Doxorubicin-mili

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOXORUBICIN-MILI (DOXORUBICIN-MILI)

Composition:

active substance: doxorubicin; doxorubicin;

1 ml of solution contains doxorubicin hydrochloride 2 mg;

excipients: sodium chloride, hydrochloric acid, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: red-colored solution.

Pharmacotherapeutic group. Antineoplastic agents. Anthracyclines 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.

Doxorubicin is an antineoplastic agent. The antitumor effect of doxorubicin is believed to be related to the drug's influence on nucleic acid synthesis, although the exact mechanism of action has not been fully elucidated.

The proposed mechanism of action includes: DNA intercalation (resulting in inhibition of DNA, RNA, and protein synthesis), formation of highly reactive free radicals and superoxides, chelation of divalent cations, inhibition of Na-K ATPase, and binding of doxorubicin to certain cellular membrane components (particularly membrane lipids, spectrin, and cardiolipin). The highest concentrations of the drug are achieved in the lungs, liver, spleen, kidneys, heart, small intestine, and bone marrow. Doxorubicin does not cross the blood-brain barrier.

Pharmacokinetics

After intravenous administration, the plasma elimination curve of doxorubicin is triphasic, with half-lives of 12 minutes, 3.3 hours, and 30 hours. The relatively prolonged terminal half-life of doxorubicin reflects its distribution into a deep tissue compartment. Only approximately 33–50% of the administered drug labeled with fluorescence or tritium (or its metabolites) was detected in urine, bile, and feces within 5 days after intravenous administration. The remainder of doxorubicin and its metabolites apparently remains in body tissues for a prolonged period.

In cancer patients, doxorubicin is reduced to doxorubicinol—a cytotoxic active compound. This reduction is apparently catalyzed by cytoplasmic NADPH-dependent aldo-keto reductases present in all tissues and plays an important role in determining the overall pharmacokinetics of doxorubicin.

Microsomal glycosidases, present in most tissues, cleave doxorubicin and doxorubicinol to inactive aglycones. The aglycones may undergo O-demethylation followed by conjugation with sulfate or glucuronide and are excreted in bile.

Clinical Characteristics

Indications

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

Doxorubicin is frequently used in combination with other cytotoxic agents as part of combination chemotherapy regimens. Doxorubicin must not be used as an antibacterial agent.

Contraindications

Hypersensitivity to doxorubicin or any other component of the medicinal product, other anthracyclines, or anthracenediones.

For intravenous administration:

• Persistent myelosuppression;
• Severe impairment of liver function;
• Severe impairment of myocardial function;
• Recent myocardial infarction;
• Severe arrhythmia;
• Prior treatment with maximum cumulative doses of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones.

Special precautions

When handling antineoplastic agents, the following safety measures must be observed:

• Personnel must be trained in proper reconstitution and handling procedures;
• Pregnant staff must not handle the drug;
• Personnel handling the drug must wear personal protective equipment: goggles, gowns, masks, and disposable gloves;
• A designated area must be provided for drug reconstitution (preferably under a laminar flow system). The work surface must be protected with absorbent plastic-backed paper;
• All materials used in drug administration or cleaning, including gloves, must be placed in high-risk waste containers designated for high-temperature incineration;
• In case of spillage or leakage, contaminated materials must be soaked in 1% sodium hypochlorite solution, then rinsed with water;
• In case of skin contact, the affected area must be thoroughly washed with soap and water or sodium bicarbonate solution. Scrubbing with a brush is not recommended;
• In case of eye contact, the eyelid should be held open and the eye irrigated with water for 15 minutes, followed by immediate medical consultation;
• Hands must always be washed after removing gloves;
• All cleaning materials must be properly disposed of.

Disposal of cytostatic agents must comply with applicable regulations.

