Doxorubicin-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOXORUBICINE-VISTA (DOXORUBICINE-VISTA)

Composition:

Active substance: doxorubicin;

1 ml of concentrate contains 2 mg of doxorubicin hydrochloride;

Excipients: sodium chloride, 0.1 M hydrochloric acid solution, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear red-colored solution.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Cytotoxic antibiotics and related substances. ATC code L01D B01.

Pharmacological properties.

Pharmacodynamics.

Doxorubicin is a cytotoxic anthracycline antibiotic isolated from the culture of Streptomyces peucetius var. caesius. Currently, doxorubicin is produced semi-synthetically from daunorubicin.

The exact mechanism of action has not been fully elucidated. Doxorubicin is believed to exert its antitumor effect through cytotoxic mechanisms of action, particularly by intercalating into DNA, inhibiting the enzyme topoisomerase II, and generating reactive oxygen species (ROS). All of these mechanisms adversely affect DNA synthesis: intercalation of the doxorubicin molecule leads to inhibition of RNA and DNA polymerases by disrupting base recognition and sequence specificity. Inhibition of topoisomerase II causes single- and double-strand breaks in the DNA helix. DNA cleavage also occurs due to chemical reactions with highly reactive oxygen species, such as the hydroxyl radical OH*, resulting in mutagenesis and chromosomal aberrations.

The specificity of doxorubicin toxicity is primarily related to the proliferative activity of healthy tissues. Thus, bone marrow, gastrointestinal tract, and gonads are the main normal tissues affected.

One of the main reasons for the inefficacy of treatment with doxorubicin and other anthracyclines is the development of resistance. To overcome cellular resistance to doxorubicin, calcium antagonists such as verapamil should be used, since the primary target is the cell membrane. Verapamid blocks slow calcium channels and may enhance cellular uptake of doxorubicin. It should be noted that severe toxic effects are observed when doxorubicin is used concomitantly with verapamil.

Pharmacokinetics.

Distribution

After intravenous administration, doxorubicin is rapidly cleared from the blood and widely distributed into tissues, including the lungs, liver, heart, spleen, lymph nodes, bone marrow, and kidneys. The volume of distribution is approximately 25 L/kg. The extent of plasma protein binding is 60–70%.

Doxorubicin does not cross the blood-brain barrier, although higher drug levels may be achieved in cerebrospinal fluid in the presence of brain metastases or leukemic cerebral dissemination. Doxorubicin rapidly distributes into ascitic fluid, where it reaches higher concentrations than in plasma. Doxorubicin is excreted into breast milk.

Elimination

Elimination of doxorubicin from blood is triphasic, with half-lives of 12 minutes (distribution phase), 3.3 hours, and 30 hours. Doxorubicin undergoes rapid metabolism in the liver. The main metabolite is the less active 13-dihydro derivative, doxorubicinol. Other metabolites include deoxyrubicin aglycone, glucuronide, and sulfate conjugates. Approximately 40–50% of the dose is excreted in bile within 7 days, of which about half is eliminated unchanged and the remainder as metabolites. Only 5–15% of the administered dose is excreted in urine.

Special patient groups

Since doxorubicin elimination occurs primarily via the liver, hepatic dysfunction leads to delayed excretion and consequently to increased retention and accumulation in plasma and tissues.

Although renal excretion is a secondary elimination pathway for doxorubicin, severe renal impairment may affect overall elimination.

In a study of patients with excess body weight (>130% of ideal body weight), doxorubicin clearance was reduced and half-life prolonged compared to the control group of patients with normal body weight.

Clinical characteristics.

Indications.

Treatment of a broad spectrum of neoplastic diseases, including acute leukemia, lymphoma, malignant tumors in children, and solid tumors in adults, particularly breast and lung carcinomas.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product, other anthracyclines or anthracenediones. Pregnancy, breastfeeding.

For intravenous administration:

Persistent myelosuppression; severe impairment of liver function; severe myocardial dysfunction; unstable angina pectoris; recent myocardial infarction; severe arrhythmia; NYHA class IV heart failure; acute inflammatory cardiomyopathy; acute myocardial infarction; acute infection; severe stomatitis induced by prior treatment with cytotoxic agents and/or radiation (including patients at high risk of bleeding); presence of oral ulcers; burning sensation may be a prodromal symptom — continuation of treatment in the presence of this symptom is not recommended; acute development of heart failure; prior treatment with maximum cumulative doses of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones.

For intravesical administration:

Urinary tract infections; bladder inflammation; hematuria.

Do not administer intravesically for bladder cancer treatment in patients with urethral stenosis in whom catheterization is not feasible; patients with invasive tumors that have penetrated through the bladder wall.

Special precautions.

Doxorubicin is a potent cytotoxic medicinal product that should be prescribed, prepared, and administered only by trained personnel experienced in the safe use of cytotoxic agents. The vial contents are under negative pressure to minimize aerosol formation during reconstitution; therefore, special caution is required when inserting the needle. Inhalation of aerosol generated during reconstitution should be avoided.

The following instructions should be observed when using doxorubicin.

Preparation:

1. Cytostatic agents should be prepared for administration only by trained personnel familiar with safe handling procedures for such medicinal products. Appropriate current guidelines should be consulted before beginning work.
2. Pregnant women should not be involved in handling this medicinal product.
3. Personnel handling doxorubicin must wear protective clothing: goggles, gown, disposable gloves, and masks.
4. A designated area (preferably under a laminar airflow hood) should be used for reconstitution. The work surface should be covered with disposable absorbent paper with a plastic backing.
5. All materials used for reconstitution, administration, or cleanup, including gloves, should be collected in bags designated for high-toxicity waste for subsequent high-temperature disposal (700 °C).
6. Hands must always be washed after removing gloves.

Contamination:

1. In case of contact with skin, the affected area should be thoroughly washed with soap and water or sodium bicarbonate solution. A brush should not be used. A mild cream may be used to treat transient skin itching.
2. In case of contact with eyes, rinse the eye(s) thoroughly, holding eyelids open, with copious amounts of water for at least 15 minutes or with 9 mg/mL (0.9%) sodium chloride injection solution. Medical advice should then be sought.
3. Any spilled or leaked solution should be diluted with sodium chloride solution containing 1% active chlorine or phosphate buffer (pH > 8) until the solution becomes colorless. Use cloth/sponge stored in the designated place. Rinse twice with water. Place all cloths into a plastic bag, seal tightly, and incinerate.

Disposal:

The product is intended for single use only. Any unused product or waste material must be disposed of in accordance with local requirements. Appropriate instructions for handling cytotoxic medicinal products must be followed.

Interaction with other medicinal products and other types of interactions.

Doxorubicin is primarily used in combination with other cytotoxic agents. Additive toxic effects may occur, particularly affecting bone marrow/hematological system and gastrointestinal tract. When doxorubicin is used in combination chemotherapy with other potentially cardiotoxic compounds or in combination with other agents affecting the heart (e.g., calcium channel blockers such as verapamil), cardiac function should be monitored during treatment. The maximum plasma concentration, terminal half-life, and volume of distribution of doxorubicin may increase with concomitant verapamil administration. Changes in liver function due to concomitant therapy may alter the metabolism and pharmacokinetics of doxorubicin, as well as its therapeutic efficacy and/or toxicity. Caution is required when doxorubicin is used after or in combination with other cardiotoxic or antineoplastic (especially myelotoxic) agents. Concurrent use of other antineoplastic agents such as anthracyclines (daunorubicin, epirubicin, idarubicin), cisplatin, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, paclitaxel, 5-fluorouracil, mitomycin C, and taxanes increases the risk of doxorubicin-induced congestive heart failure. The drugs must not be mixed in the same syringe.

