Doxorubicin (Solution, Lyophilisate, Concentrate) Instructions for Use

ATC Code

L01DB01 (Doxorubicin)

Active Substance

Doxorubicin

Clinical-Pharmacological Group

Antineoplastic antibiotic

Pharmacotherapeutic Group

Antineoplastic agents; cytotoxic antibiotics and related substances; anthracyclines and related compounds

Pharmacological Action

Doxorubicin is a cytotoxic anthracycline antibiotic isolated from the culture of Streptomyces peucetius var. caesius.

The cytotoxic action of doxorubicin on malignant cells and its toxic effects on various organs are likely due to the intercalation of nucleotide bases and the ability of doxorubicin to bind to cell membrane lipids. Intercalation inhibits nucleotide replication and the activity of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes is considered an important mechanism of the cytotoxic action of doxorubicin.

Pharmacokinetics

Distribution. The initial T_1/2 is about 5 min and indicates rapid distribution of doxorubicin in tissues; the terminal T_1/2 is 20-48 hours. The binding of doxorubicin and its main metabolite, doxorubicinol, to plasma proteins is 74-76% and is independent of the plasma concentration of doxorubicin (up to 1.1 µg/ml). Doxorubicin does not cross the blood-brain barrier.

Metabolism. Enzymatic reduction at position 7 and cleavage of the daunosamine sugar leads to the formation of aglycones, which is also accompanied by the formation of free radicals. The latter may be responsible for the cardiotoxic effects of doxorubicin. The T_1/2 of doxorubicinol is similar to that of doxorubicin. The ratio between the AUC of doxorubicinol and the AUC of doxorubicin compared to doxorubicin is 0.4-0.6.

Excretion. The clearance of doxorubicin occurs mainly through metabolism and biliary excretion. Approximately 40% of the dose is excreted in the bile within 5 days. Only 5-12% of doxorubicin and its metabolites are found in the urine over the same period. Within 7 days, less than 3% of the dose is excreted in the urine as doxorubicinol.

The systemic clearance of doxorubicin is significantly reduced in women with obesity whose body weight is more than 130% of the optimal weight.

Indications

Breast cancer, small cell lung cancer, mesothelioma, esophageal cancer, stomach cancer, primary hepatocellular carcinoma, insulinoma, carcinoid, malignant tumors of the head and neck, thyroid cancer, malignant thymoma, ovarian cancer, testicular germ cell tumors, prostate cancer, bladder cancer (treatment and prevention of recurrence after surgery), endometrial cancer, cervical cancer, soft tissue sarcoma, Ewing’s sarcoma, osteogenic sarcoma, rhabdomyosarcoma, neuroblastoma, Wilms’ tumor, AIDS-related Kaposi’s sarcoma, acute lymphoblastic leukemia, acute myeloblastic leukemia, chronic lymphocytic leukemia, Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple myeloma.

ICD codes

Dosage Regimen

Solution, Lyophilisate, Concentrate

Intravenously, intravesically, or intra-arterially. The dosage regimen and administration schedule are established individually, depending on the indications and the patient’s condition.

Intravenous administration. Administer by slow intravenous push. As monotherapy, the recommended standard dose per cycle for adults is 60-90 mg/m². The total dose of doxorubicin per cycle (every 3-4 weeks) can be administered either as a single dose or divided into several administrations: over 3 consecutive days or on days 1 and 8 of the cycle. A weekly administration regimen of doxorubicin at a dose of 10-20 mg/m² is also used. When doxorubicin is used in combination with other antineoplastic drugs with similar toxicity, the recommended dose per cycle is 30-60 mg/m².

Intravesical administration. The recommended dose for instillation is 30-50 mg in 25-50 ml of solution per instillation. Instillations can be performed at intervals from 1 week to 1 month.

Intra-arterial administration. In patients with hepatocellular carcinoma and liver metastases, to ensure intensive local and generalized effects while reducing overall 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.

Adverse Reactions

Infections and infestations: very common – secondary infections; common – sepsis.

Blood and lymphatic system disorders: very common – leukopenia, neutropenia, anemia, thrombocytopenia; frequency unknown – acute lymphocytic leukemia, acute myeloid leukemia.

Immune system disorders: frequency unknown – anaphylactic reactions.

Metabolism and nutrition disorders: common – decreased appetite, dehydration, hyperuricemia.

