Doxorubicin, lyophilizate 50 mg

Antitumor agent from the group of anthracycline antibiotics. The mechanism of action is DNA binding and inhibition of nucleic acid synthesis.

Pharmacokinetics

Vd is 20-30 l/kg. It does not penetrate through the barrier. Biotransformation occurs in the liver with the formation of an active metabolite. T1/2 for doxorubicin and doxyrubicinol varies from 20 to 48 hours. It is excreted in the bile unchanged (about 40% within 5 days) and by the kidneys unchanged and as metabolites (about 5-12% within 5 days).

Clinical Pharmacology

Antitumor antibiotic.

Indications

Active ingredient

Composition

How to take, the dosage

DOXORUBICIN can be used both as monotherapy and in combination with other antitumor drugs, therefore when choosing the dose and mode of drug administration the data of specialized literature should be used.

Intravenous administration

– as monotherapy the recommended dose is 60-75 mg/m2 at 3-week intervals. The drug is usually administered once during a cycle; however, the cycle dose may be divided into several injections (e.g., administered 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 regimen of 10-20 mg/m2 is used;

When used in combination with other antitumor drugs, doxorubicin is administered at a dose of 30-60 mg/m2 every 3-4 weeks.

Repeated administration of the drug is possible only when all signs of toxicity (especially gastrointestinal and hematologic) have disappeared.

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

Patients who have previously received radiotherapy to the mediastinal/pericardial area or who have taken other cardiotoxic drugs should be given under close monitoring of cardiac function if the total dose of doxorubicin is to exceed 450 mg/m2.

Liver function impairment:

If serum bilirubin levels are 1.2-3 mg/dL, the administered dose of the drug should be reduced by 50% of the recommended dose;

If serum bilirubin levels are greater than 3 mg/dL, then the administered dose must be reduced by 75% of the recommended dose.

Other special patient groups:

Lower doses or longer intervals between cycles are recommended in patients who have previously received intensive chemotherapy, children, elderly patients, obese patients (if body weight is more than 130% of ideal, decreased systemic clearance of doxorubicin is noted), and patients with bone marrow tumor infiltration.

Preparation of solution and administration Doxorubicin is diluted with 0.9% sodium chloride solution to a concentration of not more than 1 mg/1 ml. The drug is administered intravenously slowly (within 3-10 minutes) into the injection port of the IV system, during rapid infusion of 5% dextrose solution or 0.9% sodium chloride solution.

Before injecting, make sure that the needle or catheter is positioned exactly in the vein. Small veins and veins above joints should be avoided; caution should be exercised not to perform venipuncture and subsequent injection of doxorubicin on (edematous areas where venous and lymphatic outflow is impaired.

Injection into the bladder

Injection into the bladder is used to treat superficial bladder tumors as well as to prevent recurrence after transurethral resection. Injection into the bladder 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 injections of 1 week to 1 month, depending on the goals of therapy – treatment or prevention. Recommended solution concentration is 1 mg/1 ml of water for injection or 0.9% sodium chloride solution. In case of development of local toxicity (chemical cystitis) the dose intended for repeated instillations should be dissolved in 50 to 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 injection, patients should be turned from side to side every fifteen minutes to ensure even exposure of the drug to the bladder mucosa.

In order to avoid excessive dilution of the drug with urine, patients should be warned to refrain from taking liquids for 12 hours prior to the procedure. At the end of the instillation, the patient should empty the bladder.

Intra-arterial administration

In patients with hepatocellular cancer, doxorubicin may be administered intra-arterially into the main hepatic artery at a dose of 30-150 mg/m2 at intervals of 3 weeks to 3 months to provide intense local effects while reducing overall toxic effects. Higher doses should be used only in cases of concomitant extracorporeal excretion of the drug.

Because this method is potentially dangerous and may lead to widespread tissue necrosis, intra-arterial injection should only be given by physicians who are proficient in this technique.

Interaction

In combination with other cytotoxic agents, doxorubicin may exhibit additive toxicity, especially to the bone marrow/hematopoietic system and the gastrointestinal tract.

When using doxorubicin in combination with other potentially cardiotoxic chemotherapeutic agents as well as cardiovascular drugs (e.g., calcium channel blockers), myocardial function should be monitored.

The treatment with doxorubicin may aggravate hemorrhagic cystitis caused by cyclophosphamide and increase hepatotoxicity of mercaptopurine.

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

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

Streptozocin increases the half-life of doxorubicin.

The administration of paclitaxel prior to doxorubicin may result in increased plasma concentrations of doxorubicin and/or its metabolites. This effect is minimal when doxorubicin is administered before paclitaxel.

