Doxorubicin-Ebewe (Concentrate) Instructions for Use

Marketing Authorization Holder

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

ATC Code

L01DB01 (Doxorubicin)

Active Substance

Doxorubicin (Rec.INN registered by WHO)

Dosage Form

Doxorubicin-Ebewe

Concentrate for solution for intravascular and intravesical administration 2 mg/1 ml: fl. 5 ml, 10 ml, 25 ml, 50 ml or 100 ml 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for intravascular and intravesical administration red in color, transparent, free from foreign particles.

Excipients: sodium chloride – 9 mg, hydrochloric acid (10% solution) – 0.26 mg, water for injections – 993.74 mg.

5 ml – dark glass bottles (1) – cardboard boxes.
10 ml – dark glass bottles (1) – cardboard boxes.
25 ml – dark glass bottles (1) – cardboard boxes.
50 ml – dark glass bottles (1) – cardboard boxes.
100 ml – dark glass bottles (1) – cardboard boxes.

Clinical-Pharmacological Group

Antineoplastic antibiotic

Pharmacotherapeutic Group

Antineoplastic agent, antibiotic

Pharmacological Action

Antineoplastic antibiotic of the anthracycline class, isolated from the culture of Streptomyces peucetius var. caesius.

It has antimitotic and antiproliferative effects. Three main mechanisms of action of doxorubicin have been described: interaction with DNA, inhibition of topoisomerase I, DNA and RNA polymerases, formation of free radicals, and a direct effect on cell membranes, leading to suppression of DNA replication and nucleic acid synthesis, as well as a direct cytotoxic effect. Cells are sensitive to the drug in the S- and G2-phases of mitosis.

Pharmacokinetics

Absorption is high, distribution is relatively uniform. It does not cross the blood-brain barrier. Plasma protein binding is about 75%.

It is metabolized in the liver to form the active metabolite doxorubicinol. Enzymatic reduction of doxorubicin by oxidases, reductases, and dehydrogenases leads to the formation of free radicals, which may contribute to the manifestation of cardiotoxic effects. After intravenous administration, it rapidly disappears from the blood, concentrating in the liver, kidneys, myocardium, spleen, and lungs.

T_1/2 is 20-48 hours for doxorubicin and doxorubicinol.

Excretion: 40% in bile unchanged within 7 days, 5-12% of doxorubicin and its metabolites in urine within 5 days.

Indications

• Breast cancer;
• Lung cancer (small cell);
• Mesothelioma;
• Esophageal cancer;
• Stomach cancer;
• Primary hepatocellular carcinoma;
• Pancreatic cancer;
• Insulinoma;
• Carcinoid;
• Malignant tumors of the head and neck;
• Thyroid cancer;
• Malignant thymoma;
• Ovarian cancer;
• Testicular germ cell tumors;
• Trophoblastic tumors;
• Prostate cancer;
• Bladder cancer (treatment and prevention of recurrence after surgery);
• Endometrial cancer;
• Cervical cancer;
• Uterine sarcoma;
• Soft tissue sarcoma;
• Ewing’s sarcoma;
• Osteogenic sarcoma;
• Rhabdomyosarcoma;
• Neuroblastoma;
• Wilms’ tumor;
• Kaposi’s sarcoma;
• Acute lymphoblastic leukemia;
• Acute myeloblastic leukemia;
• Chronic lymphocytic leukemia;
• Hodgkin’s disease and non-Hodgkin’s lymphomas;
• Multiple myeloma.

ICD codes

Dosage Regimen

Doxorubicin can be used both as monotherapy and in combination with other cytostatics in various doses depending on the treatment regimen. When individually selecting the dose, one should be guided by data from specialized literature.

