Vepesid (Etoposide)

VEPESID®

Bristol

Etoposide

Antineoplastic

Action And Clinical Pharmacology: Etoposide is a semi-synthetic derivative of podophyllotoxin.

In vitro, etoposide has cytostatic action, which prevents the cells from entering mitosis or destroys them in the premitotic phase. Etoposide interferes with the synthesis of DNA and has a secondary effect on arresting cells in resting (G2) phase in experiments with human lymphoblastic cell lines.

Etoposide has a marked action on human hemopoietic cells causing leukopenia and thrombocytopenia. Animal experiments have shown evidence of teratogenicity.

An i.v. dose (259 mg/m of tritium-labelled etoposide given over 1 hour in man, showed the mean volume of distribution to be 32% of body weight. The plasma decay was biphasic with a beta half-life of 11.5 hours. Urinary recovery was 44% of which 67% was unchanged drug. Recovery in feces was variable (1.5 to 16%) over a 3-day period.

A plasma decay with a beta half-life of 6.8 hours was observed following oral administration of etoposide. The t 1/2 for oral absorption was 0.44 hour and peak plasma concentrations were noted 0.5 to 3 hours after oral administration.

In a limited number of children, etoposide administered in a dose of 200 to 250 mg/mproduced a peak serum concentration between 17 and 88 g/mL and showed a terminal half-life (t1/2ã) of 5.7±1.3 hours. Mean plasma clearance was 21.5 mL/min/mand CSF concentrations 24 hours post-infusion ranged from less than 10 ng/mL to 45 g/mL.

After either i.v. infusion or oral capsule administration of etoposide, the Cmax and AUC values exhibit marked intra- and inter-subject variability. The overall mean value of oral capsule bioavailability is approximately 50% (range 25 to 75%).

Etoposide crosses the blood brain barrier in low concentrations.

Etoposide is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. Biliary excretion, however, appears to be a minor route of etoposide elimination.

Indications And Clinical Uses: Oral and I.V.: Small-cell Carcinoma of the Lung: First-line therapy in combination with other established antineoplastic agents. Second-line combination or single agent therapy in patients who have not responded or relapsed on other chemotherapeutic regimens.

Malignant Lymphoma (histiocytic type): First-line therapy in combination with other established antineoplastic agents.

Non-small Cell Carcinoma of the Lung: For patients considered ineligible for surgery, etoposide has been shown effective alone or in combination with cisplatin. For patients who require chemotherapy following surgery.

Testicular Malignancies (germ cell tumors including seminomas): In combination with other effective chemotherapeutic agents in patients who have already received appropriate therapy. I.V. only: In the first-line combination chemotherapeutic regimens with appropriate surgical and/or radiotherapeutic procedures.

Contra-Indications: Should not be given to individuals who have demonstrated hypersensitivity to etoposide or to any component of the formulation. Also, it is contraindicated in patients having severe leukopenia, thrombocytopenia and severe hepatic and/or renal impairment. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Etoposide is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs (see Precautions). Blood counts as well as renal and hepatic function tests should be taken regularly. Discontinue the drug if abnormal depression of bone marrow or abnormal renal or hepatic function is seen. Vepesid injection contains polysorbate 80. In premature infants a life-threatening syndrome of liver and renal failure, pulmonary deterioration, thrombocytopenia and ascites has been associated with injectable vitamin E product containing polysorbate 80.

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/mmor an absolute neutrophil count below 500/mmis an indication to withhold further therapy until the blood counts have sufficiently recovered.

Bacterial infection must be brought under control before the administration of etoposide therapy because of the risk of septicemia.

Physicians should be aware of the possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnea and/or hypotension (see Adverse Effects). Treatment is symptomatic. The administration of etoposide should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician.

For parenteral administration, etoposide should be given only by slow i.v. infusion (usually over a 30-to 60-minute period) since hypotension has been reported as a possible side effect of rapid i.v. injection.

Pregnancy: Etoposide can cause fetal harm when administered to pregnant women.

Etoposide has been shown to be embryotoxic in rats and teratogenic in mice and rats. There are no adequate and well-controlled studies in pregnant women. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant and should exercise adequate contraceptive control.

Etoposide has caused reduced or absent spermatogenesis and reduced testes weights at autopsy in rats and dogs, as well as reduced weight of ovaries in female rats. Chronic toxicity studies in rats have shown etoposide to have an oncogenic potential (see Adverse Effects, Hematologic Toxicity).

Lactation: There has been evidence of etoposide being excreted in human milk.

Because of the potential for serious adverse reactions in nursing infants from etoposide, breast-feeding should be discontinued.

As with any potent antineoplastic drug, the benefit to patient versus the risk of toxicity must be carefully weighed.

