Doxolek (Concentrate) Instructions for Use

Marketing Authorization Holder

Pharmstandard JSC (Russia)

Manufactured By

Biolek Joint-Stock Company, JSC (Ukraine)

ATC Code

L01DB01 (Doxorubicin)

Active Substance

Doxorubicin (Rec.INN registered by WHO)

Dosage Form

Doxolek

Concentrate for solution for intravascular and intravesical administration 2 mg/ml: 5 ml, 25 ml and 50 ml fl.

Dosage Form, Packaging, and Composition

Concentrate for solution for intravascular and intravesical administration red in color, transparent, free from foreign particles.

Excipients: sodium chloride, diluted hydrochloric acid, water for injections.

5 ml – dark glass bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic antibiotic

Pharmacotherapeutic Group

Antineoplastic agent, antibiotic

Pharmacological Action

Doxorubicin is an anthracycline antineoplastic antibiotic isolated from the culture of Streptomyces peucetius var. caesius.

It has antimitotic and antiproliferative effects.

The mechanism of action involves direct interaction with DNA, inhibition of topoisomerase II, DNA and RNA polymerases, formation of free radicals, and a direct effect on cell membranes, leading to suppression of DNA replication and nucleic acid synthesis, as well as a direct cytotoxic effect. Cells are sensitive to the drug in the S and G2 phases.

Pharmacokinetics

After intravenous administration, Doxorubicin demonstrates multiphasic distribution: within the first five minutes, rapid uptake of doxorubicin by tissues occurs, and its plasma concentrations decrease.

The long half-life is due to the second phase, the phase of slow elimination from tissues. It concentrates in the liver, kidneys, myocardium, spleen, and lungs. It does not cross the blood-brain barrier. It penetrates the placenta and is excreted in breast milk. Plasma protein binding is about 75%. The volume of distribution ranges from 20 to 30 L/kg. Plasma clearance of the drug varies from 8 to 20 ml/min/kg.

It is metabolized in the liver to form the active metabolite doxorubicinol.

Enzymatic reduction of doxorubicin by oxidases, reductases, and dehydrogenases leads to the formation of free radicals, which may contribute to the manifestation of cardiotoxic effects. The terminal half-life of doxorubicinol is similar to that of doxorubicin and is 20-48 hours.

Clearance of doxorubicin occurs mainly through metabolism and biliary excretion.

Approximately 40% of the dose is excreted in the bile within 5 days. Only 5-12% of doxorubicin and its metabolites are found in the urine over the same period. Within 7 days, less than 3% of the dose is excreted in the urine as doxorubicinol.

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

Pharmacokinetics in special groups

Children

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

Elderly

No dose adjustment based on age is required.

Gender

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

Race

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

Hepatic impairment

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

Renal impairment

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

Indications

• Breast cancer;
• Lung cancer (small cell);
• Mesothelioma;
• Esophageal cancer;
• Stomach cancer;
• Primary hepatocellular carcinoma;
• Insulinoma;
• Carcinoid;
• Head and neck cancer;
• Thyroid cancer;
• Malignant thymoma;
• Ovarian cancer;
• Testicular germ cell tumors;
• Prostate cancer;
• Bladder cancer (treatment and prevention of recurrence after surgery);
• Endometrial cancer;
• Cervical cancer;
• Uterine sarcoma;
• Ewing’s sarcoma;
• Rhabdomyosarcoma;
• Neuroblastoma;
• Wilms’ tumor;
• Osteogenic sarcoma;
• Soft tissue sarcoma;
• Kaposi’s sarcoma;
• Acute lymphoblastic leukemia;
• Acute myeloblastic leukemia;
• Chronic lymphocytic leukemia;
• Hodgkin’s disease and non-Hodgkin’s lymphomas;
• Multiple myeloma.

ICD codes

Dosage Regimen

Intravenously, intravesically, or intra-arterially.