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

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

The concomitant administration of live viral vaccines may intensify the replication process of the vaccine virus, increase its side/adverse effects and/or decrease the production of antibodies in the patient’s body in response to the administration of the vaccine.

Special Instructions

Doxorubicin should only be used under the supervision of a physician experienced in the use of antitumor drugs.

To reduce the risk of severe toxic cardiac damage, regular monitoring of cardiac function, including evaluation of left ventricular ejection fraction by echocardiography or multichannel radioisotope angiography and ECG monitoring, is recommended before and during doxorubicin therapy.

The early clinical diagnosis of drug-induced heart failure is very important for successful treatment. If signs of chronic cardiotoxicity are detected, treatment with doxorubicin should be discontinued immediately.

Acute cardiotoxicity is transient (reversible) in most cases and is not usually considered an indication for discontinuing doxorubicin therapy. Late (delayed) cardiotoxicity (cardiomyopathy) depends on the total dose.

The likelihood of developing myocardial dysfunction is approximately 1-2% at a total dose of 300 mg/m2; it then increases slowly at a total cumulative dose of 450-550 mg/m2. With further dose increases, the risk of congestive heart failure increases quite dramatically, so it is recommended that the total cumulative dose of 550 mg/m2 not be exceeded.

. Monitoring of cardiac function should be particularly strict in patients receiving high cumulative doses of the drug and in patients with risk factors for increased cardiotoxicity (e.g., overt or occult cardiovascular disease, prior or concomitant radiation therapy to the mediastinum/pericardium, prior therapy with other anthracyclines or anthracenedion, and concomitant therapy with drugs that reduce cardiac contractility).

Cardiotoxicity may also develop with lower cumulative doses of doxorubicin regardless of the presence of risk factors. Children and adolescents have a higher risk of developing late cardiotoxicity with doxorubicin. This risk may be higher in women than in men.

The toxicity of doxorubicin and other anthracyclines or anthracenediols is probably additive.

Like other cytotoxic agents, doxorubicin can cause myelosuppression. General blood counts, including leukocyte counts and platelet counts, should be performed before and during each cycle of doxorubicin therapy.

In patients treated with anthracyclines, including doxorubicin, cases of secondary leukemia with or without preleukemic phase have been described. Secondary leukemia is more common when these drugs are used in combination with other antitumor agents that cause DNA damage, radiation therapy, and in patients who previously received intensive cytotoxic therapy or high-dose anthracyclines. Secondary leukemia may have a latency period of 1-3 years.

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

Before and during therapy with the drug, patients’ liver function parameters (level of total bilirubin in blood serum) should be monitored. In patients with elevated bilirubin level the drug clearance slowdown and increase of general toxicity are possible.

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

In intravesical administration of the drug, special attention should be paid to conditions that create obstacles to catheterization (e.g., urethral obstruction due to massive bladder tumors).

Hyperuricemia may occur with doxorubicin due to rapid lysis of tumor cells; therefore, patients should have their uric acid, potassium, calcium and creatinine levels determined during therapy. Interventions 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 mutagenic effects and can cause damage to sperm chromosomes. Men and women of childbearing age should use reliable contraception during treatment with doxorubicin and for at least 3 months after.

The rules for handling cytotoxic substances must be followed when handling the drug.

Unused remnants of the drug and all instruments and materials used in preparing solutions for infusion and administration of the drug, including gloves, must be disposed of according to the approved procedure for disposal of cytotoxic waste.

The surface contaminated with the drug is recommended to be treated with diluted solution of sodium hypochlorite (containing 1% chlorine). If the drug comes into contact with skin – immediately rinse the skin with soap and water or sodium bicarbonate solution; if it got into the eyes – pull back the eyelids and rinse the eye (eyes) with plenty of water for at least 15 minutes.

Contraindications

Developed leukopenia, anemia, thrombocytopenia; severe diseases of the cardiovascular system; acute hepatitis. Doxorubicin is not used in patients who have received the full cumulative dose of daunorubicin, idarubicin and/or other anthracyclines and anthracenes.

With caution, use in patients with heart disease (including a history of heart disease), varicella (including recent or after exposure to the disease), herpes zoster, other acute infectious diseases, gout or nephrolithiasis (including a history).

In patients who have had mediastinal radiotherapy or are concomitantly receiving cyclophosphamide.

Side effects

Overdose

Pregnancy use

Doxorubicin is contraindicated in pregnancy. Breastfeeding should be stopped if it is necessary to use it during lactation.

Women of childbearing age should use reliable contraception when using doxorubicin.

The teratogenic and embryotoxic effects of doxorubicin have been established in experimental studies.