Nervous system disorders: frequency unknown – peripheral neuropathy (with intra-arterial administration of doxorubicin, usually in combination with cisplatin), convulsions, coma (in combination with cisplatin or vincristine).

Eye disorders: common – conjunctivitis; frequency unknown – keratitis, increased lacrimation.

Cardiac disorders: very common – decreased left ventricular ejection fraction, abnormal ECG parameters; common – CHF, sinus tachycardia; uncommon – embolism; frequency unknown – AV block, tachyarrhythmia, bundle branch block, shock, hemorrhage, thrombophlebitis, phlebitis, flushing (with rapid IV administration).

Gastrointestinal disorders: very common – inflammation of the gastrointestinal mucosa, stomatitis, diarrhea, vomiting, nausea; common – esophagitis, abdominal pain; frequency unknown – gastrointestinal bleeding, erosive gastritis, colitis, discoloration of the oral mucosa.

Skin and subcutaneous tissue disorders: very common – palmar-plantar erythrodysesthesia syndrome, alopecia; common – urticaria, rash, skin hyperpigmentation, nail hyperpigmentation; frequency unknown – photosensitivity reaction, hypersensitivity of irritated skin (reaction to previous radiation), pruritus, skin changes, extremity erythema, onycholysis.

Renal and urinary disorders: frequency unknown – chromaturia (red discoloration of urine). Intravesical administration may lead to symptoms of chemical cystitis (dysuria, polyuria, nocturia, painful urination, hematuria, bladder discomfort) and bladder constriction.

Reproductive system and breast disorders: frequency unknown – amenorrhea, azoospermia, oligospermia.

General disorders and administration site conditions: very common – fever, general weakness, chills, abnormal liver transaminase activity, weight gain; frequency unknown – malaise, increased fatigue.

Local reactions: when administered into small veins or with repeated administration into the same vein – sclerosis of the vessel; with extravasation – tissue necrosis.

Intra-arterial administration: in addition to systemic toxicity, may cause ulceration of the stomach and duodenum (possibly due to reflux of doxorubicin into the gastric artery) and narrowing of the bile ducts (drug-induced sclerosing cholangitis), as well as extensive necrosis of the perfused tissue.

Contraindications

Hypersensitivity to doxorubicin or other anthracyclines and anthracenediones; pregnancy, breastfeeding period.

Intravenous administration is contraindicated in persistent myelosuppression, severe liver dysfunction, severe heart failure and severe arrhythmias, recent myocardial infarction, previous therapy with doxorubicin, daunorubicin, epirubicin, idarubicin and/or other anthracyclines and anthracenediones at the maximum cumulative doses.

Intravesical administration is contraindicated in urinary tract infections, cystitis, hematuria.

Use with caution in patients with risk factors for cardiotoxicity; patients who have previously received intensive chemotherapy, children, elderly patients, patients with obesity, gout, urate nephrolithiasis (including history), heart disease (cardiotoxic effects may occur at lower cumulative doses), patients with tumor infiltration of the bone marrow (may require lower starting doses or increased intervals between doses); bone marrow suppression, use as part of combined antineoplastic therapy, as well as in combination with radiation or other antineoplastic therapy; patients with impaired liver function.

Use in Pregnancy and Lactation

Doxorubicin is contraindicated during pregnancy. If it is necessary to use during lactation, breastfeeding should be discontinued.

Experimental studies have established the teratogenic and embryotoxic effects of doxorubicin.

Use in Hepatic Impairment

Intravenous administration is contraindicated in severe liver dysfunction.

Use in Renal Impairment

Intravesical administration is contraindicated in urinary tract infections.

Pediatric Use

Doxorubicin should be used with caution in children and adolescents. This category of patients has an increased risk of developing late cardiotoxicity from doxorubicin.

Geriatric Use

Should be used with caution in elderly patients. Administration of lower doses or increasing the intervals between cycles is recommended.

Special Precautions

Doxorubicin should be used only under the supervision of physicians experienced in the use of cytotoxic drugs.

Use with caution in patients with heart disease (including history), chickenpox (including recently contracted or after contact with patients), herpes zoster, other acute infectious diseases, gout or nephrolithiasis (including history), as well as in patients who have undergone mediastinal radiation therapy or are receiving cyclophosphamide concurrently.

During treatment, regular monitoring of peripheral blood counts, liver function tests, ECG, and cardiac ultrasound (with determination of left ventricular ejection fraction) is necessary.