Doxolek can be used both as monotherapy and in combination with other antineoplastic drugs; therefore, when selecting doses and administration regimens, one should be guided by data from specialized literature.

Intravenous administration

• As monotherapy, the recommended dose is 60-75 mg/m² at three-week intervals. The drug is usually administered as a single dose per cycle; however, the cycle dose can be divided into several administrations (e.g., 25-30 mg/m²/day for the first three consecutive days every 4 weeks);
• To reduce the toxic effects of doxorubicin, especially cardiotoxicity, a weekly administration regimen of 10-20 mg/m² is used;
• When used in combination with other antineoplastic drugs, Doxorubicin is administered at a dose of 30-60 mg/m² every 3-4 weeks.

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

The total dose of Doxolek should not exceed 550 mg/m².

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

Hepatic impairment

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

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

Solution preparation and administration

Doxolek is diluted with 0.9% sodium chloride solution to a concentration not exceeding 1 mg/1 ml.

The drug is administered intravenously slowly (over 3-10 minutes) into the injection port of an intravenous infusion system, during rapid infusion of 5% dextrose solution or 0.9% sodium chloride solution. Before injection, it is necessary to ensure that the needle or catheter is correctly placed in the vein. Avoid administration into small veins and veins over joints; caution should be exercised and venipuncture and subsequent administration of doxorubicin should not be performed on limbs with impaired venous and lymphatic drainage.

Intravesical administration

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

The recommended dose for intravesical administration is 30-50 mg per instillation with intervals between administrations from 1 week to 1 month, depending on the goals of therapy – treatment or prevention.

The recommended concentration of the solution is 1 mg/1 ml of water for injections or 0.9% sodium chloride solution. In case of local toxicity development (chemical cystitis), the dose intended for repeated instillations should be dissolved in 30-100 ml of 0.9% sodium chloride solution. Instillation should be performed using a catheter, and the drug should remain in the bladder for 1-2 hours. After administration, to ensure uniform exposure of the drug to the bladder mucosa, patients should turn from side to side every fifteen minutes. To avoid excessive dilution of the drug by urine, patients should be warned to refrain from fluid intake for 12 hours before the procedure. At the end of the instillation, the patient should empty the bladder.

Intra-arterial administration

For patients with hepatocellular carcinoma, to provide intensive local exposure while reducing overall toxic effects, Doxorubicin can be administered intra-arterially into the main hepatic artery at a dose of 30-150 mg/m² at intervals from 3 weeks to 3 months. Higher doses should be used only in cases of simultaneous extracorporeal drug removal. Since this method is potentially dangerous and can lead to extensive tissue necrosis, intra-arterial administration should be performed only by physicians who are perfectly skilled in this technique.

Adverse Reactions

From the hematopoietic system leukopenia, neutropenia, anemia, thrombocytopenia. Leukopenia and neutropenia are dose-dependent and reversible. Leukopenia usually reaches its lowest point 10-14 days after drug administration, and blood count recovery is usually observed on day 21.

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

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

The manifestation of early (acute) cardiotoxicity of doxorubicin is primarily sinus tachycardia and/or ECG abnormalities (nonspecific ST-T segment changes). Tachyarrhythmias (including ventricular extrasystole and ventricular tachycardia), bradycardia, atrioventricular block, and bundle branch block may also occur. The occurrence of these phenomena is not always a prognostic factor for the subsequent development of delayed cardiotoxicity; they are rarely clinically significant and do not require discontinuation of doxorubicin therapy. Late (delayed) cardiotoxicity usually develops in the late stages of the therapy course or within 2-3 months after its cessation, but the development of more delayed side effects (after several months or even years after the end of therapy) is possible. Late cardiotoxicity is manifested by a decrease in left ventricular ejection fraction and/or symptoms of congestive heart failure (CHF), such as shortness of breath, pulmonary edema, peripheral edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy, gallop rhythm. Subacute phenomena (pericarditis/myocarditis) may also occur. The most severe form of anthracycline-induced cardiomyopathy, which limits the cumulative dose of the drug, is life-threatening congestive heart failure. When using doxorubicin, as with other cytotoxic agents, the development of thrombophlebitis and thromboembolism, including pulmonary embolism (in some cases with fatal outcome), has sometimes been observed.