Interaction with other medicinal products and other forms of interaction

Doxorubicin is a substrate of cytochrome P450 enzymes CYP3A4 and CYP2D6, as well as P-glycoprotein (P-gp). Clinically significant interactions have been observed with inhibitors of CYP3A4, CYP2D6, and/or P-gp (e.g., verapamil), leading to increased doxorubicin concentrations and enhanced clinical effects. Doxorubicin concentrations may be reduced by inducers of CYP3A4 (e.g., phenobarbital, phenytoin, St. John’s wort) and P-gp inducers.

Combining cyclosporine with doxorubicin may increase the area under the concentration–time curve (AUC) for both doxorubicin and doxorubicinol, likely due to reduced clearance of the parent compound and decreased metabolism of doxorubicinol. Clinical studies have shown that combining cyclosporine with doxorubicin results in more pronounced and prolonged hematological toxicity compared to doxorubicin monotherapy. Cases of coma and seizures have also been reported with concomitant administration of cyclosporine and doxorubicin.

High doses of cyclosporine increase serum levels of doxorubicin and myelotoxicity.

Doxorubicin is used in combination with anticancer chemotherapy. Additive toxic effects are most commonly observed in the bone marrow, other hematopoietic organs, and the gastrointestinal tract (see section "Special Warnings and Precautions for Use"). The use of doxorubicin in combination chemotherapy with other potentially cardiotoxic agents, as well as concomitant use with other cardioactive drugs (e.g., calcium channel blockers), requires continuous monitoring of cardiac function throughout the treatment period. Hepatic function changes caused by concomitant therapy may affect doxorubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity.

If paclitaxel is administered prior to doxorubicin, it may lead to increased concentrations of doxorubicin and/or its metabolites. Some data suggest lower increases in concentration if doxorubicin is administered before paclitaxel.

The use of trastuzumab in combination with anthracyclines (such as doxorubicin) is associated with a high risk of cardiotoxicity. Cardiotoxic drugs (e.g., trastuzumab) and anthracyclines should not be administered simultaneously, except in well-controlled clinical trials with cardiac monitoring (see section "Special Warnings and Precautions for Use").

When administered concomitantly with sorafenib at a dose of 400 mg twice daily, an increase in AUC by 21% has been observed. The clinical significance of these findings is unknown.

Special precautions for use

Doxorubicin therapy should be administered under the supervision of an experienced oncologist experienced in the use of cytotoxic agents.

Prior to initiating doxorubicin treatment, patients should have recovered from acute toxicities (e.g., stomatitis, neutropenia, thrombocytopenia, and generalized infections) resulting from previous cytotoxic therapy.

In patients with excess body weight (>130% of ideal body weight), systemic clearance of doxorubicin is reduced (see section "Dosage and administration").

Cardiac function. There is a risk of developing acute or delayed manifestations of cardiotoxicity associated with anthracycline therapy.

Early (acute) cardiotoxicity. Early cardiotoxicity of doxorubicin primarily manifests as sinus tachycardia and/or electrocardiographic abnormalities such as non-specific ST-T segment changes. Tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, atrioventricular block, and bundle branch block may also occur. These manifestations generally do not predispose to late cardiotoxicity; they are rarely clinically significant and are generally not considered a reason to discontinue doxorubicin therapy.

Late (delayed) cardiotoxicity. Late cardiotoxicity usually develops at the end of the treatment course or within 2–3 months after completion of therapy, although later manifestations have been observed from several months to several years after treatment cessation. Late cardiomyopathy presents as a decline in left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure, such as dyspnea, pulmonary edema, peripheral edema, cardiomegaly, and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Subacute manifestations such as pericarditis/myocarditis have also been reported. Life-threatening congestive heart failure is the most severe form of anthracycline-induced cardiomyopathy and represents a cumulative dose-limiting toxicity of the drug.

Cardiac function should be assessed before initiating doxorubicin therapy, and regular monitoring during treatment is essential to minimize the risk of severe cardiac complications. This risk can be reduced by regular monitoring of LVEF throughout the treatment course, with immediate discontinuation of the drug at the first signs of cardiac dysfunction. The optimal quantitative methods for regular assessment of cardiac function (evaluation of left ventricular ejection fraction) are multigated radionuclide angiography (MUGA) or echocardiography (Echocardiography, EchocG). Baseline cardiac evaluation using ECG, MUGA, or EchocG is recommended, especially in patients with risk factors for increased cardiotoxicity. Regular monitoring of LVEF using MUGA or EchocG is necessary, particularly when high cumulative doses of anthracyclines are administered. Regular cardiac function monitoring using these methods should be performed throughout the entire treatment course.

