Doxorubicin-Teva (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Pharmachemie, B.V. (Netherlands)

ATC Code

L01DB01 (Doxorubicin)

Active Substance

Doxorubicin (Rec.INN registered by WHO)

Dosage Forms

	Doxorubicin-Teva	Lyophilisate for preparation of solution for intravascular and intravesical administration 10 mg: vial 1 pc.
		Lyophilisate for preparation of solution for intravascular and intravesical administration 50 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilized powder for preparation of injection solution as a powder or mass from orange-red to red color.

Excipients: lactose monohydrate.

Vials (1) – cardboard packs.
Vials (10) – foam boxes.

Lyophilized powder for preparation of injection solution as a powder or mass from orange-red to red color.

Excipients: lactose monohydrate.

Vials (1) – cardboard packs.
Vials (10) – foam boxes.

Clinical-Pharmacological Group

Antineoplastic antibiotic

Pharmacotherapeutic Group

Antineoplastic agent, antibiotic

Pharmacological Action

An anthracycline antineoplastic antibiotic isolated from the culture of Streptomyces peucetius var. caesius.

It has antimitotic and antiproliferative effects. The mechanism of action involves interaction with DNA, formation of free radicals, and a direct effect on cell membranes with suppression of nucleic acid synthesis. Cells are sensitive to the drug in the S- and G2-phases.

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

Indications

• Breast cancer;
• Lung cancer (small cell);
• Mesothelioma;
• Esophageal cancer;
• Stomach cancer;
• Primary hepatocellular carcinoma;
• Pancreatic cancer;
• Insulinoma;
• Carcinoid;
• Head and neck cancer;
• 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;
• Ewing’s sarcoma;
• Rhabdomyosarcoma;
• Neuroblastoma;
• Wilms’ tumor;
• Osteogenic sarcoma;
• Soft tissue sarcoma;
• 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 therapy 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 three 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 three consecutive days, or on day one and day eight of the cycle). Cycles are repeated every 3-4 weeks.
• To reduce the toxic effect 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 12-30 mg/L;
• By 75% when serum bilirubin concentration is above 30 mg/L.

Other special patient groups. Prescription of lower doses or increasing the intervals between cycles is recommended for patients who have previously received extensive antineoplastic therapy, for children, for elderly patients, for patients with obesity (if body weight is more than 130% of ideal, a decrease in the systemic clearance of doxorubicin is noted), and for patients with tumor infiltration of the bone marrow.

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

Before administration, the required dose of the drug should be dissolved in 0.9% sodium chloride solution or water for injections to a concentration of 2 mg/ml. The drug is administered by slow intravenous bolus.

Intravesical administration

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 fifteen 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 action (chemical cystitis, which may manifest as dysuria, polyuria, nocturia, painful urination, hematuria, bladder discomfort, necrosis of the bladder wall), the dose intended for instillation 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

For patients with hepatocellular carcinoma, to ensure intensive local exposure while simultaneously reducing the overall toxic effect, 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 removal of the drug is performed. Since this method is potentially dangerous and can lead 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: dose-dependent, reversible leukopenia and neutropenia. Thrombocytopenia and anemia may also develop. Leukopenia usually reaches its lowest value 10-14 days after drug administration, and blood count recovery is usually observed on day 21.

From the cardiovascular system: the manifestation of early (acute) cardiotoxicity of doxorubicin is primarily sinus tachycardia and/or ECG abnormalities (nonspecific ST-T wave changes). Tachyarrhythmias (including ventricular tachycardia), ventricular extrasystoles, as well as bradycardia, atrioventricular block, and bundle branch block may also be noted. The occurrence of these phenomena is not always a prognostic factor for the subsequent development of delayed cardiotoxicity; they are rarely clinically significant and do not require discontinuation of doxorubicin therapy. Late (delayed) myocardial damage is manifested by a decrease in left ventricular ejection fraction without clinical symptoms and/or symptoms of congestive heart failure (dyspnea, pulmonary edema, peripheral edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy, gallop rhythm). Subacute phenomena (pericarditis/myocarditis) may also be noted. The most severe form of anthracycline-induced cardiomyopathy is life-threatening congestive heart failure, which is the toxicity that limits the cumulative dose of the drug. Phlebitis, thrombophlebitis, thromboembolic complications, including pulmonary embolism (in some cases with fatal outcome).

From the digestive system: anorexia, nausea, vomiting, stomatitis or esophagitis (in severe cases, ulceration of the gastrointestinal mucosa may develop), 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: red coloration of urine for 1-2 days after doxorubicin administration.

From the sensory organs: conjunctivitis, keratitis, lacrimation.

From the reproductive system: amenorrhea (after completion of therapy, ovulation is restored, 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 skin and skin appendages: in most cases, reversible complete alopecia develops. Hair regrowth usually begins 2-3 months after discontinuation of the drug. Hyperpigmentation of the skin and nails, photosensitivity, urticaria, rash, itching may also occur. In some patients who had previously undergone radiation therapy, after doxorubicin administration (usually after 4-7 days), hypersensitivity of irritated skin, erythema with blistering, swelling, severe pain, moist epidermitis in areas corresponding to the radiation fields were noted.

Allergic reactions: skin rash, dermatitis, urticaria, erythema of the palms and soles, bronchospasm, anaphylaxis (rarely).