From the digestive system anorexia, nausea, vomiting, mucositis/stomatitis, hyperpigmentation of the oral mucosa, esophagitis, abdominal pain, gastric erosions, gastrointestinal bleeding, diarrhea, colitis, dehydration; increased concentration of total bilirubin and activity of “hepatic” transaminases in the blood serum.

From the urinary system: red discoloration of urine for 1-2 days after doxorubicin administration, hyperuricemia.

From the organ of vision conjunctivitis/keratitis, lacrimation.

From the reproductive system amenorrhea (after the end of therapy, ovulation is restored, but premature menopause may occur), oligospermia, azoospermia (in some cases, the sperm count returns to normal; this may occur several years after the end of therapy).

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

Nervous system disorders:peripheral neurotoxicity in the form of regional, sensory and/or motor disorders was noted in patients with intravenous administration of doxorubicin, mainly in combination with cisplatin. Seizures and coma were noted in patients receiving Doxorubicin in combination with cisplatin and vincristine.

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

Local reactions: erythematous streaking along the vein (into which the infusion was performed), local phlebitis or thrombophlebitis. When the drug is administered into a small vein or when it is repeatedly administered into the same vein, the development of phlebosclerosis is possible. Leakage of the drug into the surrounding tissues ( extravasation) can lead to pain, severe damage to soft tissues (blistering, inflammation of the subcutaneous tissue) and necrosis.

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

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

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

Contraindications

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

Intravenous administration is contraindicated in:

• Severe myelosuppression;
• Previous therapy with other anthracyclines or anthracenediones at the maximum cumulative doses;
• Severe hepatic insufficiency;
• Severe heart failure and arrhythmias;
• Recent myocardial infarction;
• Acute viral infections (including chickenpox, herpes zoster);

Intravesical administration is contraindicated in:

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

With caution

Patients with risk factors for developing cardiotoxicity; patients who have previously received intensive chemotherapy, children, elderly patients, patients with obesity, patients with tumor infiltration of the bone marrow (may require reduction of starting doses or increase of intervals between doses); use as part of combined anticancer therapy, as well as in combination with radiation or other anticancer therapy; patients with impaired liver function.

Use in Pregnancy and Lactation

The use of the drug is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Intravenous administration is contraindicated in severe hepatic insufficiency. Use with caution in case of impaired liver function.

Pediatric Use

Use with caution in children.

Geriatric Use

Use with caution in the elderly.

Special Precautions

Doxolek should be used only under the supervision of a physician experienced in the use of anticancer drugs.

To reduce the risk of severe toxic heart damage, it is recommended to perform regular monitoring of cardiac functions before starting and during doxorubicin therapy, including assessment of left ventricular ejection fraction using echocardiography or multichannel radioisotope angiography, as well as ECG monitoring. Early clinical diagnosis of drug-induced heart failure is very important for its successful treatment. If signs of chronic cardiotoxicity are detected, doxorubicin treatment should be discontinued immediately.

Acute cardiotoxicity is in most cases transient (reversible), and is usually not considered an indication for discontinuation of doxorubicin therapy. Late (delayed) cardiotoxicity (cardiomyopathy) is dose-dependent. The probability of developing myocardial dysfunction is approximately 1-2% at a cumulative dose of 300 mg/m², then slowly increases at a total cumulative dose of 450-550 mg/m². With a further increase in the dose, the risk of developing congestive heart failure increases quite sharply, therefore, it is recommended not to exceed the total cumulative dose of 550 mg/m².