The probability of developing congestive heart failure is approximately

1–2% at a cumulative dose of 300 mg/m² and increases gradually with increasing total cumulative dose up to 450–550 mg/m². Beyond this, the risk of congestive heart failure increases sharply; therefore, exceeding the maximum cumulative dose of 550 mg/m² is not recommended.

Risk factors for cardiotoxicity include active or latent cardiovascular disease, prior or concurrent mediastinal/pericardial radiotherapy, previous therapy with anthracyclines or anthracenediones, concomitant use of drugs capable of suppressing myocardial contractility or cardiotoxic agents (e.g., trastuzumab), and age over 70 years. Anthracyclines, including doxorubicin, should not be administered in combination with other cardiotoxic agents unless cardiac function is monitored (see section "Interaction with other medicinal products and other forms of interaction"). Patients who receive anthracyclines after discontinuation of other cardiotoxic agents, particularly those with a long half-life such as trastuzumab, are also at increased risk. The documented elimination half-life of trastuzumab is variable. Trastuzumab may remain in circulation for up to 7 months. Therefore, physicians should avoid anthracycline-based therapy for at least 7 months after discontinuation of trastuzumab whenever possible. If anthracyclines have been previously administered, careful monitoring of cardiac function is recommended.

Patients receiving high cumulative doses and those with the aforementioned risk factors require close monitoring of cardiac function. However, doxorubicin may induce cardiotoxic effects even at low cumulative doses or in the absence of risk factors.

The risk of late cardiotoxicity with doxorubicin therapy is higher in children and adolescents. The risk may also be higher in women than in men. Regular monitoring of cardiac function is recommended to detect potential cardiotoxic manifestations.

The toxicity of doxorubicin and other anthracyclines and anthracenediones may be additive.

Hematological toxicity. Doxorubicin may cause myelosuppression. Therefore, complete blood counts including differential leukocyte count should be performed before initiating therapy and prior to each treatment cycle. Dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) are the primary manifestations of hematological toxicity and the most common dose-limiting toxicities of the drug. Leukopenia and neutropenia typically reach their nadir 10–14 days after drug administration; leukocyte and neutrophil counts usually return to normal by day 21. Thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.

Secondary leukemia. Cases of secondary leukemia, with or without a preceding preleukemic phase, have been observed with anthracyclines (including doxorubicin). Secondary leukemia most commonly occurs with combined use of these agents with DNA-damaging antineoplastic drugs, in combination with radiotherapy, following complications from prior cytotoxic therapy, or with significant increases in anthracycline doses. This leukemia has a latency period of 1 to 3 years.

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

In women, doxorubicin may cause infertility during treatment. Amenorrhea may occur. Ovulation and menstrual cycles usually return to normal after therapy cessation, although premature menopause is possible.

Doxorubicin is mutagenic and may cause chromosomal damage in human spermatozoa. Oligospermia or azoospermia may be permanent; however, sperm counts have been reported to return to normal in some cases, sometimes several years after therapy completion. Men should use effective contraception during treatment with doxorubicin.

Embryo-fetal toxicity

Doxorubicin may cause genotoxicity. Male and female patients should use reliable contraception during and for a certain period after doxorubicin treatment, using two effective contraceptive methods (e.g., including a barrier method). Patients wishing to have children after therapy completion should be advised to seek genetic counseling if appropriate and feasible (see section "Use during pregnancy or breastfeeding").

