Adriblastin^® (Lyophilisate) Instructions for Use

ATC Code

L01DB01 (Doxorubicin)

Active Substance

Doxorubicin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antineoplastic antibiotic

Pharmacotherapeutic Group

Antineoplastic agent, antibiotic

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 minutes and indicates rapid distribution of doxorubicin into 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 penetrate the blood-brain barrier.

Metabolism

Enzymatic reduction at the 7 position 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

Doxorubicin clearance 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.

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

Pharmacokinetics in Special Groups

Children

The clearance of doxorubicin in children over 2 years of age exceeds that in adults. Clearance in children under 2 years of age approaches the clearance values in adults.

Elderly

No dose adjustment based on age is required.

Gender

The mean clearance of doxorubicin in men is significantly higher than in women. However, the terminal T_1/2 of doxorubicin in men is longer compared to women (54 and 35 hours, respectively).

Race

The influence of race on the pharmacokinetics of doxorubicin has not been studied.

Hepatic Impairment

In patients with impaired liver function, the clearance of doxorubicin and doxorubicinol is reduced.

Renal Impairment

The influence of renal function on the pharmacokinetics of doxorubicin has not been studied.

Indications

• Acute lymphoblastic leukemia;
• Acute myeloblastic leukemia;
• Chronic leukemias;
• Hodgkin’s disease and non-Hodgkin’s lymphoma;
• Multiple myeloma;
• Osteogenic sarcoma;
• Ewing’s sarcoma;
• Soft tissue sarcoma;
• Neuroblastoma;
• Rhabdomyosarcoma;
• Wilms’ tumor;
• Breast cancer;
• Endometrial cancer;
• Ovarian cancer;
• Germ cell tumors;
• Prostate cancer;
• Transitional cell carcinoma of the bladder;
• Lung cancer;
• Stomach cancer;
• Primary hepatocellular carcinoma;
• Head and neck cancer;
• Thyroid cancer.

ICD codes

Dosage Regimen

Lyophilisate

Intravenously, intravesically, or intra-arterially.

Adriblastin^® rapid-dissolving can be used both in monotherapy and in combination with other antineoplastic drugs, therefore, when choosing doses and administration regimens, one should be guided by data from specialized literature. The reconstituted drug solution is recommended to be used immediately after preparation.

Intravenous administration

As monotherapy, the recommended standard dose per cycle for adults is 60-90 mg/m². The total dose of the drug 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 the drug at a dose of 10-20 mg/m² is also used. When using doxorubicin in combination with other antineoplastic drugs with similar toxicity, the recommended dose per cycle is 30-60 mg/m².

Repeated administrations of the drug are possible only after the disappearance of all signs of toxicity (especially gastrointestinal and hematological).

To reduce the risk of thrombosis and extravasation, Adriblastin^® rapid-dissolving is recommended to be administered through the tubing of an intravenous infusion system during infusion of 0.9% sodium chloride solution or 5% dextrose solution. The duration of infusion should be from 3 to 10 minutes.

The cumulative dose of doxorubicin should not exceed 550 mg/m².

For patients who have previously received radiation therapy to the mediastinal/pericardial area or have taken other cardiotoxic drugs, if it is necessary to increase the cumulative dose of doxorubicin above 450 mg/m², the drug should be administered under strict monitoring of cardiac function.

Hepatic impairment

• If the serum bilirubin level is 1.2-3 mg/dl, the administered dose of the drug should be reduced by 50% of the recommended dose;
• If the serum bilirubin level exceeds 3 mg/dl, the administered dose of the drug should be reduced by 75% of the recommended dose.

Other special patient groups: it is recommended to prescribe lower doses or increase the intervals between cycles for patients who have previously received intensive chemotherapy, children, elderly patients, patients with obesity (if body weight is more than 130% of optimal, a decrease in systemic clearance of the drug is noted), as well as patients with tumor infiltration of the bone marrow.

Intravesical administration

Intravesical administration is used for the treatment of superficial bladder tumors, as well as for prophylaxis to reduce the likelihood of recurrence after transurethral resection. Intravesical administration is not suitable for the treatment of invasive tumors with penetration into the muscular wall of the bladder.

The recommended dose for instillation is 30-50 mg in 25-50 ml of 0.9% sodium chloride solution. In case of local toxicity (chemical cystitis), the dose should be dissolved in 50-100 ml of 0.9% sodium chloride solution. Instillations can be performed at intervals from 1 week to 1 month.