Clozapine increases the risk and severity of hematological toxicity of doxorubicin.

If therapy with doxorubicin is administered after treatment with cyclophosphamide, this may not only increase cardiotoxicity but also exacerbate hemorrhagic cystitis.

Since doxorubicin is rapidly metabolized and primarily excreted via bile, its toxicity may increase when used concomitantly with hepatotoxic chemotherapeutic agents (e.g., 6-mercaptopurine, methotrexate, streptozocin) due to reduced hepatic clearance of the drug. The dosage of doxorubicin should be adjusted if concomitant therapy with hepatotoxic drugs is unavoidable.

When high-dose cyclosporine and doxorubicin are used together, serum concentrations of both compounds increase. Combination therapy with cyclosporine and doxorubicin may lead to mutual reduction in metabolism and clearance of both substances, resulting in increased blood levels. This may cause more pronounced suppression of bone marrow function and excessive immunosuppression.

Concomitant use of agents affecting myeloid function (including antiretroviral drugs, amiodarone, phenytoin, cytostatics, sulfonamides, amidopyrine derivatives, chloramphenicol) may cause disturbances in hematopoietic function. If necessary, the dosage of doxorubicin should be adjusted. Toxic effects caused by doxorubicin therapy may increase when used in combination with other cytostatics (e.g., cytarabine, cisplatin).

Combination therapy with doxorubicin and cytostatics (including cytarabine, cisplatin) enhances toxic effects on the patient's body.

The combination of doxorubicin with amphotericin B should be avoided due to the risk of pronounced nephrotoxicity.

Increased serum levels of doxorubicin have been reported when used concomitantly with ritonavir.

Barbiturates may lead to accelerated elimination of doxorubicin from plasma.

Absorption of antiepileptic drugs (e.g., carbamazepine, phenytoin, valproate) is reduced after concomitant administration with doxorubicin.

Use of drugs that delay excretion of uric acid (e.g., sulfonamides and certain diuretics) may lead to hyperuricemia. Treatment with doxorubicin may increase plasma uric acid levels. Therefore, dose adjustment of uric acid-lowering agents may be necessary.

Doxorubicin may reduce the oral bioavailability of digoxin. Therefore, plasma digoxin levels should be monitored regularly during doxorubicin therapy.

Patients undergoing treatment with doxorubicin hydrochloride should not be vaccinated. The risk is increased in patients with immunity weakened by the underlying disease. During doxorubicin therapy, patients should also avoid contact with individuals recently vaccinated against poliomyelitis.

Doxorubicin forms complexes with heparin and 5-fluorouracil, leading to precipitation and loss of efficacy of both drugs.

Doxorubicin is metabolized by cytochrome P450 enzymes CYP3A4 and CYP2D6, as well as by P-glycoprotein (P-gp). Clinically significant interactions have been observed with inhibitors of CYP3A4, CYP2D6, and/or P-gp (e.g., verapamil), resulting in increased concentration and clinical effect of doxorubicin. The concentration of doxorubicin may be decreased by inducers of CYP3A4 (e.g., phenobarbital, phenytoin, St. John's wort) and P-gp inducers.

Concomitant use of cyclosporine with doxorubicin may increase the AUC of both doxorubicin and doxorubicinol, likely due to reduced clearance of the parent compound and decreased metabolism of doxorubicinol (dose adjustment may be required).

When cyclosporine is administered concurrently, the clearance of doxorubicin decreases by approximately 50%. The AUC of doxorubicin increases by 55%, and the AUC of doxorubicinol by 350%. This combination may allow a 40% reduction in doxorubicin dose. Cyclosporine, like verapamil, inhibits CYP3A4 and P-glycoprotein, which may explain the interaction. This leads to increased severity of adverse reactions. The combination of cyclosporine with doxorubicin causes more persistent and prolonged hematological toxicity than doxorubicin monotherapy. Cases of coma and seizures have also been reported with concomitant administration of cyclosporine and doxorubicin.

Cytochrome P450 inhibitors (e.g., cimetidine) also reduce plasma clearance and increase the AUC of doxorubicin, possibly via the same mechanism proposed for cyclosporine. This may lead to increased severity of adverse reactions. Conversely, cytochrome P450 inducers (e.g., phenobarbital and rifampicin) reduce plasma levels of doxorubicin and may thus lead to reduced efficacy.

Doxorubicin is a potent radiosensitizing agent (radiosensitizer), and the radiation recall phenomenon it may induce can be life-threatening. Any procedures involving radiotherapy, whether concurrent or sequential, may increase the cardiotoxic or hepatotoxic effects of doxorubicin. This also applies to combination therapy with cardiotoxic or hepatotoxic agents.

When doxorubicin and docetaxel are used together, the risk of developing neutropenia is higher.

Combination therapy with doxorubicin and cyclophosphamide, paclitaxel, docetaxel, rituximab, trastuzumab, or zosuquidar may enhance toxic effects. Patients receiving anthracyclines (e.g., doxorubicin) after discontinuation of other cardiotoxic agents, particularly those with long half-lives such as trastuzumab, are also at increased risk of cardiotoxicity. The half-life of trastuzumab has been reported to vary. Trastuzumab may remain in the circulatory system for up to 7 months. Therefore, physicians should, whenever possible, refrain from prescribing anthracycline-based therapy within 7 months after stopping trastuzumab. If anthracyclines are administered earlier, cardiac function should be closely monitored.

Concurrent use of anthracyclines and trastuzumab should be limited to well-controlled clinical trials with cardiac monitoring. Patients previously treated with anthracyclines also have a risk of cardiotoxicity when treated with trastuzumab, although the risk is lower than with concurrent use of trastuzumab and anthracyclines.

If paclitaxel was administered before starting doxorubicin infusion, this may lead to increased concentrations of doxorubicin and/or its metabolites. Some data suggest lower concentration increases if doxorubicin is administered before paclitaxel. Concomitant administration of paclitaxel reduces doxorubicin clearance and increases the incidence of neutropenia and stomatitis.

Enhanced neutropenia and thrombocytopenia have been observed after concomitant use of progesterone.

Increased (21–47%) or unchanged AUC of doxorubicin has been observed when co-administered with sorafenib at a dose of 400 mg twice daily. The clinical significance of these data is unknown.

Special precautions for use.

Doxorubicin therapy should be administered under the supervision of an experienced oncologist. It is recommended that at least the initial phase of doxorubicin therapy be conducted in a hospital setting, as patients require close monitoring and regular assessment of key laboratory parameters during this period. Doxorubicin doses should be determined based on tumor type, cardiac and hepatic function, and concomitant chemotherapy. Prior to initiating doxorubicin therapy, evaluation of cardiac and liver function, as well as blood analysis to determine major hematological parameters, is required.

