Etoposide-Teva (Concentrate) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Pharmachemie, B.V. (Netherlands)

ATC Code

L01CB01 (Etoposide)

Active Substance

Etoposide (Rec.INN registered by WHO)

Dosage Forms

	Etoposide-Teva	Concentrate for solution for infusion 1 g/50 ml: vial 1 pc.
		Concentrate for solution for infusion 100 mg/5 ml: vial 1 or 100 pcs.
		Concentrate for solution for infusion 200 mg/10 ml: vial 1 pc.
		Concentrate for solution for infusion 400 mg/20 ml: vial 1 pc.
		Concentrate for solution for infusion 500 mg/25 ml: vial 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion clear, yellowish, slightly viscous, free from mechanical particles.

Excipients : anhydrous citric acid, Tween-80, anhydrous ethanol, propylene glycol 300.

50 ml – vials (1) – cardboard boxes.

Concentrate for solution for infusion clear, yellowish, slightly viscous, free from visible mechanical particles.

Excipients : anhydrous citric acid, Tween-80, anhydrous ethanol, propylene glycol 300.

5 ml – vials (1) – cardboard boxes.
5 ml – vials (100) – cardboard boxes.

Concentrate for solution for infusion clear, yellowish, slightly viscous, free from visible mechanical particles.

Excipients : anhydrous citric acid, Tween-80, anhydrous ethanol, propylene glycol 300.

10 ml – vials (1) – cardboard boxes.

Concentrate for solution for infusion clear, yellowish, slightly viscous, free from visible mechanical particles.

Excipients : anhydrous citric acid, Tween-80, anhydrous ethanol, propylene glycol 300.

20 ml – vials (1) – cardboard boxes.

Concentrate for solution for infusion clear, yellowish, slightly viscous, free from visible mechanical particles.

Excipients : anhydrous citric acid, Tween-80, anhydrous ethanol, propylene glycol 300.

25 ml – vials (1) – cardboard boxes.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

Etoposide is a semi-synthetic derivative of podophyllotoxin used as an antineoplastic agent.

Etoposide exerts a cytotoxic effect by damaging DNA. The drug blocks mitosis, causing cell death in the G₂ phase and late S-phase of the mitotic cycle. High concentrations of the drug cause cell lysis in the premitotic phase.

Etoposide also inhibits the penetration of nucleotides through the plasma membrane, which impedes DNA synthesis and repair.

Pharmacokinetics

After administration, the drug is detected in saliva, liver tissue, spleen, kidneys, myometrium, and to a lesser extent in pleural fluid, bile, and brain tissues.

Etoposide crosses the placental barrier and, to a minor extent, the blood-brain barrier. Etoposide concentrations in the cerebrospinal fluid range from undetectable to 5% of the plasma concentration. Data on the excretion of the drug in breast milk are not available. Plasma protein binding is about 90%.

Etoposide is actively metabolized in the body. The elimination of etoposide is biphasic. In adults with normal renal and hepatic function, the half-life in the initial phase averages approximately 1.5 hours, with a terminal half-life ranging from 5 to 11 hours. Total clearance in adults ranges from 19 to 28 ml/min/m². Renal clearance accounts for 30 – 40% of total clearance. Etoposide is excreted in the urine as unchanged substance and metabolites (about 40% of the administered dose) within 48 – 72 hours. 2 – 16% is excreted in the feces.

Indications

The main indications for the use of Etoposide are germ cell tumors of the testis and ovary, and small cell lung cancer.

There are reports of the effectiveness of Etoposide in the treatment of bladder cancer, lymphogranulomatosis (Hodgkin’s disease), non-Hodgkin’s lymphomas, acute monoblastic and myeloblastic leukemia, Ewing’s sarcoma, trophoblastic tumors, gastric cancer, Kaposi’s sarcoma, and neuroblastoma.

ICD codes

Dosage Regimen

Etoposide is part of many chemotherapy regimens; therefore, when choosing the route of administration, regimen, and doses in each individual case, one should be guided by data from specialized literature.

Doses are 50-100 mg/m² per day for 5 days, with cycles repeated every 3-4 weeks.

A regimen of administration on alternate days – on days 1, 3, and 5 – is also often used.

Repeat courses are carried out only after normalization of peripheral blood counts.

When choosing a dose, the myelosuppressive effect of other drugs in the combination, as well as the effect of prior radiation therapy and chemotherapy, should be taken into account.

Before use, a visual inspection of the solution should be performed to detect particulate matter or color change.

Before administration, Etoposide is diluted with 0.9% sodium chloride solution or 5% dextrose/glucose solution to a final concentration of 0.2 or 0.4 mg/ml. Contact with buffered aqueous solutions with a pH above 8 should be avoided.

Etoposide is administered by 30-60-minute IV infusion.