Hepatic function. The primary route of doxorubicin elimination is via the hepatobiliary system. Serum bilirubin levels should be determined before and during doxorubicin therapy. Patients with elevated bilirubin levels exhibit slower doxorubicin clearance, leading to increased overall toxicity. Dose reduction is recommended for treatment of such patients. Doxorubicin is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Other. Doxorubicin may potentiate the toxicity of other antineoplastic agents. Cases of enhanced hemorrhagic cystitis induced by cyclophosphamide and increased hepatotoxic effects of 6-mercaptopurine have been observed. Radiation therapy may also exert toxic effects on the myocardium, mucosa, skin, and liver.

As with other cytotoxic agents, thrombophlebitis and thromboembolism (in some cases fatal), including pulmonary embolism, may occasionally occur during doxorubicin therapy.

Extravasation. Extravasation of doxorubicin during intravenous injection may cause pain at the injection site, severe tissue damage (vesiculation, severe subcutaneous inflammation), and necrosis. If signs or symptoms of extravasation occur during intravenous administration of doxorubicin, the infusion should be immediately discontinued.

Paravenous injection causes local necrosis and thrombophlebitis. A burning sensation at the infusion site indicates paravenous administration.

Management of extravasation.

Upon extravasation, infusion or injection should be immediately stopped; the needle should initially be left in place, followed by brief aspiration before removal. Application of 99% dimethyl sulfoxide (DMSO) to the affected area (twice the size of the lesion; 4 drops per 10 cm² body surface area) is recommended, repeated three times daily for at least 14 days. Wound debridement should be performed if necessary. Cooling of the affected skin area, for example to reduce pain, should be applied immediately after DMSO application (vasoconstriction versus vasodilation) due to antagonistic mechanisms of action.

Tumor lysis syndrome. Doxorubicin may cause hyperuricemia as a result of extensive purine catabolism accompanying rapid drug-induced lysis of neoplastic cells (tumor lysis syndrome). After initiating therapy, serum levels of uric acid, potassium, phosphate, calcium, and creatinine should be monitored. To prevent hyperuricemia and minimize potential complications of tumor lysis syndrome, hydration, urine alkalinization, and prophylactic administration of allopurinol are recommended.

Vaccination

Administration of live or live attenuated vaccines to patients with immunosuppression due to chemotherapy, including doxorubicin, may result in severe or fatal infections. Live vaccines should be avoided in patients receiving doxorubicin. Inactivated or neutralized vaccines may be administered, but the immune response may be suboptimal.

Use during pregnancy or breastfeeding

Pregnancy

Doxorubicin has harmful pharmacological effects on pregnancy and the fetus/newborn. Due to its embryotoxic potential, doxorubicin should not be used during pregnancy except in cases of clear necessity. Women who receive doxorubicin during pregnancy or become pregnant during treatment should be informed of the potential risk to the fetus.

Women of reproductive potential must use effective contraception during treatment (see section "Special precautions for use").

Women of reproductive potential / contraception in males and females

Women of reproductive potential should be advised to avoid pregnancy during treatment and to use two effective contraceptive methods (e.g., including a barrier method) during treatment and for at least 7 months after the last dose. Men with partners of reproductive potential should be advised to use two effective contraceptive methods (e.g., including a barrier method) during treatment with doxorubicin and for at least 4 months after the last dose.

Breastfeeding period.

Doxorubicin is excreted in breast milk. Women should refrain from breastfeeding during doxorubicin therapy and for at least 10 days after the last dose.

Fertility

Both men and women should consult regarding fertility preservation prior to treatment.

Ability to affect reaction speed when driving or operating machinery

The effect of doxorubicin on the ability to drive or operate machinery has not been established.

Method of Administration and Dosage

The total dose of doxorubicin per cycle may vary depending on its use within a specific treatment regimen (e.g., as monotherapy or in combination with other cytotoxic agents) and according to the indication.

Doxorubicin should be administered as an intravenous infusion with a free flow of fluid over a period of not less than 3 minutes and not more than 10 minutes during the injection. This method of administration minimizes the risk of thrombophlebitis or perivenous hemorrhage, which may lead to serious local reactions such as subcutaneous inflammation, blistering, and tissue necrosis. Bolus injection is not recommended due to the risk of extravasation, which may occur even when adequate backflow of blood is observed during aspiration through the needle.