Particular caution is advised in patients who have undergone, are undergoing, or are scheduled to receive radiation therapy. Severe local reactions in irradiated areas may occur with doxorubicin administration. There have been reports of associated severe, sometimes fatal, hepatotoxicity.

Prior mediastinal irradiation increases the cardiotoxicity of doxorubicin. In such cases, the maximum cumulative total dose should not exceed 400 mg/m² body surface area.

The following assessments should be performed before or during doxorubicin therapy (frequency depending on the patient’s general condition, prescribed dose, and concomitant therapy): chest X-ray; ECG; cardiac function monitoring (left ventricular ejection fraction, e.g., via ECG, echocardiography, or multigated radionuclide angiography); daily oral and pharyngeal cavity examination to detect mucosal ulcers; blood tests (to determine hematocrit, platelets, hematological parameters, ALT, AST, LDH, bilirubin, uric acid). If hepatitis B or hepatitis C is present in the patient’s history (and, if necessary, antibody testing is performed), liver function tests should be conducted during and after treatment, as disease reactivation is possible.

Severe infections and/or bleeding must be promptly and effectively treated. Existing infections should be treated prior to initiating therapy.

The patient’s condition should have recovered from the acute toxic effects of prior cytotoxic therapy (e.g., stomatitis, neutropenia, thrombocytopenia, or systemic infection) before starting doxorubicin treatment.

In obese patients (i.e., >130% of ideal body weight), systemic clearance of doxorubicin is reduced.

Nausea, vomiting, and mucosal inflammation are frequently severe during doxorubicin therapy and require appropriate management.

Doxorubicin must not be administered intrathecally, intramuscularly, subcutaneously, or via prolonged infusion (as there are reports of doxorubicin forming a precipitate when combined with heparin and 5-fluorouracil); it should also not be mixed with any other medicinal products.

Extravasation

Extravasation of doxorubicin causes severe tissue damage (vesicular rash, severe cellulitis) and progressive tissue necrosis. Symptoms of extravasation include pain and/or burning at the site of intravenous administration. If extravasation is suspected, doxorubicin infusion should be stopped immediately, and administration continued via another vein. Pain may be alleviated by cooling the affected area for 24 hours. Various measures have been reported with variable success in such cases: saline irrigation, local injection of corticosteroids or sodium bicarbonate solution (8.4%), and application of dimethyl sulfoxide. Topical application of 1% hydrocortisone ointment has shown beneficial effects. Close monitoring of the patient is required for several weeks following extravasation. In cases of extravasation, consultation with a plastic surgery specialist is recommended to evaluate the need for extensive surgical debridement of the affected area.

Cardiotoxicity

Anthracycline therapy is associated with the risk of cardiotoxicity, which may manifest as early (acute) and late (delayed) effects.

Manifestations of early (acute) cardiotoxicity. Early manifestations of doxorubicin cardiotoxicity primarily include sinus tachycardia and/or nonspecific ST-T segment changes on ECG. Tachyarrhythmias, including ventricular extrasystoles, ventricular tachycardia, bradycardia, atrioventricular block, and bundle branch block, have also been reported. These manifestations generally do not lead to delayed cardiotoxicity and usually do not require discontinuation of doxorubicin therapy.

Late (delayed) manifestations of cardiotoxicity. Delayed cardiotoxicity typically occurs late during treatment or 2–3 months after completion of therapy. However, later manifestations have been reported months or even years after treatment. Delayed cardiomyopathy is characterized by reduced left ventricular ejection fraction (LVEF) and/or symptoms of congestive heart failure (CHF), such as dyspnea, pulmonary edema, peripheral edema, cardiomegaly, hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Subacute manifestations such as pericarditis/myocarditis have also been observed. The most severe and life-threatening form of anthracycline-induced cardiomyopathy is CHF, which is a cumulative dose-limiting toxicity of the drug.

The risk of developing heart failure in oncology patients treated with doxorubicin persists throughout life. Doxorubicin-induced heart failure may be resistant to conventional treatment.

Exceeding the maximum cumulative dose (550 mg/m² body surface area in adults; 400 mg/m² body surface area in cases of prior chest irradiation or concomitant alkylating agent therapy) significantly increases the incidence of anthracycline-induced cardiomyopathy, even in the absence of prior risk factors. However, cardiotoxicity has been observed in individual cases at much lower total doses. After administration of a cumulative dose of 550 mg/m² body surface area, the risk of severe heart failure is approximately 5%. Furthermore, LVEF must be measured before each treatment cycle in such patients.

In patients with pre-existing cardiac conditions following radiation therapy to the heart or mediastinum, or those treated with other cardiotoxic non-anthracycline anticancer agents, the cumulative dose should not exceed 400 mg/m² body surface area, and careful cardiac function monitoring is required.

For patients at increased risk of developing cardiac pathology, doxorubicin should preferably be administered via 24-hour continuous intravenous infusions rather than bolus injections. This method is associated with fewer cardiotoxic effects while maintaining therapeutic efficacy.

The risk of cardiotoxic injury is higher in patients who have received mediastinal or pericardial radiation therapy, prior anthracyclines and/or anthracenediones, those with pre-existing cardiac disease, elderly patients (aged 70 years or older), and children (under 15 years of age).

Cardiotoxic effects may occur at doses below the recommended maximum cumulative dose. Irreversible CHF may develop even at a total dose of 240 mg/m² body surface area. Therefore, when determining the acceptable cumulative dose for each patient, prior or concomitant therapy with other potentially cardiotoxic agents—such as cyclophosphamide (intravenous), mitomycin C, dacarbazine, other anthracyclines (e.g., daunorubicin), and mediastinal or pericardial radiation therapy—should be considered.

Severe acute arrhythmias have been reported during or shortly after doxorubicin administration.

ECG changes such as reduced QRS complex amplitude and prolonged systolic interval, as well as reduced LVEF, may occur during doxorubicin therapy.

Particular caution is required when treating patients with pre-existing cardiac conditions (e.g., recent myocardial infarction, heart failure, cardiomyopathy, pericarditis, arrhythmias), as well as those who have received other cardiotoxic agents, such as cyclophosphamide.

The cumulative dose should be carefully considered when treating children, who generally tolerate lower total doses, have undergone additional radiotherapy, or were very young at the start of therapy, as concomitant therapy increases the risk of delayed cardiotoxicity with ventricular dysfunction, heart failure, and/or life-threatening arrhythmias. Girls are more prone than boys to delayed cardiotoxicity after doxorubicin-based therapy.

Particular caution is also required when treating children under 2 years of age and patients with prior cardiac disease (ischemic heart disease, heart failure) or those who have received hyperthermic agents.

There is a possibility that the toxic effects of doxorubicin and other anthracyclines or anthracenediones may be additive.