Intravenous administration

• As monotherapy, the recommended dose per cycle is 60-75 mg/m² every 3 weeks. The drug is usually administered as a single dose during a cycle; however, the cycle dose can be divided into several administrations (e.g., administered on the first 3 consecutive days, or on the first and eighth day of the cycle). Cycles are repeated every 3-4 weeks;
• To reduce the toxic effects of doxorubicin, especially cardiotoxicity, a weekly administration regimen of 10-20 mg/m² is used;
• In combination with other antineoplastic drugs, Doxorubicin is prescribed at a cycle dose of 30-60 mg/m² every 3-4 weeks.

Impaired liver function. In patients with hyperbilirubinemia, the dose of doxorubicin should be reduced according to the total bilirubin concentration

• By 50% when serum bilirubin concentration is 1.2-3.0 mg/dl;
• By 75% when serum bilirubin concentration is above 3.0 mg/dl.

The cumulative dose of doxorubicin should not exceed 550 mg/m². In patients who have previously received radiation therapy to the lungs and mediastinum or have been treated with other cardiotoxic drugs, the cumulative dose of doxorubicin should not exceed 400 mg/m².

Intravenous administration of doxorubicin should be performed with caution. To reduce the risk of thrombosis and extravasation, it is recommended to administer Doxorubicin through the tubing of an intravenous infusion system, during infusion of 0.9% sodium chloride solution or 5% dextrose solution, over 3-5 minutes.

Bladder instillation

Bladder instillation is used for the treatment of superficial bladder tumors, as well as for the prevention of recurrence after transurethral resection. Bladder instillation is not used for the treatment of invasive tumors with penetration into the muscular wall of the bladder.

The recommended dose for intravesical administration is 30-50 mg per instillation, with intervals between administrations from 1 week to 1 month, depending on the goals of therapy – treatment or prevention. The recommended concentration of the solution is 1 mg/1 ml of water for injections or 0.9% sodium chloride solution. After completion of the instillation, to ensure uniform exposure of the drug to the bladder mucosa, patients should turn from side to side every 15 minutes. As a rule, the drug should remain in the bladder for 1-2 hours. At the end of the instillation, the patient should empty the bladder.

To prevent excessive dilution of the drug with urine, patients should be warned to refrain from fluid intake for 12 hours before the instillation. Systemic absorption of doxorubicin during bladder instillation is very low.

In case of manifestations of local toxic effects (chemical cystitis, which may manifest as dysuria, polyuria, nocturia, painful urination, hematuria, bladder discomfort, necrosis of the bladder wall), the dose intended for instillations should be dissolved in 50-100 ml of 0.9% sodium chloride solution. Special attention should be paid to problems associated with catheterization (e.g., in case of urethral obstruction due to massive intravesical tumors).

Intra-arterial administration

In patients with hepatocellular carcinoma, to ensure intensive local exposure while reducing systemic toxicity, Doxorubicin can be administered intra-arterially into the main hepatic artery at a dose of 30-150 mg/m² at intervals from 3 weeks to 3 months. Higher doses should be used only in cases where simultaneous extracorporeal elimination of the drug is performed.

Since this method is potentially dangerous and may result in air embolism and/or arterial thrombosis leading to extensive tissue necrosis, intra-arterial administration should be performed only by physicians who are perfectly skilled in this technique.

Adverse Reactions

From the hematopoietic system very common – dose-dependent reversible myelosuppression (leukopenia and neutropenia, thrombocytopenia, anemia). Leukopenia usually reaches its nadir 10-14 days after drug administration, and blood count recovery is usually observed by day 21.

From the cardiovascular system common – early (acute) cardiotoxicity, manifestations of which include sinus tachycardia, tachyarrhythmias (including ventricular tachycardia), supraventricular or ventricular extrasystoles, as well as bradycardia, AV block, bundle branch block and/or pathological changes on ECG (nonspecific ST-T wave changes), decreased blood pressure, palpitations; late (delayed) cardiotoxicity, which manifests as a decrease in left ventricular ejection fraction without clinical symptoms and/or with symptoms of congestive heart failure – shortness of breath, pulmonary edema, peripheral edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy, gallop rhythm, pericarditis, myocarditis; very rare – phlebitis, thrombophlebitis, thromboembolic complications, including pulmonary embolism (in some cases with fatal outcome).

