Etoposide-Ebewe^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Sandoz, d.d. (Slovenia)

Manufactured By

Ebewe Pharma Ges.m.b.H.Nfg.KG (Austria)

ATC Code

L01CB01 (Etoposide)

Active Substance

Etoposide (Rec.INN registered by WHO)

Dosage Forms

	Etoposide-Ebewe®	Concentrate for solution for infusion 50 mg/2.5 ml: 1 vial.
		Concentrate for solution for infusion 100 mg/5 ml: 1 vial.
		Concentrate for solution for infusion 200 mg/10 ml: 1 vial.
		Concentrate for solution for infusion 400 mg/20 ml: 1 vial.

Dosage Form, Packaging, and Composition

Concentrated solution for infusion light yellow, transparent.

Excipients: macrogol 300, polysorbate 80, benzyl alcohol, citric acid, ethanol.

2.5 ml – dark glass vials (1) – cardboard packs.

Concentrated solution for infusion light yellow, transparent.

Excipients: macrogol 300, polysorbate 80, benzyl alcohol, citric acid, ethanol.

5 ml – dark glass vials (1) – cardboard packs.

Concentrated solution for infusion light yellow, transparent.

Excipients: macrogol 300, polysorbate 80, benzyl alcohol, citric acid, ethanol.

10 ml – dark glass vials (1) – cardboard packs.

Concentrated solution for infusion light yellow, transparent.

Excipients: macrogol 300, polysorbate 80, benzyl alcohol, citric acid, ethanol.

20 ml – dark glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

Etoposide is a semi-synthetic derivative of podophyllotoxin.

The mechanism of action is associated with the inhibition of topoisomerase II. Etoposide exerts a cytotoxic effect by damaging DNA. The drug blocks mitosis, causing cell death in the G-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 IV administration, C_max in plasma is 30 µg/ml.

The drug is detected in pleural fluid, saliva, liver tissue, spleen, kidneys, myometrium, and brain tissues. Etoposide penetrates the blood-brain barrier and placental barrier. The concentration values of etoposide in the cerebrospinal fluid range from undetectable to 5% of the plasma concentration. There are no data on the excretion of the drug in breast milk. Plasma protein binding is approximately 97%.

Etoposide is actively metabolized in the body.

Elimination of etoposide is biphasic. In adults with normal renal and hepatic function, T_1/2 averages approximately 0.6-2 hours with a T_1/2 in the terminal phase within 5.3-10.8 hours. Etoposide is excreted in the urine as unchanged substance (29%) and metabolites (about 15%) within 48-72 hours. 2-16% is excreted in the feces.

Indications

• Germ cell tumors of the testis and ovaries;
• Lung cancer.

There are reports of the effectiveness of Etoposide-Ebewe in the treatment of

• Bladder cancer;
• Lymphogranulomatosis (Hodgkin’s disease);
• Non-Hodgkin lymphomas;
• Acute monoblastic and myeloblastic leukemia;
• Ewing’s sarcoma;
• Trophoblastic tumors;
• Stomach cancer;
• Kaposi’s sarcoma;
• Neuroblastoma.

ICD codes

Dosage Regimen

When choosing the route of administration, regimen, and doses in each individual case, one should be guided by data from specialized literature.

The dosage regimen is established individually, depending on the chemotherapy regimen used (when choosing the dose, the myelosuppressive effect of other drugs in the combination, as well as the effect of previous radiation therapy and chemotherapy, should be taken into account).

IV Etoposide-Ebewe is administered over 30-60 minutes, with Etoposide-Ebewe doses usually being 50-100 mg/m²/day for 4-5 days, with cycles repeated every 3-4 weeks.

A regimen of administering Etoposide-Ebewe every other day at 100-125 mg/m² on days 1, 3, and 5 is also often used.

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

Before IV administration, Etoposide-Ebewe is diluted in 250 ml of 0.9% sodium chloride solution or 5% dextrose solution to a final concentration of 0.2-0.4 mg/ml. Contact with buffered aqueous solutions with a pH above 8 should be avoided.

Adverse Reactions

From the hematopoietic organs: a decrease in the number of leukocytes and granulocytes is dose-dependent and is the main dose-limiting toxic manifestation of Etoposide-Ebewe. The maximum decrease in the number of granulocytes 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 30-40% of patients. Usually, these phenomena are 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 noted. Sometimes temporary hyperbilirubinemia and increased transaminase levels occur . This most often occurs when using doses exceeding the recommended ones.