Cardiac function monitoring

Cardiac function should be assessed before initiating doxorubicin therapy, monitored regularly during treatment, and evaluated after completion of therapy. There is a risk of developing anthracycline-induced cumulative dose-dependent cardiomyopathy. Therefore, the maximum cumulative dose should not exceed 450–550 mg/m². The risk of heart failure increases significantly at doses above this level. Doxorubicin-induced cardiotoxicity usually develops during or within two months after discontinuation of therapy, but late complications (months to years after treatment) have also been reported. ECG monitoring is recommended before and after each drug administration. ECG changes such as T-wave depression or inversion, ST-segment depression, or arrhythmias are common signs of acute, transient (reversible) toxic effects of doxorubicin and are not grounds for discontinuing therapy. However, persistent reduction in QRS complex amplitude and prolonged systolic interval are considered signs of anthracycline-induced cardiotoxic injury. A 30% reduction in QRS amplitude or a 5% decrease in shortening fraction warrants discontinuation of doxorubicin therapy.

The most characteristic sign of cardiomyopathy risk is reduced LVEF. This risk may be reduced by regular monitoring of LVEF during therapy and immediate discontinuation of the drug at the first signs of worsening cardiac function. Appropriate quantitative methods for regular cardiac function assessment (LVEF) include multigated radionuclide angiography (MUGA) or echocardiography (EchocG). It is recommended to assess baseline cardiac status using ECG and MUGA or EchocG, especially in patients with risk factors for increased cardiotoxicity. Regular LVEF monitoring via MUGA or EchocG is necessary, particularly with high cumulative doses of anthracyclines. Regular cardiac function monitoring using these methods should be performed throughout the treatment course.

The risk of CHF, estimated at approximately 1–2% at a cumulative dose of 300 mg/m², increases gradually with increasing cumulative dose up to 450–550 mg/m². Beyond this, the risk of CHF rises sharply; therefore, exceeding the maximum cumulative dose of 550 mg/m² is not recommended.

LVEF should be assessed before treatment initiation and repeated after each cumulative dose of approximately 100 mg/m² and whenever clinical signs of heart failure appear. Typically, an absolute reduction in LVEF of ≥10% or below 50% in patients with normal baseline LVEF values indicates worsening cardiac function. The risk of cardiotoxicity increases in patients who previously received mediastinal radiation, prior anthracyclines and/or anthracenediones, patients aged 70 years or older or under 15 years, and those with a history of cardiac disease. Long-term doxorubicin therapy should be prescribed cautiously in such cases. The risk of cardiotoxicity may increase in patients who have undergone prior or concomitant therapy with other potentially cardiotoxic agents, such as high-dose intravenous cyclophosphamide, mediastinal radiation, or anthracycline-related compounds like daunorubicin.

Severe arrhythmias have been reported during or shortly after doxorubicin administration.

ECG changes such as T-wave depression or inversion, ST-segment depression, or arrhythmias are usually signs of acute, transient (reversible) toxic effects and are not considered indications for discontinuing doxorubicin therapy. However, reduced QRS complex amplitude and prolonged systolic interval are considered more significant signs of anthracycline-induced cardiotoxicity.

Risk factors for cardiotoxicity include active or latent cardiovascular diseases, prior or concomitant mediastinal or pericardial radiation therapy, prior therapy with anthracyclines or anthracenediones, and concomitant use of agents that may depress myocardial contractility or are cardiotoxic (e.g., trastuzumab). Anthracyclines, including doxorubicin, should not be administered in combination with other cardiotoxic agents unless cardiac function can be closely monitored. Patients receiving anthracyclines after discontinuation of other cardiotoxic agents, particularly those with long half-lives such as trastuzumab, may also have an increased risk of cardiotoxicity. The half-life of trastuzumab has been reported to vary. Trastuzumab may remain in the circulatory system for up to 7 months. Therefore, physicians should, whenever possible, avoid prescribing anthracycline therapy within 7 months after discontinuation of trastuzumab.

If anthracyclines are prescribed earlier than this, cardiac function should be closely monitored.

Cardiac function should be monitored especially carefully in patients receiving high cumulative doses and those with risk factors. However, doxorubicin may cause cardiotoxic effects even at low cumulative doses or in the absence of the aforementioned risk factors.

Children and adolescents have a higher risk of developing delayed cardiotoxicity following doxorubicin use. The likelihood of cardiotoxicity is higher in women than in men. Regular cardiological examinations are recommended to monitor this drug effect.

The toxic effects of doxorubicin and other anthracyclines or anthracenediones may be additive.

Cardiac disease symptoms may also manifest during pregnancy in women previously treated with doxorubicin (under 20 years of age), even if no prior cardiac side effects were observed. Cases of CHF and pulmonary edema have been reported. Women previously treated with doxorubicin should be monitored for cardiac side effects during pregnancy.

1 mL of doxorubicin hydrochloride 2 mg/mL solution contains 3.54 mg of sodium.

Myelosuppression

Like other cytotoxic agents, doxorubicin may cause myelosuppression. Since bone marrow suppression is frequently observed during doxorubicin therapy, hematological parameters should be monitored. Myelosuppression may be more pronounced during combination chemotherapy due to additive drug effects. Neutropenia is most commonly observed, less frequently thrombocytopenia and anemia. Dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) are the main hematological toxic effects of doxorubicin and the most common acute dose-limiting effect. The lowest blood cell counts occur 10–14 days after doxorubicin administration. Hematological parameters usually normalize within 21 days after drug administration. Thrombocytopenia and anemia may also occur. Clinical manifestations of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, bleeding, and tissue hypoxia. A fatal outcome is possible. Doxorubicin should not be used in cases of severe myelosuppression; dose reduction or discontinuation is required.

Blood parameter monitoring. Before each treatment cycle, differential blood analysis for leukocyte, erythrocyte, and platelet counts is necessary. Bone marrow suppression caused by doxorubicin hydrochloride primarily affects leukocyte counts. Leukocyte levels require careful monitoring, as severe bone marrow dysfunction may lead to superinfections and bleeding. Severe leukopenia may occur with doses recommended for solid tumor treatment (leukocyte count of 1000/mm³ or less is expected with full-dose doxorubicin hydrochloride). Leukopenia is most pronounced on days 10–14 after treatment initiation, with leukocyte levels returning to normal in most cases by day 21. Treatment should not be initiated or continued if segmented granulocyte count is below 2000/mm³. In acute leukemia treatment, this value may be lower, depending on circumstances. Regular hematological monitoring is also required due to the risk of secondary leukemia following antineoplastic therapy. Remission in acute leukemia may be achieved with early diagnosis and appropriate chemotherapy regimens. Severe myelosuppression may lead to bleeding or superinfection, necessitating dose reduction or discontinuation of doxorubicin therapy.

Since doxorubicin acts as an immunosuppressor, measures should be taken to prevent secondary infections.

Secondary leukemia. Secondary leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines. Secondary leukemia is more common when these agents are used in combination with DNA-damaging antineoplastic agents, in patients who have experienced severe prior cytotoxic therapy, or with increased anthracycline doses. The latent period for such leukemias may range from 1 to 3 years.

Gastrointestinal disorders

Doxorubicin has emetogenic properties. Mucositis or stomatitis usually occur soon after treatment initiation and, in severe cases, may progress to mucosal ulceration within several days. Most patients recover from these side effects by the third week of therapy. Doxorubicin should not be administered in cases of inflammation, ulceration, or diarrhea.

In patients with acute non-lymphocytic leukemia undergoing polychemotherapy including doxorubicin and cytarabine over 3 days, colonic ulcers or necrosis may occur. These manifestations may lead to fatal outcomes due to hemorrhage and intercurrent infections.

