Etoposide-mili

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ETOPOSIDE-MILI (ETOPOSIDE-MILI)

Composition:

Active substance: etoposide;

1 ml of solution contains 20 mg of etoposide;

Excipients: benzyl alcohol*, polyethylene glycol 300, citric acid, anhydrous; polysorbate 80, ethanol 96%**.

*The content of benzyl alcohol in the preparation is 30 mg.

**The ethanol content in the preparation is 30.5% by volume.

Pharmaceutical form. Concentrate for solution for infusion.

Main physico-chemical properties: clear, colorless or slightly yellowish solution.

Pharmacotherapeutic group. Antineoplastic agents. Podophyllotoxin derivatives.

ATC code L01C B01.

Pharmacological Properties.

Pharmacodynamics.

Etoposide is a semisynthetic derivative of podophyllotoxin. It exerts a pronounced cytotoxic effect, which largely depends on the dose and treatment regimen. Etoposide affects the function of topoisomerase II (an enzyme that cleaves DNA) and inhibits DNA synthesis in the terminal phase. As a result, single-strand and double-strand DNA breaks are formed. The cytotoxic effect depends on the concentration and duration of exposure to etoposide. The drug blocks mitosis, causing cell death in the S-phase and early G2-phase of the cell cycle. Unlike other known podophyllotoxins, it does not cause accumulation of cells in the metaphase stage.

Pharmacokinetics.

There is considerable inter-subject variability in pharmacokinetic parameters. Etoposide is rapidly distributed throughout the body. Plasma protein binding is approximately 94%. The pharmacokinetics of etoposide after intravenous administration follows a biexponential two-compartment model. The distribution half-life in the first phase is approximately 1.5 hours, and the terminal elimination half-life ranges from 4 to 11 hours. Etoposide penetrates poorly into the cerebrospinal fluid. Approximately 45% of the administered dose is excreted in the urine, two-thirds of which is excreted unchanged within 72 hours. Phenylbutazone, sodium salicylate, and salicylic acid may displace etoposide bound to plasma proteins.

Clinical characteristics.

Indications.

• Small cell lung cancer.
• Non-seminomatous carcinoma of the testis.
• Acute myelomonocytic and myelocytic leukemia (AML, subtypes M4 or M5 according to FAB classification) as part of combination therapy when induction therapy is ineffective.
• Palliative therapy of non-small cell lung cancer, reinduction therapy of Hodgkin’s disease, induction therapy of non-Hodgkin’s lymphoma and acute myelocytic leukemia, as well as induction and reinduction therapy of choriocarcinoma.

Contraindications.

• Hypersensitivity to etoposide or to any other component of the drug.
• Severe impairment of liver function.
• Severe impairment of renal function (creatinine clearance < 15 mL/min).
• Marked suppression of bone marrow function.
• Etoposide must not be administered intraarterially or intracavitarily (into pleural, peritoneal, or other cavities).
• Acute infections.
• Administration of yellow fever vaccine or other live vaccines during treatment with the drug in patients with immunosuppression.

Special safety precautions.

When handling the drug, general safety rules for cytotoxic substances must be observed.

Solutions for infusion should be prepared in an isolated cabinet or a biological safety cabinet designed for handling cytostatic agents. Protective clothing (disposable gloves, masks, goggles, gowns and caps or coveralls) must be used. Measures must be taken to prevent contact of etoposide solutions with skin or mucous membranes. If the drug comes into contact with skin or mucous membranes, the affected area should be immediately washed with copious amounts of water.

Pregnant healthcare personnel must not handle the drug.

Unused drug residues and all instruments and materials used in the preparation and administration of infusion solutions must be disposed of according to an approved procedure for disposal of cytotoxic waste.

Interaction with other medicinal products and other types of interactions.

Etoposide may potentiate the cytotoxic and myelosuppressive effects of other drugs (particularly cyclosporine). Concurrent therapy with high doses of cyclosporine has been associated with increased etoposide exposure and reduced clearance.

Concomitant radiotherapy or chemotherapy with myelosuppressive agents may enhance bone marrow suppression caused by etoposide.

Etoposide may potentiate the effect of oral anticoagulants.