From the digestive system very common – nausea, vomiting, ulcerative lesions of the gastrointestinal mucosa (stomatitis, esophagitis, ulcerative colitis, usually on days 5-10 after the start of treatment and may progress with repeated therapeutic cycles), hyperpigmentation of the oral mucosa, abdominal pain, gastrointestinal bleeding, diarrhea, colitis. Increased concentration of total bilirubin and activity of liver transaminases in the blood serum.

From the urinary system common – red coloration of urine for 1-2 days after doxorubicin administration, hematuria, polyuria, strangury, painful urination, hemorrhagic cystitis, amenorrhea (ovulation usually recovers after the end of therapy, but premature menopause may occur), oligospermia, azoospermia (in some cases, the sperm count returns to normal levels; this may occur several years after the end of therapy); rare – nephropathy associated with increased uric acid formation.

From the reproductive system common – amenorrhea (ovulation usually recovers after the end of therapy, but premature menopause may occur), oligospermia, azoospermia (in some cases, the sperm count returns to normal levels; this may occur several years after the end of therapy).

From the sensory organs conjunctivitis, keratitis, lacrimation.

From the skin and skin appendages very common – reversible complete alopecia (hair regrowth usually begins 2-3 months after discontinuation of the drug), hyperpigmentation of the skin and nails, photosensitivity, urticaria, rash, itching. In some patients who had previously undergone radiation therapy, after doxorubicin administration (usually after 4-7 days), hypersensitivity of the irritated skin, erythema with blistering, edema, severe pain, and moist epidermitis were observed in areas corresponding to the radiation fields.

From the respiratory system: very rare – tachypnea, dyspnea, exudative pleurisy, bronchospasm, interstitial pneumonia.

Local reactions uncommon – erythematous streaking along the vein into which the infusion was performed, followed by local phlebitis or thrombophlebitis. Phlebosclerosis may also develop, especially if Doxorubicin is repeatedly administered into a small vein. If the drug enters the surrounding tissues, local pain, severe inflammation of the subcutaneous tissue, and tissue necrosis may occur.

With intra-arterial administration in addition to systemic toxicity, gastric and duodenal ulcers may be observed (probably due to reflux of the drugs into the gastric artery); narrowing of the bile ducts due to drug-induced sclerosing cholangitis.

With intravesical administration cystitis.

Other malaise, drowsiness, asthenia, fever, chills, facial flushing, development of acute lymphocytic or myelocytic leukemia, in children – development of late neoplastic diseases, in particular – myeloid leukemia.

Contraindications

• Hypersensitivity to doxorubicin or other components of the drug, as well as to other anthracyclines and anthracenediones;
• Pregnancy;
• Period of lactation (breastfeeding).

Intravenous administration is contraindicated in

• Severe myelosuppression (neutrophil count less than 1500 cells/µl);
• Severe hepatic insufficiency;
• Severe heart failure and arrhythmias;
• Recent myocardial infarction;
• Prior therapy with other anthracyclines or anthracenediones at the maximum cumulative doses;
• Acute viral infections (including chickenpox, herpes zoster).

Bladder instillation is contraindicated in

• Invasive tumors with penetration into the bladder wall;
• Urinary tract infections;
• Inflammatory diseases of the bladder.

With caution the drug should be used in patients who have previously received intensive chemotherapy; with heart disease; with risk factors for cardiotoxicity; with obesity, with tumor infiltration of the bone marrow, with severe liver dysfunction (may require reduction of initial doses or increase of intervals between doses); with urate nephrolithiasis (including history); as part of combined antineoplastic therapy, as well as in combination with radiation or other antineoplastic therapy; in children; in elderly patients.

Use in Pregnancy and Lactation

No controlled studies on the use of doxorubicin in pregnant women have been conducted. Animal studies have shown embryotoxic, teratogenic, and mutagenic effects of doxorubicin. Therefore, Doxorubicin should not be used during pregnancy.

