenously 30 to 60 minutes on days 1, 3, and 5 of each 21-day (or 28-day cycle).
Small Cell Lung Cancer: The recommended dose of Etoposide is 35 mg/m² to 50 mg/m² per day administered intravenously over 30 to 60 minutes or longer for 4 consecutive days of each 21-day cycle.
Regimens vary; the usual intravenous dose of etoposide ranges from 50 to 120 mg/m² daily for 5 days. Somewhat lower doses have been suggested in lung cancer. Alternatively, 100 mg/m² has been given on alternate days to a total of 300 mg/m². Courses may be repeated after 3 to 4 weeks. Doses should be reduced in renal impairment.
MODE OF ADMINISTRATION: Administration in renal impairment: In patients with a creatinine clearance (CLcr) of between 15 and 50 mL/minute be given 75% of the recommended dose.
Data are not available in patients with creatinine clearance less than 15 ml/min.
Administration: Hypotension following rapid intravenous administration has been reported; hence, it is recommended that the etoposide 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 a concern. Etoposide should not be given by rapid intravenous injection.
Preparation for Intravenous Administration: Etoposide 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.
Leaching of the plasticiser diethylhexyl phthalate (which is potentially toxic and carcinogenic) from PVC bags and tubing has been reported with etoposide, and it has been suggested that these should also not be used if possible when preparing and giving the drug.
Etoposide Injection should not be physically mixed with any other drug.

No antidote has been established for etoposide overdosage in humans.

Etoposide is contraindicated in patients with a history of a severe hypersensitivity reaction to etoposide products.

Fytosid (Etoposide Injection USP) 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.

Myelosuppression: Bone marrow suppression is the dose limiting toxicity of etoposide therapy. Therefore, patients being treated with etoposide must be frequently observed for myelosuppression both during and after therapy. Regular monitoring of blood counts should be done at the start of therapy and prior to each subsequent course of etoposide. If the platelet count is below 50,000/mm³ or an absolute neutrophil count below 500/mm³ therapy should either be withheld or the dosage be reduced, as the case may be.
Secondary Leukemias: Secondary leukemias have occurred with long term use of etoposide.
Hypersensitivity Reactions: Etoposide can cause hypersensitivity reactions, including rash, urticaria, pruritus, and anaphylaxis. If hypersensitivity reactions occur, immediately interrupt etoposide and institute supportive management. Permanently discontinue etoposide in patients who experience a severe hypersensitivity reaction.
Embryo-Fetal Toxicity: Females: Based on animal studies and its mechanism of action, etoposide can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential hazard to the fetus.
Advise females of reproductive potential to use effective contraception during treatment with etoposide and for at least 6 months after the final dose.
Males: Etoposide may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during treatment with etoposide and for 4 months after the final dose.
Carcinogenesis, Mutagenesis and Impairment of Fertility: Etoposide was embryotoxic and teratogenic in animal experiments. Etoposide was genotoxic in in vitro and in vivo tests. No conventional carcinogenicity studies have been conducted, but based on its genotoxic properties, etoposide is considered to be a potential carcinogen. In rats, an oral dose of etoposide at 86.0 mg/kg/day (about 10 times the human dose on a mg/m² basis) or above administered for 5 consecutive days resulted in irreversible testicular atrophy. Irreversible testicular atrophy was also present in rats treated with etoposide intravenously for 30 days at 5.11 mg/kg/day (about 0.5 times the 50 mg/m² human dose based on BSA).
Infertility: Females: In females of reproductive potential, etoposide may cause infertility and result in amenorrhea. Premature menopause can occur with etoposide. Recovery of menses and ovulation is related to age at treatment.
Males: In male patients, etoposide may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men, and in some cases, have occurred several years after the end of therapy.
Use in Children: Safety and effectiveness in pediatric patients have not been established.
Etoposide 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.
This product contains benzyl alcohol, which has been associated with a fatal "gasping syndrome" in premature infants.
Use in the Elderly: In elderly patients taking etoposide, a small dose reduction and careful monitoring has thus been advised, even in those with normal renal and hepatic function.

Pregnancy: Category D.
Based on animal data and its mechanism of action, etoposide can cause fetal harm when administered to a pregnant woman. Etoposide is teratogenic in mice and rats. Advise pregnant women of the potential hazard to a fetus.
Advise women of childbearing potential to avoid becoming pregnant.
Nursing mothers: There is no information regarding the presence of etoposide in human milk or its effects on breastfed infant milk production. Because of the potential for serious adverse reactions in nursing infants from etoposide, advise women not to breastfeed during treatment with etoposide.

The following serious adverse reactions are described elsewhere in the labeling: Myelosuppression, secondary leukemias, hypersensitivity reactions.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates, observed in the clinical trials of a drug, cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The most common adverse reaction was neutropenia.
Other Important Adverse Reactions: Gastrointestinal Toxicity: Nausea and vomiting are the major gastrointestinal toxicities. The severity of nausea and vomiting is generally mild to moderate, with treatment discontinuation required in 1% of patients. Nausea and vomiting are managed with standard antiemetic therapy.
Cardiovascular Toxicity: Transient hypotension following rapid intravenous administration has been reported in 1-2% of patients. It has not been associated with cardiac toxicity or ECG changes. To prevent it, Etoposide should be administered by slow intravenous infusion over 30-60 min. period. If hypotension does occur, it usually responds to cessation of the infusion and administration of fluids of other supportive therapy, as appropriate. When restarting the infusion, a slower administration rate should be used.
Other Toxicities: Other clinically important adverse reactions in clinical trials were: Gastrointestinal: abdominal pain, constipation, dysphagia.
General: fever.
Ocular: transient cortical blindness, optic neuritis.
Respiratory: interstitial pneumonitis/pulmonary fibrosis.
Skin: pigmentation, radiation recall dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Neurologic: seizure, aftertaste.
Hepatobiliary disorder: hepatotoxicity.
Extravasation: Extravasation, resulting in local soft tissue toxicity, was identified.
Extravasation of etoposide may result in swelling, pain, cellulitis, and necrosis including skin necrosis.

Warfarin: Co-administration of etoposide with warfarin may result in elevated international normalized ratio (INR). Measure INR frequently.
Studies in animals and clinical trials in human indicate that the antineoplastic activity of Etoposide and Cisplatin may be synergistic against some tumors. Limited data, however indicates that patients previously treated with Cisplatin may have impaired elimination of Etoposide.

Handling and Disposal: Caution should be exercised when handling etoposide. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published.
To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing etoposide. If dermal contact occurs, immediately and thoroughly wash areas of skin contact with soap and water and flush mucosa with water.

Store below 30°C. Protect from light. Do not freeze.

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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