Monitoring of heart function should be especially strict in patients receiving high cumulative doses of the drug and in patients with risk factors for increased cardiotoxicity (for example, overt or latent cardiovascular disease, previous or concomitant radiotherapy to the mediastinum/pericardium, previous therapy with other anthracyclines or anthracenediones and concomitant therapy with drugs that reduce myocardial contractility). Cardiotoxicity can also develop at lower cumulative doses of doxorubicin, regardless of the presence of risk factors. In children and adolescents, the risk of developing late doxorubicin cardiotoxicity is increased. In women, this risk may be higher than in men.

The toxicity of doxorubicin and other anthracyclines or anthracenediones is likely to be additive.
Like other cytotoxic agents, Doxorubicin can cause myelosuppression. A complete blood count, including a leukocyte count and platelet count, should be performed before and during each cycle of doxorubicin therapy.

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

Mucositis/stomatitis usually develops shortly after drug administration and in severe cases can lead to ulceration of the mucous membrane within a few days. In most cases, these adverse events resolve by the third week of therapy.

Before starting and during therapy with the drug, patients should monitor liver function parameters (serum total bilirubin level). In patients with elevated bilirubin levels, a slowdown in drug clearance and an increase in overall toxicity are possible.

At the first signs of doxorubicin extravasation (burning or pain at the injection site), the infusion should be stopped immediately and then resumed in another vein until the full dose is administered; local measures should be taken to eliminate the consequences of extravasation. The use of ice packs is advisable.

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

When using doxorubicin, hyperuricemia may be observed due to rapid lysis of tumor cells, in connection with which, patients are recommended to determine the level of uric acid, potassium/calcium and creatinine in the blood during therapy. Measures such as hydration, alkalinization and prophylaxis with allopurinol to prevent hyperuricemia can minimize the risk of complications associated with tumor lysis syndrome.

In men, Doxorubicin has a mutagenic effect and can cause damage to sperm chromosomes.

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

When working with the drug, the rules for handling cytotoxic substances must be observed. Unused drug residues and all tools and materials that were used in the preparation of infusion solutions and administration of the drug, including gloves, must be destroyed in accordance with the approved procedure for the disposal of cytotoxic waste. Surfaces contaminated with the drug are recommended to be treated with a diluted sodium hypochlorite solution (containing 1% chlorine). In case of contact: if the drug gets on the skin – immediately wash the skin abundantly with water and soap or a sodium bicarbonate solution; if it gets into the eyes – pull back the eyelids and rinse the eye(s) with plenty of water for at least 15 minutes.

Overdose

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

There is no known antidote for doxorubicin. In case of overdose, symptomatic therapy accompanied by hospitalization and the prescription of antibacterial drugs is recommended.

Drug Interactions

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

When doxorubicin is used in combination with other potentially cardiotoxic chemotherapeutic agents, as well as cardiovascular drugs (for example, calcium channel blockers), myocardial function should be monitored.

Against the background of doxorubicin therapy, an increase in the phenomena of hemorrhagic cystitis caused by cyclophosphamide and an increase in the hepatotoxicity of mercaptopurine is possible.

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

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

Streptozocin increases the half-life of doxorubicin.

Administration of paclitaxel prior to doxorubicin may lead to an increase in plasma concentrations of doxorubicin and/or its metabolites in plasma. This effect is minimal when Doxorubicin is administered before paclitaxel.

Doxolek should not be mixed with other drugs. Contact with alkaline solutions should be avoided as this may lead to hydrolysis of doxorubicin.

Pharmaceutically incompatible with heparin, dexamethasone, hydrocortisone, sodium succinate, aminophylline, cephalothin, fluorouracil and other anticancer drugs.

When taken concomitantly with live viral vaccines, intensification of the vaccine virus replication process, increased side/adverse effects and/or decreased antibody production in the patient’s body in response to vaccine administration may occur.

Storage Conditions

In a place protected from light, at a temperature from 2°C (35.6°F) to 8°C (46.4°F). Keep out of reach of children. Do not freeze.

Shelf Life

Shelf life – 1.5 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.