Cases of severe, life-threatening arrhythmias occurring immediately or within a few hours after doxorubicin administration have been described.

Children and adolescents have an increased risk of developing late cardiotoxicity from doxorubicin. Periodic monitoring of the cardiovascular system after completion of therapy is recommended.

Like other cytotoxic agents, Doxorubicin can cause myelosuppression. A complete blood count, including leukocyte differential, should be performed before and during each cycle of doxorubicin therapy.

Cases of secondary leukemia, with or without a preleukemic phase, have been described in patients treated with anthracyclines, including Doxorubicin. Secondary leukemia is more common when these drugs are used in combination with other DNA-damaging antineoplastic agents, radiation therapy, and in patients who have previously received intensive cytotoxic therapy or high doses of anthracyclines. Secondary leukemias may have a latent period of 1-3 years.

Before starting and during doxorubicin therapy, patients should have their liver function parameters (serum total bilirubin concentration) monitored. In patients with elevated bilirubin concentrations, clearance of the drug may be slowed and overall toxicity may be increased.

In women, Doxorubicin may cause infertility and amenorrhea. Ovulation and menstruation usually resume after treatment is discontinued, although early menopause may occur.

In men, Doxorubicin has a mutagenic effect and may cause damage to sperm chromosomes. Oligospermia or azoospermia may be irreversible, although in some cases recovery of sperm count has been observed, sometimes several years after treatment cessation.

Men and women receiving doxorubicin therapy should use reliable methods of contraception.

Vaccination of patients and their family members is not recommended.

Doxorubicin may cause red discoloration of urine for 1-2 days after administration.

Experimental studies have established the carcinogenic and mutagenic effects of doxorubicin.

Effect on ability to drive and operate machinery

When using doxorubicin, nausea, vomiting, drowsiness, and other symptoms affecting the general condition are possible. In this regard, if the above side effects occur during treatment with doxorubicin, it is recommended to refrain from driving vehicles and other activities requiring increased concentration and speed of psychomotor reactions.

Drug Interactions

Doxorubicin is a substrate of the CYP3A4 and CYP2D6 isoenzymes, as well as P-glycoprotein (Pgp). Clinically significant interactions have been noted with the use of inhibitors of CYP3A4, CYP2D6 isoenzymes and/or Pgp (e.g., verapamil), leading to an increase in the concentration and clinical effect of doxorubicin. Inducers of the CYP3A4 isoenzyme (e.g., phenobarbital, phenytoin, St. John’s wort preparations) and Pgp inducers may reduce the concentration of doxorubicin.

Concomitant use of cyclosporine and doxorubicin may lead to an increase in the AUC of both; their simultaneous use may lead to more severe and prolonged hematological toxicity than with doxorubicin alone.

When doxorubicin is used in combination with other cytotoxic agents, additive toxicity may occur, especially with respect to the bone marrow/blood system and the gastrointestinal tract.

When doxorubicin is used in combination with other potentially cardiotoxic agents, as well as cardiovascular drugs (e.g., calcium channel blockers), heart function should be monitored. Cases of exacerbation of cyclophosphamide-induced hemorrhagic cystitis and increased hepatotoxicity of 6-mercaptopurine have been described.

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

Changes in liver function caused by concomitant therapy may affect the metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity of doxorubicin.

Administration of paclitaxel prior to doxorubicin may lead to increased plasma concentrations of doxorubicin and/or its metabolites.

This effect is minimal when Doxorubicin is administered before paclitaxel.

When treating hyperuricemia and gout, adjustment of the dosing regimen of antigout medications may be required due to increased uric acid concentrations during doxorubicin treatment.

Doxorubicin should not be mixed with other drugs.

Contact with alkaline solutions should be avoided as this may lead to hydrolysis of doxorubicin.

Due to chemical incompatibility, Doxorubicin should not be mixed with heparin (mixing results in precipitate formation).

Doxorubicin should not be mixed with fluorouracil (for example, in the same infusion bag or administered through the same catheter), as this may lead to precipitate formation.

If their simultaneous administration is necessary, it is recommended to flush the catheter between administrations of doxorubicin and fluorouracil.

Concomitant use with progesterone enhances Doxorubicin-induced neutropenia and thrombocytopenia.

Storage Conditions

Store at 15°C (59°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.