Doxorubicin dosage is typically calculated based on body surface area (mg/m²). When using the medicinal product Doxorubicin-Mili as monotherapy in adults, the recommended initial dose is 60–75 mg/m² of body surface area per cycle. The total initial dose per cycle may be administered as a single dose, divided over three consecutive days, or administered on days 1 and 8. If normal recovery from toxic effects (particularly bone marrow suppression and stomatitis) occurs, treatment cycles may be repeated every 3–4 weeks. In combination therapy with other cytotoxic agents that have overlapping toxic potential, the recommended dose is 30–60 mg/m² of body surface area every 3 weeks.

If dosing is based on body weight, observations indicate that administering doxorubicin as a single dose every three weeks significantly reduces adverse toxic effects, including mucositis. However, some specialists believe that dividing the dose over three consecutive days (0.4–0.8 mg/kg or 20–25 mg/m² daily) provides greater efficacy, albeit at the expense of increased toxicity. If the dose is calculated based on body weight, 1.2–2.4 mg/kg of the drug should be administered as a single dose every three weeks.

Studies have shown that weekly administration of doxorubicin is as effective as administration once every three weeks. The recommended dose is 20 mg/m² once weekly, although objective responses have been observed at 16 mg/m². Weekly administration reduces cardiotoxicity.

Dose reductions may be required for children, elderly patients, and patients with excessive body weight.

Reduced initial doses or longer intervals between treatment cycles should be applied for patients who have previously undergone intensive therapy or for patients with tumor infiltration of the bone marrow.

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 (see section "Contraindications").

Children

The drug can be used from birth. In children and adolescents, there is a higher risk of developing delayed cardiotoxicity following doxorubicin administration.

Female children may be at greater risk than male children.

Overdose

Single doses of 250 mg and 500 mg of doxorubicin have been reported to be fatal. Such doses of doxorubicin may cause acute heart failure within 24 hours, as well as severe myelosuppression (predominantly leukopenia and thrombocytopenia), which usually develops 10–15 days after administration. Treatment should be supportive during this period, including measures such as blood transfusions and placement of the patient in an aseptic environment.

Acute overdose of doxorubicin also leads to toxic effects on the gastrointestinal tract (mainly mucositis). These symptoms usually develop early after drug administration, but most patients recover within three weeks.

Late-onset heart failure may occur up to six months after overdose. Patients should therefore be carefully monitored, and if symptoms of heart failure appear, they should be treated according to standard guidelines.

Adverse Reactions

The adverse reactions listed below occur in connection with the use of doxorubicin, classified by system organ classes (MedDRA) and frequency: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1000), very rare (≤1/10,000), and not known (cannot be estimated from the available data).

a Within 1-2 days after administration

b Observed in women with breast cancer who are receiving combination adjuvant therapy with doxorubicin.

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

Store in the original packaging at a temperature of 2–8 °C, protected from light and out of reach of children.

Incompatibilities

Doxorubicin should not be mixed with heparin, as their chemical incompatibility may lead to precipitation. Doxorubicin should not be mixed with other substances. Avoid contact with alkaline solutions, as this may lead to hydrolysis of doxorubicin.

Doxorubicin should not be mixed with fluorouracil (e.g., in the same infusion vial or Y-site infusion line), as incompatibility between these agents has been reported due to potential precipitate formation. If concomitant therapy with doxorubicin and fluorouracil is required, catheter flushing is recommended after administration of each agent.

Packaging

5 mL (10 mg), 25 mL (50 mg), or 50 mL (100 mg) of solution in a vial; 1 vial per cardboard box.

Prescription status

Prescription only.

Manufacturer

Venus Remedies Limited.

Manufacturer's address

Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn.), Bhatoli Kalan, Baddi, District Solan, Himachal Pradesh, 173205, India.

Marketing Authorization Holder

Mili Healthcare Limited.

Address of the Marketing Authorization Holder

2nd Floor, Office Premises, 4 Charterfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, United Kingdom.