Secondary oral cavity neoplasms

Rare cases of oral cavity cancer have been reported in patients undergoing prolonged (over 1 year) doxorubicin therapy or receiving cumulative doses exceeding 720 mg/m². Cases of secondary oral cancer have been diagnosed both during doxorubicin therapy and up to 6 years after the last dose. Patients should be regularly examined for oral ulcers or any discomfort that may indicate secondary oral cancer.

Skin reactions at the injection site

Phlebosclerosis may occur with administration into small veins or repeated administration into the same vein. Strict adherence to the recommended administration method reduces the risk of phlebitis/thrombophlebitis at the injection site.

Pulmonary toxicity

When using combination chemotherapy with other cytostatics (e.g., gemcitabine, bleomycin, taxanes, or rituximab), including in combination with mediastinal radiation therapy, and in patients predisposed to pulmonary diseases, the potential for doxorubicin-induced pulmonary toxicity should be considered.

Hyperuricemia

As with other antineoplastic agents, rapid tumor lysis during doxorubicin therapy may cause hyperuricemia, leading to acute gout or urate nephropathy.

Serum uric acid levels should be monitored regularly. Patients should consume adequate fluids (minimum 3 L/m² body surface area per day). Xanthine oxidase inhibitors (allopurinol) may be used if necessary.

Hepatic function impairment

Since doxorubicin is primarily excreted via bile, hepatic dysfunction or liver failure may slow its elimination and increase toxicity. Therefore, liver function tests (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and bilirubin levels) are recommended before and during therapy, as dose adjustment may be necessary. In patients with elevated bilirubin levels, drug clearance may be delayed, increasing overall toxicity. Dose reduction is recommended for such patients. Doxorubicin should not be administered to patients with severe hepatic dysfunction. Severe hepatotoxicity has been reported in patients with prior mediastinal radiation therapy, sometimes leading to fatal outcomes. Total plasma bilirubin levels should be assessed before and during doxorubicin therapy.

Renal function

Dose reduction may be required in patients with severe renal impairment. Patients should be informed that doxorubicin may discolor urine red, especially shortly after administration. This should not cause concern.

Other

Doxorubicin may potentiate the toxicity of other antineoplastic agents. Cases of cyclophosphamide-induced hemorrhagic cystitis exacerbation and increased hepatotoxicity of 6-mercaptopurine have been reported. Radiation therapy toxicity (to myocardium, mucous membranes, skin, and liver) may also be enhanced.

As with other cytotoxic agents, thrombophlebitis and thromboembolic events, including pulmonary artery embolism (sometimes fatal), have occasionally been reported during doxorubicin therapy.

Tumor lysis syndrome

Doxorubicin may cause hyperuricemia as a result of extensive purine catabolism accompanying rapid lysis of neoplastic cells (tumor lysis syndrome) induced by the drug. Therefore, serum levels of uric acid, potassium, phosphate, calcium, and creatinine should be determined after treatment initiation. Hydration, urine alkalinization, and allopurinol prophylaxis minimize the risk of tumor cell lysis complications. Antihyperuricemic therapy should be initiated if hyperuricemia occurs. Plasma uric acid levels should be monitored; patients should consume adequate fluids (minimum daily 3 L/m²). A xanthine oxidase inhibitor (allopurinol) may be administered if necessary.

Vaccination

Administration of live or live-attenuated vaccines to immunocompromised patients due to chemotherapy, including doxorubicin, may lead to severe or fatal infections. Live vaccination should be avoided in patients receiving doxorubicin. Inactivated or killed vaccines may be administered, but the immune response may be weak.

Embryo-fetal toxicity

Doxorubicin may cause genotoxicity. Male and female patients should use effective contraception during and after doxorubicin therapy. Patients wishing to have children after treatment completion should be advised to seek genetic counseling.

Intravesical administration

Particular caution is required when administering doxorubicin intravesically.

Intravesical administration of doxorubicin may cause symptoms of chemical cystitis (e.g., dysuria, polyuria, nocturia, urinary hesitancy, hematuria, bladder discomfort, bladder wall necrosis) and bladder spasm. Special attention should be paid to catheterization issues (e.g., urethral obstruction due to bulky intravesical tumors). Thorough perimeatal irrigation is recommended during drug instillation and immediately after its removal from the bladder.

Intravesical therapy for superficial bladder cancer and carcinoma in situ

The optimal treatment duration has not yet been established and may range from 6 to 12 months. With intravesical administration (unlike intravenous), there is no limit on maximum cumulative dose, as systemic absorption of doxorubicin is minimal.

Intravesical administration is contraindicated in patients with invasive tumors penetrating the bladder wall, urinary tract infections, or inflammatory bladder diseases.

Doxorubicin must not be administered intrathecally, intramuscularly, or subcutaneously. Doxorubicin should not be mixed with other medicinal products.

Intra-arterial administration of doxorubicin (transcatheter arterial chemoembolization) is recommended for localized or regional therapy of primary hepatocellular carcinoma or liver metastases. Intra-arterial administration may cause (in addition to systemic toxicity manifestations qualitatively similar to those observed with intravenous doxorubicin) gastric and duodenal ulcers (likely due to drug reflux into gastric arteries) and biliary strictures due to drug-induced sclerosing cholangitis. This route of administration may lead to extensive tissue necrosis in the perfused area.

Carcinogenesis, mutagenesis, fertility impairment. Doxorubicin has shown genotoxic and mutagenic properties in in vitro and in vivo tests.

Use during pregnancy or breastfeeding.

Fertility

Women

In women, doxorubicin may cause infertility during treatment. Doxorubicin may induce amenorrhea and infertility. Ovulation and menstrual cycles usually return after therapy completion, although premature menopause is possible.

Men

Doxorubicin has mutagenic properties and may cause chromosomal damage in human spermatozoa. Oligospermia or azoospermia may be permanent, although sperm counts have been reported to return to normal in some cases, sometimes years after therapy completion.

Both men and women should seek fertility preservation counseling before starting therapy.

Pregnancy

Doxorubicin is contraindicated during the first trimester of pregnancy and during the second and third trimesters, except in cases of clear necessity and only with strict indications, when the benefit to the mother outweighs the potential risk to the fetus.

In vivo and in vitro studies have confirmed the embryotoxicity of doxorubicin.

Animal studies have demonstrated reproductive toxicity of doxorubicin, including fetal developmental abnormalities.

If a woman receives doxorubicin during pregnancy or becomes pregnant during therapy, she should be informed of the potential risk to the fetus.

Patients wishing to have children after treatment completion are advised to seek genetic counseling.

Women of reproductive age/Contraception in men and women

Women of reproductive age should avoid pregnancy and use effective contraception during doxorubicin therapy and for at least 6 months and 10 days after the last dose.

Men with female partners of reproductive age should be informed to use effective contraception during doxorubicin therapy and for at least 3 months and 10 days after the last dose.

Lactation

Doxorubicin passes into breast milk. Due to the potential for serious adverse reactions in breastfed infants, women should avoid breastfeeding during doxorubicin therapy and for at least 10 days after the last dose.

Ability to affect reaction speed when driving or operating machinery.