Precautions: General: The physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of etoposide therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness to the possible recurrence of toxicity.

Etoposide should be administered by individuals experienced in the use of antineoplastic therapy.

Neutropenia is at its lowest level 7 to 14 days after initial therapy. Thrombocytopenia is at its lowest level 9 to 16 days after initial therapy. Bone marrow recovery requires 20 days.

Liver and renal function should be regularly monitored.

Professional staff administering etoposide injection should exercise particular care to prevent spillage and self-contact with the drug. Skin reactions, at times severe, associated with accidental exposure to etoposide may occur. Gloves should be worn by anyone handling the drug. If etoposide solution contacts the skin, immediately wash thoroughly with soap and water. If etoposide solution contacts mucous membranes, flush thoroughly with water. Materials used for cleaning accidental spills should be disposed of by incineration.

Carcinogenesis: Carcinogenicity tests with etoposide have not been conducted in laboratory animals. Given its mechanism of action, it should be considered a possible carcinogen in humans.

The occurrence of acute leukemia, which can occur with or without a preleukemic phase, has been reported rarely in patients treated with etoposide in association with other antineoplastic drugs. Neither the cumulative risk, nor the predisposing factors related to the development of secondary leukemia are known. The roles of both administration schedules and cumulative doses of etoposide have been suggested, but have not been clearly defined.

An 11q23 chromosome abnormality has been observed in some cases of secondary leukemia in patients who have received epipodophyllotoxins. This abnormality has also been seen in patients developing secondary leukemia after being treated with chemotherapy regimens not containing epipodophyllotoxins and in leukemia occurring de novo. Another characteristic that has been associated with secondary leukemia in patients who have received epipodophyllotoxins appears to be a short latency period, with average median time to development of leukemia being approximately 32 months.

Drug Interactions: Severe cases of neuropathy have been reported in 0.7% of patients possibly due to an interaction of vincristine and etoposide.

Children: Clinical experience in childhood malignancies is very limited (see Warnings).

Adverse Reactions: The following data on adverse reactions are based on both oral and i.v. administration of etoposide as a single agent, using several different dose schedules for treatment of a wide variety of malignancies.

Hematologic Toxicity: Since leukopenia and thrombocytopenia have been reported in patients on etoposide therapy, platelets and white blood cell counts should be performed prior to each cycle.

A white blood cell count of between 2 000 to 3 000 cells/mmsuggests that the dose of etoposide should be reduced by 50%. Platelet counts between 75 000 to 100 000 cells/mmrequire a dosage reduction of 50%. Should the neutrophil count fall below 500 cells/mmor the platelet count fall below 50 000 cells/mm etoposide should be discontinued and should not be resumed until counts have returned to normal (see Warnings). Myelosuppression is dose related and dose limiting, with granulocyte nadirs occurring 7 to 14 days 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.

The occurrence of acute leukemia with or without a preleukemic phase has been reported 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. Gastrointestinal toxicities are slightly more frequent after oral administration than after i.v. infusion. Mild to severe mucositis/eosophagitis may occur.

Hypotension: Transient hypotension following rapid i.v. administration has been reported in 1 to 2% of patients. It has not been associated with cardiac toxicity or ECG changes. No delayed hypotension has been noted. To prevent this occurrence, it is recommended that etoposide be administered by slow i.v. 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.

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 during or immediately after etoposide administration. Higher rates of anaphylactic-like reactions have been reported in children who received etoposide infusions at concentrations higher than those recommended. The role that concentration of infusion (or rate of infusion) plays in the development of anaphylactic-like reactions is uncertain. Reactions have occurred very rarely in patients treated with oral capsules. Anaphylactic-like reactions have usually responded promptly to etoposide cessation, and subsequent administration of pressor agents, corticosteroids, antihistamines or volume expanders as appropriate. Acute fatal reactions associated with bronchospasm have been reported. Hypertension and/or flushing have also been reported. Blood pressure usually normalizes within a few hours after cessation of the infusion. Anaphylactic-like reactions can occur with the initial dose of etoposide. Apnea with spontaneous resumption of breathing following discontinuation has been described in patients receiving etoposide infusion.

Alopecia: Reversible alopecia, sometimes progressing to total baldness was observed in up to 66% of patients.

Neuropathy: The use of etoposide has been reported to cause peripheral neuropathy in 0.7% of patients. The associated use of vincristine sulfate can possibly enhance this neuropathy.

Other Toxicities: Weakness (3%), mouth ulceration (2%). The following have been reported in less than 1%: hyperuricemia, sepsis, numbness and tingling, dizziness, depression, nail pigmentation and moniliasis. The following adverse reactions have been infrequently reported: somnolence and fatigue, liver toxicity, fever, aftertaste, rash, pigmentation, pruritus, urticaria, constipation, dysphagia, transient cortical blindness and a single report of radiation recall dermatitis.