Since Doxorubicin is excreted in breast milk, breastfeeding should be discontinued during treatment to avoid the toxic effects of the drug on the infant.

Men and women of reproductive potential should use reliable methods of contraception during treatment with doxorubicin and for at least 3 months thereafter.

Use in Hepatic Impairment

In patients with hyperbilirubinemia, the dose of doxorubicin should be reduced according to the total bilirubin concentration.

• By 50% for a serum bilirubin concentration of 1.2-3.0 mg/dL;
• By 75% for a serum bilirubin concentration above 3.0 mg/dL.

Intravenous administration is contraindicated in severe hepatic impairment.

Pediatric Use

Lower doses or increased intervals between cycles are recommended for children.

Geriatric Use

Lower doses or increased intervals between cycles are recommended for elderly patients.

Special Precautions

Treatment with Doxorubicin-Ebewe should be carried out under the supervision of physicians experienced in the use of antineoplastic agents.

To reduce the risk of cardiotoxicity, regular monitoring of cardiac function using various diagnostic methods (echocardiography, scintigraphy, ECG) is recommended before and during doxorubicin therapy. Early clinical diagnosis of drug-induced heart failure is very important for successful treatment. If signs of cardiotoxicity are detected (clinical signs – decreased blood pressure, cardiac arrhythmias, chest pain; instrumental signs – a decrease in left ventricular ejection fraction by more than 10% or below 50% in patients with initially normal cardiac contractility, enlarged heart size), doxorubicin treatment should be discontinued immediately.

Acute cardiotoxicity is mostly reversible (ECG shows ST-segment depression or mild arrhythmias) and is usually not considered an indication for discontinuation of doxorubicin therapy. However, if a 30% decrease in QRS complex amplitude from baseline, QRS complex widening on ECG, or a 5% decrease in left ventricular fractional shortening on echocardiogram occurs, discontinuation of doxorubicin treatment is recommended. Late (delayed) cardiotoxicity (cardiomyopathy) is dose-dependent. The probability of developing myocardial dysfunction is approximately 1-2% at a cumulative dose of 300 mg/m²; this probability slowly increases at a total cumulative dose of 450-550 mg/m². Exceeding this dose sharply increases the risk of developing congestive heart failure, therefore it is recommended to discontinue doxorubicin treatment upon reaching a total cumulative dose of 550 mg/m². If the patient has any additional risk of cardiotoxicity (e.g., history of heart disease, prior therapy with anthracyclines or anthracenediones, prior mediastinal radiation therapy, concurrent use of other potentially cardiotoxic drugs such as cyclophosphamide and 5-fluorouracil, age under 15 or over 70 years), toxic effects may occur at lower cumulative doses, and cardiac function monitoring should be particularly thorough. Doxorubicin-induced cardiotoxicity develops mainly during the course of therapy or within two months after its completion; however, delayed adverse effects may occur (several months or even years after the end of therapy).

During doxorubicin treatment, hematological parameters should be assessed before and during each treatment cycle, including determination of leukocyte, platelet, hemoglobin, blood cell counts, and liver function tests.

Patients with developed neutropenia/leukopenia should be closely monitored for signs of superinfection.

At the first signs of doxorubicin extravasation (burning or pain at the injection site), the infusion should be stopped immediately and then resumed in another vein to administer the full dose. Local measures should be taken to manage the consequences of extravasation. The use of ice packs is advisable.

If possible, administration into veins over joints or into limbs with impaired venous or lymphatic drainage should be avoided.

Due to rapid tumor cell lysis, hyperuricemia may occur with the use of doxorubicin; therefore, it is recommended to monitor serum uric acid, potassium, calcium, and creatinine levels during therapy. Measures such as increased hydration, urine alkalinization, and prophylactic administration of allopurinol to prevent hyperuricemia can minimize the risk of complications associated with tumor lysis syndrome. When treating hyperuricemia and gout, dose adjustment of antigout agents may be required due to increased uric acid concentration during treatment with the drug.