Doxorubicin may have a slight or moderate effect on the ability to drive or operate machinery.

Method of Administration and Dosage.

Doxorubicin-Vista should be administered only under the supervision of a qualified physician experienced in cytotoxic therapy. In addition, careful monitoring of the patient's condition during treatment is required.

Due to the risk of fatal cardiomyopathy, the risk-benefit ratio must be individually assessed for each patient prior to each administration.

Prior to initiating treatment, liver function tests should be performed, including AST (aspartate aminotransferase), ALT (alanine aminotransferase), ALP (alkaline phosphatase), and bilirubin, as well as assessment of renal function.

An evaluation of left ventricular ejection fraction by echocardiography or radionuclide angiocardiography should be performed to assess cardiac status. This procedure should be conducted prior to starting treatment and after each cumulative dose of approximately 100 mg/m².

Doxorubicin must not be administered intramuscularly, subcutaneously, orally, or intrathecally. Doxorubicin should be administered intravenously and, for local tumor treatment, via slow intra-arterial infusion or intravesical instillation through a catheter. Doxorubicin must not be used as an antibacterial agent.

Doxorubicin 0.2% is not interchangeable with liposomal formulations of doxorubicin hydrochloride.

Intravenous Administration

Doxorubicin-Vista may be administered intravenously as a bolus over several minutes, as a short infusion over one hour, or as a continuous infusion over up to 24 hours. In monotherapy, the dose may be divided and administered over 2–3 consecutive days. The solution should be administered through an infusion line as an intravenous infusion with free-flowing fluid, using either 9 mg/ml (0.9%) sodium chloride injection or 50 mg/ml (5%) dextrose injection, over 2–15 minutes. This method minimizes the risk of thrombophlebitis or perivenous extravasation, which may lead to serious local reactions such as subcutaneous inflammation, blistering, and tissue necrosis. Rapid bolus injection is not recommended due to the risk of extravasation, which may occur even when adequate backflow of blood is observed during needle aspiration.

The dose of doxorubicin depends on the treatment regimen, the patient’s general condition, and prior therapy. The dosing regimen may vary depending on the indication (solid tumors or acute leukemia) and whether doxorubicin is used as monotherapy or in combination with other cytotoxic agents, or as part of a multimodal treatment approach including chemotherapy, surgery, radiotherapy, and/or hormonal therapy.

Monotherapy. The dose is typically calculated based on body surface area (mg/m²). The recommended dose for doxorubicin monotherapy is 60–75 mg/m² of body surface area every three weeks.

The drug should be administered by intravenous infusion with a 21-day interval, depending on hematological and bone marrow status, provided there is normal recovery from the drug’s toxic effects (particularly myelosuppression and stomatitis). A lower dose (60 mg/m²) is recommended for patients with reduced bone marrow reserve due to advanced age, prior therapy, or tumor infiltration of the bone marrow. The recommended dose per cycle may be administered as a single infusion or divided into 2–3 administrations over consecutive days. For pediatric patients, an alternative dose of 30 mg/m²/day intravenously for 3 consecutive days is recommended; treatment cycles should be repeated every 4 weeks. Dosing schedules and doses may be adjusted according to protocol. For precise dosing information, refer to current protocols.

Combination Therapy. When doxorubicin hydrochloride is administered in combination with other antineoplastic agents that may potentiate toxicity—such as high-dose intravenous cyclophosphamide or related anthracyclines (e.g., daunorubicin, idarubicin, and/or epirubicin)—the dose of doxorubicin should be reduced to 30–60 mg/m² every 3–4 weeks.

For patients unable to receive a full dose (e.g., due to immunosuppression or advanced age), an alternative dose is 15–20 mg/m² of body surface area per week.

Patients at Risk of Cardiac Disorders

To prevent cardiomyopathy, the cumulative lifetime dose of doxorubicin (including related agents such as daunorubicin) should not exceed 450–550 mg/m² of body surface area. For patients with pre-existing heart disease, those who have received mediastinal and/or cardiac irradiation, those previously treated with alkylating agents, those receiving concomitant potentially cardiotoxic drugs, and those at increased risk (e.g., patients with arterial hypertension lasting more than 5 years, coronary, valvular, or myocardial heart disease, or patients aged 70 years or older), the recommended maximum cumulative dose should not exceed 400 mg/m² of body surface area, and careful monitoring of cardiac function is required.

For patients at increased risk of cardiac toxicity, treatment should be administered as a 24-hour infusion rather than as a bolus injection. This method reduces the risk of cardiac toxicity without compromising therapeutic efficacy. Such patients should undergo left ventricular ejection fraction assessment before each treatment cycle.

Patients with Impaired Bone Marrow Reserve Unrelated to Disease-Related Bone Marrow Involvement

The dose may be reduced in patients with a history of myelosuppressive therapy, as their bone marrow reserve may be insufficient.

Hepatic Impairment

The dose should be reduced in patients with impaired liver function, as shown in Table 1:

Table 1

Doxorubicin should not be administered to patients with severe hepatic impairment (>85 μmol/L).

Renal impairment

There is no need to adjust the recommended dose of the drug when administered to patients with moderate renal impairment due to the low urinary excretion of doxorubicin. In patients with renal insufficiency and a glomerular filtration rate (GFR) less than 10 mL/min, 75% of the calculated dose should be administered.

Patients with excess body weight

A reduction in the initial dose or prolongation of the interval between doses may be required in patients with excess body weight.

Children

Due to the significant risk of cardiotoxicity associated with doxorubicin, maximum cumulative doses dependent on age should be applied in children. For children (under 12 years of age), the maximum cumulative dose is considered to be 300 mg/m², whereas for adolescents (12 years of age and older), the maximum cumulative dose is 450 mg/m². For infants, maximum cumulative doses have not yet been established, but lower tolerance is expected.

Doses for children should be reduced, as they have an increased risk of developing cardiotoxicity, particularly delayed toxicity. Myelotoxicity is expected to occur at least 10–14 days after initiation of treatment.

Intravesical administration

Doxorubicin-Vista may be used for intravesical instillation for the treatment of superficial bladder cancer or for the prevention of recurrence after transurethral resection (TUR). The recommended dose for a single instillation in the intravesical treatment of superficial bladder cancer is 30–50 mg of the drug dissolved in 25–50 mL of physiological saline. The optimal concentration is approximately 1 mg/mL. The solution should remain in the bladder for 1–2 hours. During this period, the patient should change body position every 15 minutes by rotating 90 degrees. To avoid unwanted dilution by urine, patients should be advised to refrain from drinking fluids for 12 hours prior to instillation (this should reduce urine output to approximately 50 mL per hour).

Restrictions regarding intravenous administration of the drug do not apply to intravesical administration, as absorption of doxorubicin and its entry into the bloodstream are extremely low.

Since various treatment regimens are currently in use, complicating interpretation, the following supplementary information is provided:

• the drug should be administered through a catheter, and the solution should remain in the bladder for 1–2 hours;
• the optimal concentration of doxorubicin in the bladder should be ≈1 mg/mL;
• to avoid unwanted dilution by urine, patients should be advised to refrain from drinking fluids for 12 hours prior to instillation, which should reduce urine output to approximately 50 mL per hour;
• after administration of the drug, the patient should change body position by 90 degrees every 15 minutes to increase the surface area of contact between the solution and the bladder wall and mucosa.

