Vepesid^® (Capsules) Instructions for Use

Marketing Authorization Holder

Bristol-Myers Squibb S.r.L. (Italy)

ATC Code

L01CB01 (Etoposide)

Active Substance

Etoposide (Rec.INN registered by WHO)

Dosage Forms

	Vepesid®	Capsules 50 mg: 20 pcs.
		Capsules 100 mg: 10 pcs.
		Concentrate for solution for infusion 20 mg/1 ml: vial 5 ml 1 pc.

Dosage Form, Packaging, and Composition

Capsules soft gelatin, opaque, pink, oval in shape; capsule contents – a colorless or slightly yellowish syrupy liquid.

Excipients: anhydrous citric acid, polyethylene glycol, glycerol, purified water, gelatin, sodium propyl hydroxybenzoate, sodium ethyl hydroxybenzoate, red iron oxide, titanium dioxide.

20 pcs. – dark glass bottles (1) – cardboard packs.

Capsules soft gelatin, opaque, pink, oval in shape; capsule contents – a colorless or slightly yellowish syrupy liquid.

Excipients: anhydrous citric acid, polyethylene glycol, glycerol, purified water, gelatin, sodium propyl hydroxybenzoate, sodium ethyl hydroxybenzoate, red iron oxide, titanium dioxide.

10 pcs. – dark glass bottles (1) – cardboard packs.

Concentrate for solution for infusion clear, almost colorless or slightly yellowish solution.

Excipients: anhydrous citric acid, benzyl alcohol, purified polysorbate 80, polyethylene glycol, anhydrous ethanol.

5 ml – vials (1) – cardboard boxes.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

Antineoplastic drug of plant origin.

Etoposide is a semi-synthetic derivative of podophyllotoxin. The mechanism of action is associated with 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 intravenous administration, the peak plasma concentration is 30 µg/ml. When taken orally, Etoposide is absorbed from the gastrointestinal tract. Bioavailability averages 50%.

The drug is detected in pleural fluid, saliva, liver tissue, spleen, kidneys, myometrium, and brain tissues. Etoposide crosses the blood-brain and placental barriers. 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 approximately 97%.

Etoposide is actively metabolized in the body. Elimination of etoposide occurs in a biphasic manner. In adults with normal renal and hepatic function, the half-life averages approximately 0.6 – 2 hours with a terminal half-life in the range of 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 in the treatment of bladder cancer, lymphogranulomatosis, non-Hodgkin’s lymphomas, acute monoblastic and myeloblastic leukemia, Ewing’s sarcoma, trophoblastic tumors, stomach cancer, Kaposi’s sarcoma, and 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 selecting the 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).

IV Vepesid^® is administered at a dose of 50-100 mg/m²/day over 30-60 minutes, the course of treatment is 4-5 days, the interval between courses is 3-4 weeks. Vepesid^® can also be administered IV at 100-125 mg/m² every other day – on days 1, 3, and 5 of the course.

When taken orally, Vepesid^® is prescribed at 50 mg/m² daily for 21 days, with cycles repeated every 28 days, or at 100-200 mg/m² for 5 consecutive days with a 3-week interval.

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

Before IV administration, Vepesid^® 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.

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

Adverse Reactions

From the hematopoietic system: a decrease in the number of leukocytes and granulocytes is dose-dependent and is the main dose-limiting toxic manifestation of Vepesid^®. 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 Vepesid^® administration. Blood count recovery usually occurs by day 20 after administration of the standard dose. Anemia is not common.

From the digestive system: 30-40% – usually moderate nausea and vomiting (treatment discontinuation is rarely required; antiemetics are indicated); possible – diarrhea, abdominal pain, stomatitis, esophagitis, dysphagia, anorexia; sometimes – transient hyperbilirubinemia and increased transaminase levels (more often when used in doses exceeding the recommended ones).

From the cardiovascular system: 1-2% (with rapid IV administration) – temporary decrease in blood pressure (usually recovers upon cessation of infusion and administration of fluids or other supportive therapy; if Vepesid^® administration needs to be resumed, the infusion rate should be reduced).

Allergic reactions: chills, fever, tachycardia, bronchospasm, shortness of breath, and decreased blood pressure (usually observed during or immediately after Vepesid^® administration and cease upon discontinuation of the infusion and use of corticosteroids or antihistamines); rarely – Stevens-Johnson syndrome, toxic epidermal necrolysis.

Dermatological reactions: at least 66% – reversible alopecia, sometimes leading to complete hair loss; rarely – pigmentation, itching; in one case, a relapse of radiation dermatitis was observed.

From the CNS and peripheral nervous system rarely – peripheral neuropathy, drowsiness, increased fatigue, optic neuritis, transient cortical blindness.

From metabolism rarely – metabolic acidosis, hyperuricemia.

Local reactions phlebitis with IV administration; if the drug gets under the skin – a pronounced local irritant effect up to necrosis of surrounding tissues.

Other rarely – residual taste in the mouth, fever, interstitial pneumonitis/pulmonary fibrosis, muscle cramps.

Contraindications

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

With caution, the drug should be used in patients with epilepsy, alcoholism, in children under 2 years of age (safety and efficacy for children have not been established).

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation (breastfeeding).

Women and men of childbearing potential receiving therapy with Vepesid^® should use reliable methods of contraception.

Use in Hepatic Impairment

The drug should be prescribed with caution to patients with hepatic insufficiency.

Use in Renal Impairment

The drug should be prescribed with caution to patients with renal insufficiency.

Pediatric Use

^{With caution, the drug should be used in children under 2 years of age (safety and efficacy for children have not been established).}

Special Precautions

Vepesid^® should be used only under the constant supervision of a physician experienced in therapy with cytotoxic drugs.

The drug should be prescribed with caution to patients with hepatic or renal insufficiency.

Bone marrow suppression is the dose-limiting effect of Vepesid^®. Blood cell counts should be regularly monitored before starting treatment, during breaks, and before each subsequent course of Vepesid^®. If radiation therapy and/or chemotherapy was performed before starting therapy with Vepesid^®, a sufficient interval between these two types of treatment should be observed to ensure recovery of bone marrow function. If the platelet count falls below 50,000/µl and/or the absolute neutrophil count falls to 500/µl, therapy must be discontinued until blood counts are fully restored.

If anaphylactic reactions occur, the administration of Vepesid^® must be discontinued and treatment with corticosteroids and/or antihistamines should be initiated against the background of infusion therapy.

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

Occasionally, patients receiving therapy with Vepesid^® in combination with other antineoplastic drugs may develop acute leukemia, both with and without a preleukemic phase.

When working with Vepesid^®, 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 soap and water.

The Vepesid^® solution 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 overdose with etoposide in humans have been reported to date.

Symptoms it can be assumed that the main manifestations of overdose will be toxic effects on the blood and gastrointestinal tract.

Treatment symptomatic therapy. There is no specific antidote.

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.

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 completion of therapy.

Pharmaceutical interaction

Etoposide should not be mixed with other drugs in the same solution. Pharmaceutically incompatible with solutions having alkaline pH values.

Storage Conditions

The drug should be stored out of the 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.