Instillation should be performed using a catheter, and the drug should remain in the bladder for 1-2 hours. To ensure uniform exposure of the drug to the bladder mucosa, the patient should turn from side to side during instillation. To avoid excessive dilution of the drug by urine, patients should be warned to refrain from fluid intake for 12 hours before instillation. At the end of the instillation, the patient should empty the bladder.

Intra-arterial administration

In patients with hepatocellular carcinoma, to provide intensive local exposure while reducing the overall toxic effect, the drug 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 of simultaneous extracorporeal removal of the drug. Lower doses are suitable for administration of doxorubicin in combination with iodinated oil. 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 leukopenia, neutropenia, anemia, thrombocytopenia.

From the cardiovascular system sinus tachycardia, tachyarrhythmias, atrioventricular block, bundle branch block, congestive heart failure, hemorrhage, flushing, phlebitis, thrombophlebitis, thromboembolism, shock, ECG changes, asymptomatic decrease in left ventricular ejection fraction.

During therapy with anthracyclines, there is a risk of developing cardiotoxicity – early (i.e., acute) or late (delayed).

The manifestation of early cardiotoxicity of doxorubicin is mainly sinus tachycardia and/or ECG abnormalities (nonspecific ST-T wave changes). Tachyarrhythmias (including ventricular extrasystole and ventricular tachycardia), bradycardia, atrioventricular block, and bundle branch block may also occur. These effects are not always predictive of the subsequent development of delayed cardiotoxicity, are rarely clinically significant, and usually do not require discontinuation of therapy with the drug.

Late cardiotoxicity usually develops in the late stages of the course of therapy or within 2-3 months after its cessation, however, the development of more delayed adverse effects is possible (several months or even years after the end of therapy). Late cardiotoxicity is manifested by a decrease in left ventricular ejection fraction and/or symptoms of congestive heart failure, such as dyspnea, pulmonary edema, edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy, and gallop rhythm. Subacute phenomena such as pericarditis and myocarditis may also occur. The most severe form of anthracycline-induced cardiomyopathy, which limits the cumulative dose of the drug, is life-threatening congestive heart failure. When using doxorubicin, as with other cytotoxic agents, the development of thrombophlebitis and thromboembolism, including pulmonary embolism (in some cases with fatal outcome), has sometimes been observed.

From the digestive system anorexia, nausea/vomiting, mucositis/stomatitis, hyperpigmentation of the oral mucosa, esophagitis, abdominal pain, gastric erosions, gastrointestinal bleeding, diarrhea, colitis, dehydration, changes in transaminase levels.

From the urinary system red coloration of urine for 1-2 days after drug administration, hyperuricemia.

From the organ of vision conjunctivitis/keratitis, lacrimation.

From the skin and skin appendages alopecia, rash/itching, skin changes, hyperpigmentation of the skin and nails, photosensitivity, hypersensitivity of irritated skin (anamnestic reaction to radiation), urticaria, extremity erythema, palmar-plantar erythrodysesthesia.

From the reproductive system amenorrhea, oligospermia, azoospermia.

Local reactions extravasation during intravenous infusion of doxorubicin can lead to pain, severe tissue damage (blistering, severe inflammation of the subcutaneous tissue) and necrosis. When the drug is administered into a small vein or when it is repeatedly administered into the same vein, phlebosclerosis may develop.

Other malaise/asthenia, fever, chills, anaphylaxis, development of acute lymphocytic leukemia or acute myeloid leukemia, addition of secondary infections, sepsis/septicemia, weight gain.

Intravesical administration may lead to symptoms of chemical cystitis (dysuria, polyuria, nocturia, painful urination, hematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction.

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

Contraindications

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

Intravenous administration is contraindicated in persistent myelosuppression, severe liver dysfunction, severe heart failure and severe arrhythmias, recent myocardial infarction, prior 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, bladder inflammation, hematuria.

With caution in patients with risk factors for cardiotoxicity; patients who have previously received intensive chemotherapy, children, elderly patients, patients with obesity, patients with tumor infiltration of the bone marrow (may require lower starting doses or increased intervals between doses); 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

Contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Use with caution in patients with impaired liver function.

Pediatric Use

Children are recommended to be prescribed lower doses or increased intervals between cycles.