Immunization is not recommended unless approved by a physician in the interval from 3 months to 1 year after taking the drug; other family members living with the patient should avoid immunization with oral polio vaccine; avoid contact with people who have received the polio vaccine, or wear a protective mask covering the nose and mouth.

Doxorubicin may cause red discoloration of urine.

When handling doxorubicin, the rules for working with cytotoxic substances must be observed. Surfaces contaminated with the drug should be treated with a diluted sodium hypochlorite solution (containing 1% chlorine). If the drug gets on the skin – immediately wash the skin thoroughly with water and soap or a sodium bicarbonate solution; if it gets into the eyes – pull back the eyelids and rinse the eye(s) with plenty of water for at least 15 minutes.

Residues of the drug and all instruments and materials used for preparing solutions for intravascular and intravesical administration of Doxorubicin-Ebewe must be destroyed in accordance with the standard hospital procedure for the disposal of cytotoxic waste, taking into account the current regulations for the disposal of hazardous waste.

Effect on ability to drive vehicles and operate machinery

Due to the likelihood of side effects such as nausea, vomiting, and drowsiness, caution should be exercised when engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Overdose

Symptoms severe myelosuppression (primarily leukopenia, thrombocytopenia), toxic gastrointestinal lesions (nausea, vomiting, stomatitis, enteritis, diarrhea), acute cardiac lesions (decreased blood pressure, tachycardia, arrhythmia, chest pain, acute heart failure).

Treatment no specific antidote for doxorubicin is known. In case of overdose, symptomatic therapy is recommended. Hemodialysis is not effective.

Drug Interactions

Doxorubicin may enhance the toxicity of other antineoplastic agents, especially myelotoxicity and gastrointestinal toxicity.

When doxorubicin is used concomitantly with other cytotoxic drugs that have potential cardiotoxicity (e.g., daunorubicin, dactinomycin, 5-fluorouracil, mitomycin, cyclophosphamide), careful monitoring of cardiac function throughout the course of therapy is required. The recommended dose of doxorubicin is no more than 400 mg/m². The use of doxorubicin in patients who have received full cumulative doses of daunorubicin or doxorubicin (in their medical history) is not recommended.

Against the background of doxorubicin, the manifestations of hemorrhagic cystitis caused by cyclophosphamide and the hepatotoxicity of 6-mercaptopurine may be enhanced.

Streptozotocin increases the T_1/2 of doxorubicin.

Doxorubicin enhances the radiation-induced toxic effects on the myocardium, mucous membranes, skin, and liver.

Uricosuric antigout drugs increase the risk of nephropathy.

When cyclosporine and doxorubicin are used together, the plasma concentrations of both drugs increase. This may lead to an increased risk of myelotoxicity and immunosuppression.

Hepatotoxic drugs, by impairing liver function, may increase the toxicity of doxorubicin.

Inhibitors of the cytochrome P450 enzyme system (e.g., cimetidine, ranitidine) may reduce the metabolism of doxorubicin, thereby increasing the risk of its toxic effects.

Inducers of the cytochrome P450 enzyme system (e.g., rifampicin, barbiturates) may increase the rate of doxorubicin metabolism, thereby reducing its effectiveness.

When used concomitantly with slow calcium channel blockers (e.g., verapamil), the cytotoxicity of doxorubicin increases.

Since doxorubicin treatment may suppress natural defense mechanisms, vaccination is recommended only after some time (from 3 months to 1 year) after the end of treatment.

Pharmaceutical interactions

Doxorubicin should not be mixed with other drugs. Contact with alkaline solutions should be avoided as this may lead to hydrolysis of doxorubicin.

Pharmaceutically incompatible with heparin, dexamethasone, fluorouracil, hydrocortisone, sodium succinate, aminophylline, cephalothin, and other antineoplastic drugs.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature between 2°C (35.6°F) and 8°C (46.4°F).

Shelf Life

The shelf life is 2 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.