Phenylbutazone, sodium salicylate, and salicylic acid may reduce etoposide binding to plasma proteins.

Cross-resistance between anthracyclines and etoposide has been demonstrated experimentally.

Information regarding the use of etoposide in combination with drugs that inhibit phosphatase activity (e.g., levamisole hydrochloride) is lacking.

Combination therapy with cisplatin is associated with reduced total clearance of etoposide. Conversely, concomitant use with phenytoin is associated with increased total clearance of etoposide and reduced efficacy.

Concomitant therapy with warfarin may lead to an increase in the international normalized ratio (INR). Careful monitoring of prothrombin time is recommended.

Vaccination with live vaccines in immunocompromised patients after chemotherapy may lead to the development of severe and fatal infections.

Potentially favorable interactions

When etoposide is used in combination with other cytotoxic agents (particularly methotrexate and cisplatin), a synergistic therapeutic effect is observed.

Special precautions for use.

Etoposide-Mili concentrate for infusion solution must not be administered undiluted.

Etoposide-Mili may be diluted only with 5 % glucose solution or 0.9 % sodium chloride solution. The concentration of etoposide in the infusion solution must not exceed 0.4 mg/mL due to the risk of precipitate formation.

Only clear infusion solutions practically free from mechanical particles should be administered.

Etoposide treatment must be conducted under the supervision of an oncologist.

If radiotherapy and/or chemotherapy were administered prior to etoposide therapy, etoposide treatment must not be initiated until normal bone marrow function has been restored.

Reactions at the injection site may occur during administration. When etoposide is administered intravenously, care should be taken to avoid extravasation. It is recommended to closely monitor the injection site for possible infiltration during drug administration. Specific treatment for extravasation reactions is currently unknown.

Etoposide is not recommended for use in patients with neutrophil counts < 1,500/mm³ (1.5 × 10⁹/L) or platelet counts < 100,000/mm³ (100 × 10⁹/L), unless such reductions are not caused by malignant disease. Dose modification should be considered after the initial dose if neutrophil counts are less than 500/mm³ (0.5 × 10⁹/L) for 5 or more days or if the reduction is associated with fever or infection, if platelet counts are less than 25,000/mm³ (25 × 10⁹/L), if other signs of grade 3 or 4 toxicity occur, or if renal clearance is less than 50 mL/min.

Acute leukemia, which may be associated with myelodysplastic syndrome, has been reported in patients undergoing chemotherapy with etoposide-containing drugs.

Severe myelosuppression may occur, leading to infections or bleeding. Cases of fatal myelosuppression have been reported following etoposide administration. Patients undergoing etoposide therapy should be regularly and carefully monitored for myelosuppression both during and after treatment.

Complete blood counts and liver function tests should be monitored. If white blood cell counts decrease to less than 2,000/mm³ and platelet counts to less than 50,000/mm³, treatment should be suspended until hematological parameters normalize (white blood cell count > 4,000/mm³, platelet count > 100,000/mm³). The time required for bone marrow recovery depends on whether etoposide is administered as monotherapy or in combination with other chemotherapeutic agents. Hematological parameters usually normalize within 21 days.

Bacterial infections should be treated prior to initiating etoposide therapy.

Anaphylactic reactions (flushing, tachycardia, bronchospasm, hypotension) may occur during etoposide administration.

Nausea and vomiting occur in 30–40 % of patients. Anti-emetic agents can reduce the intensity of these adverse reactions.

Etoposide should be used with caution in patients with cardiac arrhythmias, history of myocardial infarction, hepatic or renal dysfunction, peripheral neuropathy, urinary disorders, epilepsy or brain injury, oral mucositis, and in patients previously treated with radiotherapy or chemotherapy.

In rare cases, patients treated with etoposide in combination with other antineoplastic agents may develop acute leukemia (with or without a pre-leukemic phase). The risk of secondary acute non-lymphoblastic leukemia increases with cumulative etoposide doses > 2,000 mg/m² body surface area.