Geriatric Use

Elderly patients are recommended to be prescribed lower doses or increased intervals between cycles.

Special Precautions

Adriblastin^® rapid-dissolving should be used only under the supervision of physicians experienced in the use of cytotoxic drugs.

Before starting treatment, the patient should have recovered from the acute toxic effects of previous cytotoxic therapy (such as stomatitis, neutropenia, thrombocytopenia, and systemic infections).

Before and during therapy with the drug, heart function must be monitored to minimize the risk of its severe damage. For this purpose, left ventricular ejection fraction should be regularly determined and treatment should be stopped immediately at the first signs of worsening heart function. Adequate methods for quantitative analysis of heart function (measurement of left ventricular ejection fractions) include radioisotope angiography (MUGA) and echocardiography. Before starting treatment, it is recommended to evaluate heart function using ECG and one of the following methods – radioisotope scanning or echocardiography, especially in patients with risk factors for increased cardiotoxicity (for example, overt or latent cardiovascular disease, prior or concomitant radiotherapy to the mediastinum/pericardium, prior therapy with other anthracyclines or anthracenediones, and concomitant therapy with drugs that reduce myocardial contractility). Left ventricular ejection fraction should be measured dynamically, especially with increasing cumulative doses of anthracycline. In this case, it is advisable to consistently use the same method.

The risk of developing congestive heart failure, which is about 1-2% at a cumulative dose of 300 mg/m², increases slowly until a total cumulative dose of 450-550 mg/m² is reached, after which a sharp increase in risk is noted. In this regard, the maximum cumulative dose should not exceed 550 mg/m².

Monitoring of heart function should be particularly strict in patients receiving high cumulative doses of the drug and in patients with risk factors for increased cardiotoxicity. However, cardiotoxicity can develop at lower cumulative doses of doxorubicin regardless of the presence of risk factors.

Children and adolescents have an increased risk of developing late cardiotoxicity from doxorubicin. In women, this risk may be higher than in men.

The toxicity of doxorubicin and other anthracyclines or anthracenediones is likely to be additive.

Like other cytotoxic agents, Doxorubicin can cause myelosuppression. A complete blood count, including a leukocyte differential, should be performed before and during each cycle of doxorubicin therapy. Dose-dependent reversible leukopenia and/or granulocytopenia (neutropenia) are the main manifestation of doxorubicin’s hematological toxicity and the most common sign of acute toxicity that limits the drug’s dose. Leukopenia and neutropenia in most cases reach their maximum severity 10-14 days after drug administration, with white blood cell/neutrophil counts returning to normal by day 21. Thrombocytopenia and anemia may also develop. Clinical complications of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, bleeding, tissue hypoxia, or death.

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 anticancer agents, radiotherapy, 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.

Mucositis/stomatitis usually develops shortly after drug administration and in severe cases can lead to mucosal ulceration within a few days. Most patients recover from these adverse events by the third week of therapy.

Before and during therapy with the drug, patients must have liver function parameters monitored (serum total bilirubin level). In patients with elevated bilirubin levels, drug clearance may be slowed and overall toxicity increased. At the first signs of doxorubicin extravasation (burning or pain at the injection site), the infusion should be stopped immediately and then restarted in another vein until the full dose is administered; local measures should be taken to manage the consequences of extravasation. The use of ice packs is advisable.

Strict adherence to the instructions for use of the drug minimizes the risk of developing phlebitis/thrombophlebitis at the injection site.

When using the drug intravesically, special attention should be paid to conditions that create obstacles for catheterization (for example, urethral obstruction due to massive bladder tumors).

When using doxorubicin, hyperuricemia may be observed due to rapid lysis of tumor cells, therefore it is recommended that patients have blood levels of uric acid, potassium, calcium, and creatinine monitored during therapy. Measures such as hydration, alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia help minimize the risk of complications associated with tumor lysis syndrome.

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

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

Men and women receiving therapy with Adriblastin^® rapid dissolution should use reliable methods of contraception.

When working with the drug, 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 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.

Overdose

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

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

Drug Interactions

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 chemotherapeutic agents, as well as cardiovascular drugs (for example, 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.

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 (a precipitate forms upon mixing).

Storage Conditions

List A. At a temperature from +15°C (59°F) to +25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life of the lyophilisate is 4 years, the solvent is 5 years.

Dispensing Status

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.