Occasionally following extravasation, soft tissue irritation and inflammation has occurred; ulceration is generally not seen.

The incidences of adverse reactions in Table I are derived from multiple data bases from studies in patients when etoposide was used either orally or by injection as a single agent.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The anticipated acute complications would be related to etoposide’s hematotoxicity.

Total doses of 2.4 g/mto 3.5 g/madministered i.v. over 3 days resulted in severe mucositis and myelotoxicity.

Metabolic acidosis and cases of serious hepatic toxicity have been reported in patients receiving higher than recommended i.v. doses of etoposide.

There is no known antidote and therefore symptomatic measures should be taken to sustain the patient through any period of toxicity that might occur. Patients’ renal and hepatic functions should be monitored for 3 to 4 weeks in case of delayed toxicity.

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. This effect has not been reported with diluted etoposide.

I.V.: 50 to 100 mg/mdaily for 5 days.

Hypotension following rapid i.v. administration has been reported, hence, it is recommended that the etoposide solution be administered over a period of not less than 30 minutes (usually over 30 to 60 minutes). Longer infusion times may be required based on patient tolerance. Etoposide should not be given by rapid i.v. injection.

Oral: 100 to 200 mg/mdaily for 5 days.

The dose of etoposide capsules is based on the recommended i.v. dose with consideration given to the bioavailability of etoposide capsules appearing to be dependent upon the dose administered. A 100 mg oral dose would be comparable to a 75 mg i.v. dose; a 400 mg oral dose would be comparable to a 200 mg i.v. dose. The bioavailability also varies from patient to patient following any oral dose. This should be taken into consideration when prescribing this medication. In view of significant intra-patient variability, dose adjustment may be required to achieve the desired therapeutic effect.

Dosage should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy which may have compromised bone marrow reserve.

Capsules should be taken on an empty stomach.

Preparation of I.V. Solutions: 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 or 0.4 mg/mL. More concentrated solutions show crystal formation upon stirring or seeding within 5 minutes and should not be given i.v. Etoposide diluted to 0.4 mg/mL and administered through tubing connected to a pump with peristaltic mechanism may precipitate out of solution in the tubing. Contact with buffered aqueous solutions above pH 8 should be avoided. Reconstitution results in a clear, colorless solution. Etoposide diluted with 0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP to a concentration of 0.2 to 0.4 mg/mL is stable for 96 and 24 hours respectively, at room temperature under room light in both glass and plastic containers. Etoposide should not be mixed with other antineoplastic drugs. Care should be taken to prevent spillage and self-contact with the drug. If etoposide solution contacts the skin, immediately wash thoroughly with soap and water. If etoposide solution contacts mucous membranes, flush thoroughly with water.

Preparation for I.V. Administration: Etoposide injection must be diluted with 5% Dextrose Injection USP or 0.9% Sodium Chloride Injection USP to give a concentration of 0.2 or 0.4 mg/mL.

As with all parenteral drug products, i.v. drug admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit.

Stability: Injection: When diluted with 0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP to a concentration of 0.2 or 0.4 mg/mL, etoposide solutions are physically and chemically stable for 96 and 24 hours respectively, at room temperature (25°C) under room light in both glass and plastic containers.

Special Instructions: Handling and Disposal: 1. Preparation of etoposide should be done in a vertical laminar flow hood (Biological Safety Cabinet – Class II). 2. Personnel preparing etoposide should wear PVC gloves, safety glasses, disposable gowns and masks. 3. All needles, syringes, vials and other materials that have come in contact with etoposide should be segregated and incinerated at 1 000 °C or more. Sealed containers may explode. Intact vials should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport. 4. Personnel regularly involved in the preparation and handling of etoposide should have biannual blood examinations.

Availability And Storage: Capsules: Each pink, liquid-filled, soft gelatin capsule printed with edible ink, contains: etoposide 50 mg. Nonmedicinal ingredients: citric acid, glycerol, polyethylene glycol and water; capsule shell: gelatin, glycerol, iron oxide red, parabens (ethyl and propyl), purified water, sorbitol and titanium dioxide. Bottles of 20.

Injection: Each mL of clear yellow solution contains: etoposide 20 mg. Nonmedicinal ingredients: alcohol, benzyl alcohol, citric acid, polyethylene glycol and polysorbate 80. The pH is 3 to 4. Vials and ampuls of 5 mL. Vials of 25 and 50 mL.

Store at room temperature (15 to 25°C). (Shown in Product Recognition Section)

VEPESID® Bristol Etoposide Antineoplastic

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