The cumulative risk or factors contributing to secondary leukemia are currently unknown. Both treatment regimens and etoposide accumulation have been implicated but not clearly defined. In some cases of secondary leukemia in patients treated with epipodophyllotoxins, chromosome 11q23 abnormalities were observed. This abnormality has also been reported in patients with secondary leukemia after chemotherapy regimens not including epipodophyllotoxins and in de novo leukemia. Another factor associated with secondary leukemia in patients treated with epipodophyllotoxins is a short latent period—the median time to leukemia development was approximately 32 months.

Physicians should be aware of the potential for anaphylactic reactions to etoposide, with symptoms including chills, fever, tachycardia, respiratory arrest, and hypotension, which may lead to fatal outcomes. Treatment is symptomatic. Infusion should be stopped immediately, and vasopressors, corticosteroids, antihistamines, or plasma expanders should be administered as clinically indicated. An increased risk of infusion-related hypersensitivity reactions has been observed when in-line filters are used during etoposide administration. In-line filters should not be used. Etoposide should be administered only by slow intravenous infusion (usually over 30–60 minutes), as hypotension may occur with rapid intravenous injection. Whenever etoposide is selected for chemotherapy, the physician must weigh the potential benefits against the risk of adverse reactions. Most such reactions are manageable if detected early. If severe reactions occur, the dose should be reduced or treatment discontinued, and corrective measures implemented based on clinical assessment. Re-administration should be done cautiously, with careful evaluation of the continued need for the drug and consideration of the potential for recurrent toxicity. Patients with low serum albumin levels are at increased risk of etoposide-related toxicity. Patients with hepatic or renal impairment require regular monitoring of organ function due to the risk of drug accumulation.

Each 1 mL of Etoposide-Mili contains 260.6 mg of ethanol. At a dose of 120 mg/m², a patient with a body surface area of 1.6 m² receives 2.5 g of ethanol. This should be considered when prescribing the drug to patients with a history of alcohol dependence or those taking disulfiram. This fact should also be taken into account when treating pregnant women, breastfeeding women, children, and patients at special risk, such as those with liver disease or epilepsy. Etoposide injections contain polysorbate 80. In preterm infants, administration of vitamin E injection products containing polysorbate 80 has been associated with life-threatening conditions such as hepatic and renal failure, pulmonary dysfunction, thrombocytopenia, and ascites.

Since the product contains benzyl alcohol, it should not be administered to children under 6 months of age due to the risk of metabolic acidosis. Benzyl alcohol may also cause toxic and allergic reactions in children under 3 years of age.

Etoposide is mutagenic and carcinogenic. This should be considered during long-term therapy.

Because etoposide may exert genotoxic effects, men are advised not to father children during treatment and for 6 months after completion of etoposide therapy.

Due to the potential for irreversible infertility, male patients are advised to undergo sperm cryopreservation prior to starting etoposide therapy.

Acute renal failure

Cases of reversible acute renal failure have been reported, primarily in children receiving high-dose etoposide (2,220 mg/m² or 60 mg/kg) in combination with total body irradiation for hematopoietic stem cell transplantation. Renal function should be assessed before and after etoposide administration until full recovery.

Renal impairment

Etoposide should be administered at a reduced dose in patients with moderate (creatinine clearance 15–50 mL/min) or severe (creatinine clearance <15 mL/min) renal impairment undergoing hemodialysis (see section "Dosage and administration"). Hematological parameters should be monitored, and doses adjusted in subsequent cycles based on hematological toxicity and clinical response in patients with moderate to severe renal impairment.

Use during pregnancy or breastfeeding.

There is evidence that etoposide may cause severe fetal abnormalities when used during pregnancy; therefore, the drug should not be administered during pregnancy except for life-saving indications.

Patients of reproductive age should use effective contraception during treatment to prevent pregnancy. If pregnancy occurs, the continuation of therapy should be carefully evaluated considering the potential benefit to the mother and the possible risk to the fetus.

It is currently unknown whether etoposide is excreted in breast milk; therefore, adverse effects in breastfed infants cannot be excluded. Breastfeeding must be discontinued during etoposide treatment.

Ability to influence reaction speed when driving or operating machinery.

No studies on the effect of etoposide on the ability to drive or operate machinery have been conducted.

Since etoposide may cause increased fatigue and transient blindness, patients are advised not to drive or operate machinery after drug administration.