After completion of the procedure, the patient should empty the bladder.

The duration of treatment is determined individually by the physician.

Instillations may be performed at intervals ranging from 1 week to 1 month, depending on whether the treatment is therapeutic or prophylactic.

Children

The drug may be used from birth. Children and adolescents have a higher risk of developing delayed cardiotoxicity following doxorubicin administration.

Overdose

There is no known specific antidote for doxorubicin.

Manifestations of acute intoxication may occur within 24 hours, including heart failure with chest pain, angina, and myocardial infarction. In such cases, consultation with a cardiologist is required. Acute overdose with doxorubicin may lead to myelosuppression (particularly leukopenia and thrombocytopenia), typically occurring 10–14 days after administration, and gastrointestinal toxic effects (particularly mucositis). If signs of intoxication appear, administration of doxorubicin should be immediately discontinued. Treatment includes intravenous antibiotics, granulocyte and platelet transfusions, and management of gastrointestinal symptoms and cardiac dysfunction. Consideration should be given to transferring the patient to a sterile environment and using hematopoietic growth factors.

Single doses of 250 mg and 500 mg of doxorubicin have been reported to be fatal.

Chronic overdose with a cumulative dose exceeding 550 mg/m² increases the risk of cardiomyopathy and may lead to heart failure, which should be managed with conventional therapy. Delayed onset heart failure may occur up to 6 months after overdose.

Hemodialysis is unlikely to be effective in treating doxorubicin intoxication, as doxorubicin has a very large volume of distribution and only 5% of the dose is excreted by the kidneys.

Extravasation

Accidental perivenous administration causes local necrosis and thrombophlebitis. A burning sensation at the infusion site is a sign of perivenous administration.

In case of extravasation, infusion or injection should be immediately stopped; the needle should be left in place briefly, followed by short-term aspiration before removal.

In case of extravasation, intravenous infusion of dexrazoxane should be initiated no later than 6 hours after the extravasation event. If dexrazoxane is contraindicated, topical application of 99% dimethyl sulfoxide (DMSO) is recommended on an area twice the size of the affected area (4 drops per 10 cm² of skin surface); this procedure should be performed 3 times daily for at least 14 days. Wound debridement should be performed if necessary. Due to an antagonistic mechanism, the area should be cooled after application of dimethyl sulfoxide to reduce pain. Dimethyl sulfoxide should not be used in patients receiving dexrazoxane for the treatment of anthracycline-induced extravasation.

Adverse Reactions

Doxorubicin therapy frequently causes adverse reactions, some of which are serious, necessitating careful patient monitoring. The frequency and type of adverse reactions depend on the rate of administration and the dose of the drug.

The main adverse effects are bone marrow suppression and cardiotoxicity (see section "Special Warnings and Precautions for Use"). Myelosuppression is an acute, dose-limiting adverse reaction, but in most cases, it is transient. Clinical consequences of bone marrow/hematological toxicity of doxorubicin may include elevated body temperature, infections, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or fatal outcome. Nausea and vomiting occur in nearly all patients.

The most common adverse effect, occurring in 86% of cases, is alopecia. In men, treatment is associated with cessation of beard and moustache growth; however, hair regrowth resumes after discontinuation of therapy.

Stomatitis may develop approximately 5–10 days after initiation of treatment. The condition manifests as painful erosions located on the lateral edges of the tongue and the sublingual mucosa. Frequency and severity are higher with dosing regimens involving administration of doxorubicin for 3 consecutive days.

Intravesical administration may cause the following adverse reactions: hematuria, bladder and urethral irritation, burning sensation in the bladder area and during urination, dysuria, difficult urination, and pollakiuria. These reactions are usually of moderate severity and transient.

Intravesical administration of doxorubicin may occasionally cause hemorrhagic cystitis, which may lead to reduced bladder capacity.

Extravasation may result in severe cellulitis, blistering, thrombophlebitis, lymphangitis, and local tissue necrosis, which may require surgical intervention (including skin grafting). Phlebitis, particularly, is observed when the drug is administered into small-diameter vessels or with repeated injections into the same vein (see section "Dosage and Administration").

The following classification of adverse reactions associated with doxorubicin use is based on affected organ system classes (MedDRA) and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations: very common – infections; common – sepsis, septicemia.

Benign and malignant neoplasms* and proliferative disorders of unknown etiology (including cysts and polyps): uncommon – acute lymphoblastic leukemia, acute myeloblastic leukemia (with or without preleukemic phase) in patients treated with doxorubicin in combination with other DNA-damaging antineoplastic agents. The latent period in such cases may be short (1–3 years).

Blood and lymphatic system disorders: very common – myelosuppression**, leukopenia, neutropenia, anemia, and thrombocytopenia; very rare – septic shock, hemorrhage, tissue hypoxia, or fatal outcome.

Immune system disorders: rare – anaphylactic reactions; frequency not known – anaphylactic shock.

Reproductive system disorders: very rare – amenorrhea, oligospermia or azoospermia, hot flushes.

Metabolism and nutrition disorders: very common – decreased appetite, weight loss; very rare – hyperuricemia; frequency not known – dehydration, anorexia.

Eye disorders: common – conjunctivitis; frequency not known – increased lacrimation, blurred vision, keratitis.

Cardiac disorders: very common – cardiotoxicity***, which may manifest as tachycardia, including supraventricular tachycardia, and ECG changes; common – congestive heart failure (CHF), congestive (dilated) cardiomyopathy with life-threatening potential (after cumulative dose of 550 mg/m²), sinus tachycardia, ventricular tachycardia, supraventricular and ventricular extrasystoles, bradycardia, arrhythmia, asymptomatic decrease in left ventricular ejection fraction; very rare – non-specific ECG changes (S-T segment changes, low voltage, prolonged Q-T interval), isolated life-threatening arrhythmias, acute left ventricular failure, pericarditis, pericarditis/myocarditis syndrome with fatal outcome; frequency not known – atrioventricular block, tachyarrhythmia, bundle branch block.

The risk of developing cardiomyopathy increases with increasing cumulative dose of the drug. The cumulative dose should not exceed 450–550 mg/m² body surface area, although irreversible CHF may occur even at doses as low as 240 mg/m² body surface area.

Risk factors include age ≥70 years or ≤15 years. There are reports that prior or concomitant administration of mitomycin C, cyclophosphamide, or dacarbazine may contribute to the development of doxorubicin-induced cardiomyopathy.

Cardiotoxic effects may occur several weeks, months, or even years after completion of doxorubicin therapy. The risk of heart failure in cancer patients receiving doxorubicin persists throughout life.

Vascular disorders: common – hemorrhage; uncommon – thromboembolism; frequency not known – phlebitis, thrombophlebitis, flushing, shock.

Respiratory, thoracic and mediastinal disorders: rare – toxic lung injury (manifesting as tachypnea, dyspnea/pleural effusion, obliterative bronchiolitis with pneumonia, bronchiocentric granulomatosis/respiratory depression threatening life; post-pneumonectomy-like syndrome; interstitial pneumonitis; radiation pneumonitis; pulmonary artery embolism); increased cough, pharyngitis, upper respiratory tract infections.