From the cardiovascular system with rapid IV administration, 1-2% of patients experienced a temporary decrease in blood pressure, which usually recovers when the infusion is stopped and fluids or other supportive therapy are administered. If it is necessary to resume Etoposide-Ebewe administration, the infusion rate should be reduced.

Allergic reactions: symptoms resembling anaphylactic, such as chills, fever, tachycardia, bronchospasm, shortness of breath, and decreased blood pressure. These reactions are usually observed during or immediately after etoposide administration and cease when the infusion is stopped and corticosteroids or antihistamines are used.

Dermatological reactions: reversible alopecia, sometimes leading to complete hair loss, occurs in at least 66% of patients. Pigmentation, itching are rarely noted. In one case, a relapse of radiation dermatitis was observed.

Other toxic manifestations: peripheral neuropathy, drowsiness, increased fatigue, residual taste in the mouth, fever, and interstitial pneumonitis/pulmonary fibrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, optic neuritis, transient cortical blindness, muscle cramps, metabolic acidosis, hyperuricemia, phlebitis with IV administration are occasionally noted. If the drug gets under the skin – a pronounced local irritant effect up to necrosis of surrounding tissues.

Contraindications

• Myelosuppression (neutrophil count below 1500/µl and/or platelet count below 75,000/µl);
• Severe liver dysfunction;
• Acute infections;
• Pregnancy and breastfeeding period;
• Hypersensitivity to etoposide or excipients.

With caution alcoholism, epilepsy, children’s age (under 2 years – safety and efficacy for children have not been established).

Use in Pregnancy and Lactation

Contraindication: pregnancy and breastfeeding period.

Use in Hepatic Impairment

Contraindication: severe liver dysfunction.

Pediatric Use

With caution: children’s age (under 2 years).

Special Precautions

Etoposide-Ebewe should be used only under the constant supervision of a physician experienced in therapy with cytotoxic drugs.

When working with Etoposide-Ebewe, the Rules for handling cytotoxic drugs should be observed. In case of contact with skin or mucous membranes, the affected areas should be immediately washed with water and soap.

Suppression of bone marrow function is the dose-limiting action of Etoposide-Ebewe. Regular monitoring of blood composition is necessary before starting treatment, during breaks, and before each subsequent course of Etoposide-Ebewe. If radiation therapy and/or chemotherapy was performed before starting therapy with Etoposide-Ebewe, a sufficient interval between these two types of treatment should be observed to ensure the restoration of bone marrow function. If the platelet count falls below 50,000/µl and/or the absolute neutrophil count falls to 500/µl, therapy should be discontinued until blood counts are fully restored.

If anaphylactic reactions occur, the administration of Etoposide-Ebewe must be stopped and treatment with corticosteroids and/or antihistamines should be initiated against the background of infusion therapy.

In case of accidental extravasal administration, the injection should be stopped immediately and the remaining portion should be injected into another vein. Administration is stopped as soon as a burning sensation appears. Subcutaneous injections of hydrocortisone are performed around the affected area and 1% hydrocortisone ointment is applied (until the erythema disappears) under a dry bandage for 24 hours.

Precautions should be observed when prescribing the drug to patients with hepatic or renal insufficiency.

Men and women receiving therapy with Etoposide-Ebewe should use reliable methods of contraception.

Occasionally, patients receiving therapy with Etoposide-Ebewe in combination with other antineoplastic drugs may develop acute leukemia, both with and without a preleukemic phase.

Before use, a visual assessment of the solution should be performed to detect solid particles or color change.

The solution of Etoposide-Ebewe for IV administration contains ethyl alcohol as a filler, which may be a risk factor for patients suffering from liver diseases, alcoholism, epilepsy, as well as for children.

Overdose

No cases of etoposide overdose in humans have been registered to date. It can be assumed that the main manifestations of overdose would be toxic effects on the blood and gastrointestinal tract. In such cases, mainly symptomatic therapy is 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 one solution. Pharmaceutically incompatible with solutions having alkaline pH values.

Due to the immunosuppressive effect of the drug and the possibility of developing severe infection, it is not recommended to use live vaccines during chemotherapy. Vaccination should be carried out 3 months after the completion of therapy.

Storage Conditions

Store in a light-protected place, out of reach of children, at a temperature from 15°C (59°F) to 25°C (77°F).

Shelf Life

Shelf life – 3 years.

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.