Administration and Dosage

Etoposide-Mili should be administered only by slow intravenous infusion (usually over 30–60 minutes), as hypotension may occur following rapid intravenous infusions.

Immediately before administration, the required amount of the drug should be diluted with 5% glucose solution or 0.9% sodium chloride solution to a final etoposide concentration of 0.2–0.4 mg/mL (usually not exceeding 0.25 mg/mL). The diluted solution should then be administered by intravenous infusion over at least 30 minutes.

Precautions must be taken to prevent extravasation.

Etoposide-Mili is recommended at a dose of 60–120 mg/m² of body surface area daily for 5 consecutive days. Since etoposide suppresses bone marrow function, treatment cycles should be repeated with intervals of at least 10–20 days.

In the treatment of non-hematological malignancies, intervals between treatment cycles should be at least 21 days. The next course of etoposide therapy should only be initiated after normalization of blood cell counts.

The dosage of etoposide should be adjusted according to the myelosuppressive effects of other concomitant drugs, or prior radiotherapy or chemotherapy, which may reduce bone marrow reserve.

A new course of etoposide therapy should only be initiated if the neutrophil count is not less than 1,500/mm³ (1.5 × 10⁹/L) and the platelet count is not less than 100,000/mm³ (100 × 10⁹/L), except in cases where the decline in counts is due to tumor infiltration.

Dosage modification after the initial dose should be considered if the neutrophil count is less than 500/mm³ (0.5 × 10⁹/L) for 5 or more days, or if the neutropenia is associated with fever or infection; if the platelet count is less than 25,000/mm³ (25 × 10⁹/L); if other signs of grade 3 or 4 toxicity occur; or if renal clearance is less than 50 mL/min.

Treatment of elderly patients

Dose adjustment is not required for elderly patients.

Treatment of patients with renal impairment

Patients with impaired renal function but normal liver function should receive lower doses, and key hematological parameters and renal function should be closely monitored. Etoposide dosage should be adjusted according to creatinine clearance as per the recommendations below.

Subsequent dosing should be based on patient tolerance and clinical response. There are currently no data regarding optimal dosing in patients with creatinine clearance <15 mL/min; therefore, further dose reduction is recommended in this patient group.

Children.

The safety and efficacy of the drug in children have not been sufficiently studied.

Given the limited experience with etoposide use in children, the justification for its use should be carefully evaluated considering the potential benefit and possible risk.

Overdose.

Intravenous administration of etoposide at total doses of 2.4–3.5 g/m² body surface area over three days has caused severe mucositis and bone marrow suppression. Severe hepatotoxic effects and development of metabolic acidosis have been reported in patients who received etoposide at doses higher than recommended. There is no specific antidote for etoposide. In case of overdose, symptomatic and supportive treatment should be administered.

Adverse Reactions

The frequency and severity of adverse reactions depend on the dose of etoposide and the intervals between administrations. Dose-limiting adverse reactions are leukopenia and thrombocytopenia.

With combination chemotherapy, the frequency and severity of adverse effects increase.

Infections * and infestations: varicella, sepsis, influenza.

*Including opportunistic infections such as Pneumocystis pneumonia.

Cases of progressive multifocal leukoencephalopathy and other opportunistic infections have been reported.

Benign and malignant neoplasms (including cysts and polyps): secondary acute leukemia (with or without preleukemic phase) in patients treated with etoposide in combination with other antineoplastic agents.

In some patients with secondary leukemia following therapy with epipodophyllotoxins, an abnormality of chromosome 11q23 has been observed. The latency period for secondary leukemia in patients receiving epipodophyllotoxins was short (average 32 months).

Blood and lymphatic system disorders: myelosuppression (with fatal outcome), leukopenia and thrombocytopenia, neutropenia, anemia. White blood cell counts usually reach a nadir 5–15 days after drug administration (granulocytes – 7–14 days). Leukopenia (including WHO grade III or IV) occurs more frequently than thrombocytopenia. Hematological parameters usually return to normal within 24–28 days after the last dose. Cumulative toxicity is not observed with etoposide monotherapy. Decreased hemoglobin levels (approximately by 40%), anemia, infections, and bleeding due to severe myelosuppression.