Gastrointestinal disorders: very common – mucositis/stomatitis, esophagitis, gastrointestinal disorders****, diarrhea, nausea, vomiting, colitis; common – abdominal pain; uncommon – gastrointestinal bleeding, abdominal pain, necrosis of the large intestine with massive hemorrhage and severe infections; very rare – erosions/ulcers of gastric mucosa, mucosal ulcers (oral cavity, pharynx, esophagus, gastrointestinal tract), hyperpigmentation of oral mucosa.

Hepatobiliary disorders: frequency not known – hepatotoxicity (sometimes progressing to cirrhosis), mild transient elevation of liver enzymes, increased total bilirubin. In cases of concomitant radiotherapy to the liver area, severe hepatotoxic effects may occur, potentially leading to liver cirrhosis.

Skin and subcutaneous tissue disorders: very common – palmar-plantar erythrodysesthesia (PPE), dose-dependent reversible alopecia occurring in most patients; erythema, photosensitization; common – local hypersensitivity reactions in irradiated areas (radiation recall phenomenon), urticaria, rash, local toxicity, skin and nail hyperpigmentation, pruritus; rare – exanthema, onycholysis, extravasation (may lead to severe cellulitis, blistering, thrombophlebitis, lymphangitis, and local tissue necrosis); very rare – blister formation; frequency not known – skin inflammation, actinic keratosis.

Musculoskeletal and connective tissue disorders: frequency not known – generalized myasthenia, arthralgia.

Renal and urinary disorders: very common – red discoloration of urine;

common – necrosis of bladder wall, decreased bladder capacity, dysuria, chemical cystitis due to intravesical administration (with symptoms such as bladder and urethral irritation, dysuria, stranguria, pollakiuria, hematuria, vesical spasms, hemorrhagic cystitis); very rare – acute renal failure, hyperuricemia and subsequent uric acid nephropathy due to massive tumor lysis.

Nervous system disorders: rare – tremor, dizziness.

Reproductive system and breast disorders: frequency not known – amenorrhea, azoospermia, oligospermia.

General disorders and administration site conditions: very common – increased body temperature, asthenia, fever; common – injection site reactions (erythematous reactions along the vein, pain, phlebitis, phlebosclerosis); uncommon – dehydration; frequency not known – discomfort, severe cellulitis.

Investigations: very common – ECG abnormalities, changes in transaminase levels, increase/decrease in body weightb.

Surgical and medical procedures: frequency not known – radiation-induced injuries (skin, lungs, esophagus, gastric mucosa, heart), which were previously healing, may reappear after doxorubicin administration.

a Within 1–2 days after administration.

b Observed in women with breast cancer receiving combined adjuvant therapy including doxorubicin.

* Secondary leukemia (sometimes) with or without preleukemic phase has been observed in patients treated with anthracyclines (including doxorubicin). Secondary leukemia is more frequently observed when anthracyclines are used in combination with DNA-damaging cytostatic agents (alkylating compounds, platinum derivatives), with radiotherapy, after prior intensive therapy with cytotoxic agents, or with increased anthracycline doses. Such leukemia may occur after a latency period of 1–7 years.

** One of the dose-limiting effects is bone marrow function suppression, which can be severe. This is mainly manifested by decreased leukocyte count. Leukopenia was observed in nearly 75% of patients with adequate bone marrow reserve receiving treatment at a dose of 60 mg/m² body surface area every 21 days. Thrombocytopenia, neutropenia, and anemia have also been reported, but less frequently. Superinfections (very common) and hemorrhages related to bone marrow suppression have also been observed. The nadir of bone marrow suppression usually occurs on days 10–14 after doxorubicin administration, and recovery is generally observed between days 21 and 28. Thrombocytopenia or anemia, if they occur, are observed during this same period but are usually less severe.

*** Doxorubicin is cardiotoxic. The risk of cardiotoxic adverse effects is increased during and after therapy involving mediastinal irradiation, after prior treatment with potentially cardiotoxic agents (e.g., anthracyclines, cyclophosphamides), and in elderly patients (aged ≥60 years) and patients with hypertension.

The cardiotoxic effect of doxorubicin may manifest in two forms.

Acute form

Adverse effects of the acute form occur in most cases within the first 24–48 hours after initiation of therapy; they are dose-independent and characterized by: transient arrhythmia (common), particularly sinus tachycardia (common), supraventricular and ventricular extrasystoles. They (very rare) may be characterized by non-specific ECG changes (S-T changes, low voltage, prolonged Q-T interval). These changes are generally reversible, and their occurrence is not a contraindication for repeated administration of doxorubicin. However, life-threatening arrhythmias may occur during or several hours after doxorubicin administration; in isolated cases, acute left ventricular failure, pericarditis, or pericarditis/myocarditis with fatal outcome have been reported.

Delayed form

Adverse effects of the delayed form are manifested as cumulative, dose-dependent organ toxicity, generally irreversible and often life-threatening. These effects frequently present as congestive (dilated) cardiomyopathy with signs of left ventricular failure occurring several months after completion of therapy. However, cardiotoxicity may first manifest even years after therapy ends; the risk increases with increasing total cumulative dose.

**** Doxorubicin has a pronounced emetogenic effect; moderate to severe nausea and vomiting occur in approximately 80% of patients on the first day of treatment and later. Subsequently, loss of appetite (common) and blister formation on the mucous membranes of the mouth, pharynx, esophagus, and gastrointestinal tract may occur. In severe cases, this may lead to infections. Diarrhea (very common) may occur secondarily due to inhibition of intestinal epithelial proliferation. Necrosis of the large intestine with massive hemorrhage and severe infections (uncommon) has been reported in association with concomitant cytarabine use. Esophagitis (uncommon) may occur during radiotherapy and may lead to esophageal stricture during doxorubicin therapy.

Adverse effects in patients receiving doxorubicin as adjuvant therapy for breast cancer. According to results of a randomized open-label study evaluating doxorubicin and cyclophosphamide for treatment of early metastatic breast cancer to axillary lymph nodes, the most common adverse effect (in addition to those typical for doxorubicin) was weight loss.

Shelf life.

2 years.

Storage conditions.

Store at 2–8°C in the original packaging. Keep out of reach of children.

Incompatibilities.

Doxorubicin should not be mixed with heparin, as precipitation may occur. Doxorubicin is incompatible with aminophylline, cephalothin, fluorouracil, and hydrocortisone. If concomitant therapy with doxorubicin and fluorouracil is required, the catheter should be flushed after administration of these drugs. Contact with aluminum should be avoided. Prolonged contact with any solution of alkaline pH should be avoided, as it leads to hydrolysis of the drug.

In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products.

Packaging.

5 ml, 10 ml, 25 ml, 50 ml, 75 ml, 100 ml in a vial; 1 vial in a cardboard box.

Prescription status. Prescription only.

Manufacturers.

Actavis Italia S.p.A.

Sindan Pharma S.R.L.

Manufacturer locations and addresses of places of business.

Via Pasteur, 10 - 20014 Nerviano (Milan), Italy.

Bd. Ion Mihalache, 11, Sector 1, 011171, Bucharest, Romania.