Adverse Reactions

From the hematopoietic system: a decrease in the number of leukocytes and platelets is dose-dependent and is the main dose-limiting toxic manifestation of etoposide. The maximum decrease in granulocyte count is usually observed on days 7-14 after drug administration. Thrombocytopenia occurs less frequently, and the maximum decrease in platelets is observed on days 9-16 after etoposide administration. Blood count recovery usually occurs by day 20 after administration of the standard dose. Anemia is uncommon.

From the digestive system: nausea and vomiting occur in approximately one-third of patients. These phenomena are usually moderate, and it is rarely necessary to discontinue treatment because of them. Antiemetic drugs are indicated to control these side effects. In addition, diarrhea, abdominal pain, stomatitis, esophagitis, dysphagia, and anorexia have been reported. Mild transient hyperbilirubinemia and increased serum transaminase levels sometimes occur. This occurs more often when using doses exceeding the recommended ones.

From the cardiovascular system: with rapid IV administration, 1-2% of patients experience a temporary decrease in blood pressure, which usually recovers upon discontinuation of the infusion and administration of fluids or other supportive therapy. If it is necessary to resume etoposide administration, the infusion rate should be reduced.

Allergic reactions : symptoms resembling anaphylactic, such as chills, fever, tachycardia, bronchospasm, shortness of breath, apnea. These reactions are usually observed during or immediately after etoposide administration and cease upon discontinuation of the infusion. However, fatal cases associated with bronchospasm have also been recorded. When such reactions occurred, therapy was discontinued and, if necessary, vasopressor drugs, corticosteroids, antihistamines were administered, and infusion-transfusion therapy was performed.

From the skin and skin appendages: reversible alopecia, sometimes leading to complete hair loss, occurs in approximately 66% of patients. The appearance of pigmentation, itching, and urticaria has also been noted. In one case, a recurrence of radiation dermatitis was observed.

Other toxic manifestations: peripheral neuropathy, drowsiness, increased fatigue, residual taste in the mouth, fever, and transient cortical blindness are occasionally noted.

Contraindications

• Hypersensitivity to the drug;
• Severe myelosuppression;
• Severe liver function impairment;
• Acute infections;
• Pregnancy and breastfeeding period.

Use in children: safety and efficacy have not been established.

Use in Pregnancy and Lactation

The use of the drug during pregnancy and lactation is contraindicated.

Use in Hepatic Impairment

Contraindicated in severe liver function impairment.

Pediatric Use

Use in children: safety and efficacy have not been established.

Special Precautions

Since Etoposide is a cytotoxic antineoplastic drug, proper use and handling measures must be observed. Infusions may only be administered by healthcare professionals with sufficient experience in handling antineoplastic drugs. Medical personnel are advised to wear gloves. In case of contact with skin or mucous membranes, the affected areas should be washed immediately with soap and water.

Bone marrow suppression is the dose-limiting effect of etoposide. Regular monitoring of blood counts is necessary before starting treatment, during intervals, and before each subsequent course of etoposide. If radiation therapy and/or chemotherapy was performed before starting etoposide therapy, a sufficient interval between these two types of therapy should be observed to allow for bone marrow function recovery. If the platelet count falls below 50,000/mm³ and/or the absolute neutrophil count falls to 500/mm³, therapy must be discontinued until blood counts have fully recovered.

If anaphylactic reactions occur, the administration of etoposide must be discontinued and treatment with corticosteroids and/or antihistamines, infusion therapy should be initiated.

Caution should be exercised when prescribing the drug to patients with hepatic or renal insufficiency.

Since this drug has mutagenic potential, it may cause damage to human sperm chromosomes; therefore, men receiving etoposide therapy should use contraception.

Occasionally, patients receiving etoposide therapy in combination with other antineoplastic drugs may develop acute leukemia, either with or without a preleukemic phase.

Etoposide is intended for administration only as an IV infusion; other routes of administration are not permitted. The drug should be administered carefully to avoid extravasation during infusion. However, if extravasation does occur, the following measures are taken

• The perfusion should be stopped as soon as a burning sensation is felt;
• Subcutaneous injections of a corticosteroid (hydrocortisone) should be made around the affected site;
• Apply 1% hydrocortisone ointment to the affected area until the erythema disappears;
• Apply a dry dressing to the affected area for 24 hours.

Etoposide contains ethanol as an excipient: this may be a risk factor for patients suffering from liver disease, alcoholism, and epilepsy, as well as for children.

Overdose

No cases of etoposide overdose in humans have been reported to date. It can be assumed that the main manifestation of overdose would be toxic effects on the blood and gastrointestinal tract. In such cases, symptomatic therapy is mainly indicated. There are no specific antidotes.

Drug Interactions

The antineoplastic effect of etoposide is enhanced when used in combination with cisplatin; however, it should be taken into account that in patients previously treated with cisplatin, the elimination of etoposide may be impaired.

Etoposide should not be mixed with other drugs in the same solution.

Storage Conditions

The drug should be stored in a place protected from light and out of the reach of children at a temperature of 15-25°C (59-77°F).

Shelf Life

Shelf life 3 years.

The drug should not be used after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.