Local reactions: erythematous streaking along the vein into which the infusion was performed is often detected, then local phlebitis or thrombophlebitis may occur. 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, red coloration of urine.

Other: malaise, asthenia, fever, chills, facial flushing, hyperuricemia or nephropathy associated with increased uric acid formation, development of acute lymphocytic or myelocytic leukemia.

Contraindications

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

Intravenous administration is contraindicated in

• Severe myelosuppression;
• Severe hepatic insufficiency;
• Severe heart failure and arrhythmias;
• Recent myocardial infarction;
• Prior therapy with other anthracyclines or anthracenediones at the maximum cumulative doses;
• Chickenpox;
• Herpes zoster.

Intravesical administration is contraindicated in

• Invasive tumors with penetration into the bladder wall;
• Urinary tract infection;
• Bladder inflammation.

With caution– gastric and duodenal ulcer, hyperbilirubinemia, previously conducted radiation therapy or chemotherapy, urate nephrolithiasis (including history), heart disease (cardiotoxic effect may be noted at lower cumulative doses), hepatic insufficiency, bone marrow infiltration with tumor cells.

Use in Pregnancy and Lactation

Contraindication: pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Intravenous administration is contraindicated in severe hepatic insufficiency.

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

• By 50% when serum bilirubin concentration is 12-30 mg/L;
• By 75% when serum bilirubin concentration is above 30 mg/L.

Pediatric Use

Administration of lower doses or increasing the intervals between cycles is recommended in children.

Geriatric Use

Administration of lower doses or increasing the intervals between cycles is recommended in elderly patients.

Special Precautions

Treatment with doxorubicin should be carried out under the supervision of physicians experienced in the use of anticancer drugs.

To reduce the risk of cardiac toxicity, regular monitoring of its function is recommended before starting and during doxorubicin therapy, including assessment of left ventricular ejection fraction by echocardiography or multigated radionuclide angiography, as well as ECG monitoring. Early clinical diagnosis of drug-induced heart failure is very important for its successful treatment. If signs of chronic cardiotoxicity are detected, doxorubicin treatment should be discontinued immediately.

Acute cardiotoxicity is mostly transient (reversible) and is usually not considered an indication for discontinuation of doxorubicin therapy. 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. Then the risk of developing congestive heart failure increases sharply, so it is recommended not to exceed the 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 radiation therapy to the mediastinal area, concurrent use of other potentially cardiotoxic drugs such as cyclophosphamide and 5-fluorouracil), then toxic effects may occur at lower cumulative doses, and cardiac function monitoring should be particularly strict. 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.

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 until the full dose is administered. Locally carry out measures to eliminate the consequences of extravasation. The use of ice packs is advisable.

Administration into veins over joints or into limbs with impaired venous or lymphatic drainage should be avoided if possible.

When using doxorubicin, hyperuricemia may be observed due to rapid tumor cell lysis; therefore, it is recommended to determine the concentration of uric acid, potassium, calcium and creatinine in patients during therapy. Measures such as increased hydration, urine alkalinization and prophylactic administration of allopurinol to prevent hyperuricemia minimize the risk of complications associated with tumor lysis syndrome. When treating hyperuricemia and gout, adjustment of the doses of anti-gout agents may be required due to increased uric acid concentration during treatment with the drug.

Patients with developed neutropenia/leukopenia should be carefully monitored for signs of infection.

Avoid immunization 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.

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

When working with doxorubicin, the rules for handling cytotoxic substances must be observed. Surfaces contaminated with the drug are recommended to be treated with a diluted sodium hypochlorite solution (containing 1% chlorine). If the drug gets on the skin – immediately wash the skin abundantly with water and soap or 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.

Overdose

Acute overdose of doxorubicin can lead to severe myelosuppression (mainly leukopenia and thrombocytopenia), toxic effects on the gastrointestinal tract, and cause acute heart damage.

There is no known antidote for doxorubicin. In case of overdose, symptomatic therapy is recommended.

Drug Interactions

Doxorubicin may enhance the toxicity of other anticancer agents, especially myelotoxicity and toxic effects on the gastrointestinal tract.

When doxorubicin is used concomitantly with other cytotoxic drugs that have potential cardiotoxicity (e.g., 5-fluorouracil and/or cyclophosphamide), careful monitoring of cardiac function throughout the course of therapy is required.

Against the background of doxorubicin, it is possible to enhance the phenomena of hemorrhagic cystitis caused by cyclophosphamide and to enhance the hepatotoxicity of 6-mercaptopurine.

Streptozotocin increases the half-life of doxorubicin. Doxorubicin enhances the radiation-induced toxic effects on the myocardium, mucous membranes, skin and liver. Uricosuric anti-gout drugs increase the risk of nephropathy.

Hepatotoxic drugs, by impairing liver function, may lead to increased toxicity of doxorubicin.

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, hydrocortisone, sodium succinate, aminophylline, cephalothin, 5-fluorouracil and other anticancer drugs.

When taken concomitantly with live viral vaccines, intensification of the vaccine virus replication process, enhancement of its side/adverse effects and/or reduction of antibody production in the patient’s body in response to vaccine administration is possible.

Storage Conditions

List A. Store at a temperature of 15-25°C (-13°F) in a place inaccessible to children.

Shelf Life

The shelf life is 5 years. Do not use after the expiration date stated 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.