Immune system disorders: anaphylactic reactions (with symptoms such as malaise, chills, fever, facial flushing, tachycardia, dyspnea, apnea, bronchospasm, arterial hypotension), angioneurotic edema (Quincke's edema), anaphylactic shock. Anaphylactic reactions were more frequently observed in children who received infusion solutions with etoposide concentrations higher than recommended. The dependence of anaphylactic reactions on the concentration of infusion solutions or the rate of drug administration has not been established. In case of anaphylactic reactions, the drug should be discontinued and symptomatic treatment initiated with vasopressor agents (e.g., adrenaline), corticosteroids, antihistamines, and, if necessary, plasma expanders.

In isolated cases, hypersensitivity reactions may be caused by benzyl alcohol contained in the formulation.

Metabolic disorders: hyperuricemia, metabolic acidosis, tumor lysis syndrome (often with fatal outcome).

Nervous system disorders: peripheral neuropathy, seizures (episodically associated with allergic reactions), symptoms of neurotoxicity (including somnolence, increased fatigue), confusion, hyperkinesia, akinesia, dizziness, taste alterations, transient cortical blindness, numbness of extremities, headache.

Eye disorders: optic neuritis, lacrimation.

Cardiac disorders: myocardial infarction, cardiac arrhythmias, chest pain, pathological changes on electrocardiogram.

Vascular disorders: unstable systolic hypotension accompanying rapid intravenous administration (blood pressure normalizes when infusion rate is reduced); arterial hypertension and facial flushing (blood pressure usually normalizes within several hours after completion of drug administration); phlebitis.

Respiratory, thoracic and mediastinal disorders: apnea with spontaneous recovery of breathing after completion of etoposide treatment; cough, laryngospasm, cyanosis; interstitial pneumonitis/pulmonary fibrosis, pneumonia, dyspnea, sudden fatal reactions associated with bronchospasm, nasal congestion.

Gastrointestinal disorders: nausea, vomiting, diarrhea, anorexia; mucosal inflammation of the oral cavity (including stomatitis and esophagitis); abdominal pain, constipation, dysphagia, dysgeusia.

Hepatobiliary disorders: since high concentrations of etoposide are achieved in the liver, it may impair liver function due to accumulation, increased levels of liver enzymes, increased levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, hyperbilirubinemia.

Skin and subcutaneous tissue disorders: reversible alopecia (sometimes complete hair loss), facial and tongue edema, increased sweating, skin rashes, urticaria, skin pigmentation changes, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, alopecia, pruritus, dermatitis, hyperemia, including facial hyperemia, recurrence of radiation dermatitis symptoms.

Renal and urinary disorders: since high concentrations of etoposide are achieved in the kidneys, it may impair kidney function due to accumulation, increased urea and creatinine levels, acute renal failure.

Reproductive system disorders: amenorrhea, anovulatory cycles, reduced fertility, hypomenorrhea, azoospermia.

General disorders and administration site reactions: asthenia, general malaise, extravasation (with toxicity to adjacent soft tissues, swelling, pain, connective tissue inflammation, and skin necrosis), phlebitis.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging, out of reach of children.

Incompatibilities.

Etoposide-Mil should not be diluted with buffer solutions with pH > 8, as precipitation may occur.

Etoposide-Mil must not be mixed with other medicinal products in the same infusion bag or vial.

Cases of cracking in components of syringes and infusion systems made of acrylic polymers or acrylonitrile-butadiene-styrene (ABS) have been reported upon contact with undiluted Etoposide-Mil 20 mg/mL infusion concentrate. This effect is not observed with diluted infusion solutions.

Packaging.

Infusion concentrate in glass vials of 50 mg/2.5 mL; 100 mg/5 mL; 200 mg/10 mL in cardboard boxes.

Prescription category. Prescription only.

Manufacturer. Venus Remedies Limited.

Manufacturer's address and place of business.

Hill Top Industrial Estate, Jharmajri, ERIP Phase-I (Ext.), Batoli Kalan, Baddi, Solan District, Himachal Pradesh 173205, India.

Marketing Authorization Holder. Milpharm Limited.

Address of Marketing Authorization Holder: 2nd Floor, Office Suite, 4 Charterfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, United Kingdom.