Pharmacological properties
Pharmacodynamics. Animal experiments and clinical studies have proven the antineoplastic activity of doxorubicin, but the mechanism of its action (as well as that of other anthracyclines) has not been definitively elucidated. Three main biochemical mechanisms of action of doxorubicin have been proposed. These are DNA intercalation, membrane binding, and metabolic activation by reduction.
One of the main reasons for the ineffectiveness of treatment with doxorubicin and other anthracyclines is the development of resistance. To overcome the resistance of tumor cells to doxorubicin, calcium ion antagonists (e.g. verapamil) are used. Verapamil blocks slow membrane calcium channels and enhances cellular uptake of doxorubicin. Verapamil has been shown to potentiate the cytotoxic effect of doxorubicin in vitro in three pancreatic cancer cell lines. It should be noted that severe toxic effects are observed when doxorubicin and verapamil are used in combination. Doxorubicinol, the main metabolite of doxorubicin, does not affect the intracellular accumulation and retention of doxorubicin.
Pharmacokinetics. After intravenous administration of the drug, rapid clearance of doxorubicin from blood plasma (half-life - 10 min) and significant binding to tissues are observed. The duration of the half-life in the terminal phase is approximately 30 hours. Doxorubicin is metabolized to form doxorubicinol and doxorubicin aglycone, and then conjugated to form glucuronide and sulfate. Doxorubicin is excreted mainly with bile and feces. Approximately 10% of the dose is excreted by the kidneys. The binding of doxorubicin to plasma proteins is 50-85%, the volume of distribution is 800-3500 l / m 2.
Doxorubicin is not absorbed orally. It does not cross the blood-brain barrier. In cases of impaired liver function, the clearance of doxorubicin and its metabolites may be reduced.
Indication
Soft tissue sarcoma, osteogenic sarcoma, Hodgkin's disease and non-Hodgkin's lymphomas, acute lymphoblastic leukemia, acute myeloblastic leukemia, thyroid cancer, breast cancer, ovarian cancer, bladder cancer, small cell lung cancer, neuroblastoma.
Doxorubicin is also used to treat multiple myeloma, endometrial cancer, cervical cancer, Wilms' tumor, head and neck tumors, stomach cancer, pancreatic cancer, prostate cancer, testicular cancer, and liver cancer.
Doxorubicin can be used intravesically to treat superficial bladder cancer.
Application
Doxorubicin can be administered by intravenous injection over 2-5 minutes or by continuous infusion after dilution with 0.9% sodium chloride solution, 5% glucose solution, or a mixture of 0.9% sodium chloride solution and 5% glucose solution. When the drug is administered by injection, higher plasma concentrations of doxorubicin are observed, which may increase the risk of cardiotoxicity.
When administering doxorubicin, perivenous extravasation should be prevented, which may cause local tissue necrosis and thrombophlebitis.
Doxorubicin should not be administered intrathecally, intramuscularly, or subcutaneously.
Doxorubicin should not be mixed with other drugs.
Adult doses. Doses of doxorubicin are determined individually, taking into account the type of tumor, functional state of the liver and concomitant chemotherapy.
In the case of monotherapy, the recommended dose of doxorubicin is 60-75 mg/m2 of body surface area when administered by intravenous injection once every 3 weeks. Doxorubicin can also be administered intravenously at a dose of 20 mg/m2 for 3 consecutive days with a repeat course after 3 weeks.
The maximum permissible cumulative dose for monotherapy is 550 mg/m2 of body surface area.
Studies have shown that with weekly administration of the drug, the effectiveness of therapy is the same as with the administration of doxorubicin every 3 weeks, but cardiotoxic effects are observed less often. The recommended dose for this treatment regimen is 20 mg / m 2 weekly, although an objective effect is already observed when used in doses of 6-12 mg / m 2 of body surface.
When using doxorubicin in combination with other cytotoxic drugs with a similar toxicity profile, the dose should be reduced.
After radiotherapy to the mediastinum, treatment with other cardiotoxic non-anthracycline anticancer drugs, and if the patient has heart disease, it is not recommended to exceed the maximum cumulative dose of 450 mg/m2 of body surface area.
Dose adjustments in the treatment of specific groups of patients. In the treatment of patients with impaired liver function, the dose of doxorubicin should be reduced. When the serum bilirubin level increases to 12-30 mg, the dose is halved, and when the bilirubin level is 30 mg, the dose is 4 times reduced.
Use in patients at increased cardiac risk. In cases of increased risk of cardiotoxic effects, doxorubicin should be administered by 24-hour continuous infusions rather than injections. With this method of administration, cardiotoxic effects are less common and treatment efficacy is not reduced. In such patients, the ejection fraction should be measured before each course of treatment. The risk of cardiomyopathy gradually increases with increasing total dose of the drug. The cumulative dose of 550 mg/m2 should not be exceeded. Regular monitoring of ECG, echocardiography and carotid pulse characteristics is required during doxorubicin treatment. If the amplitude of the QRS complex decreases by 30% or the shortening fraction decreases by 5%, treatment is recommended to be discontinued. In the presence of heart disease or in the case of previous radiotherapy to the heart, the cumulative dose of doxorubicin should be avoided exceeding 400 mg/m2 of body surface area.
When doxorubicin is used in combination with other anticancer drugs, the dose of doxorubicin is reduced to 50-75 mg/m2 of body surface area. In the case of combination chemotherapy, myelosuppression may be more severe due to an additive effect.
Use in children. Doses for children may be reduced, since cardiotoxicity (especially some time after the end of treatment) is observed more often in children. For the same reason, regular cardiac examinations of children are recommended after the end of the course of therapy.
In children, as in adult patients, bone marrow suppression is also observed. The number of formed blood elements decreases to a minimum 10-14 days after the start of treatment, but after this, hematological parameters usually return to normal quickly due to the greater bone marrow reserves in children compared with its reserve capabilities in adults.
Superficial bladder cancer and carcinoma in situ. The recommended dose of doxorubicin for intravesical administration is 50 mg in 50 ml of saline. The drug is administered through a sterile catheter initially weekly and then monthly. The optimal duration of treatment has not yet been determined, it may be in the range of 6-12 months.
There are no restrictions on the maximum cumulative dose for intravesical administration (as opposed to intravenous administration), since in this case the systemic absorption of doxorubicin is very small.
Instructions for medical personnel. Only one-time withdrawal of the drug from the vials is allowed. When manipulating the drug, the rules for working with cytostatics should be followed. Given the toxicity of the drug, the following safety measures are recommended: personnel should be familiar with the rules for safe handling of the drug; pregnant women should not be allowed to work with the drug; manipulations with the drug should be performed in protective clothing - a gown, safety glasses, disposable gloves and masks; all items and materials that have come into contact with doxorubicin, including gloves, are placed in special high-strength bags for hazardous waste for subsequent destruction at high temperature (700 °C).
In case of accidental contact of doxorubicin solution with the skin or eyes, the affected area should be washed immediately with plenty of water, soap and water, or sodium bicarbonate solution.
In case of splashing or spillage of doxorubicin solution, the contaminated area should be treated (poured) with a dilute solution of sodium hypochlorite (1% based on chlorite), preferably for a long time (overnight), and then rinsed with water. All materials used during cleanup should be destroyed according to the procedure described above.
Contraindication
Severe myelosuppression (e.g. due to previous chemotherapy).
Acute heart failure (current or history).
Previous treatment with doxorubicin or daunorubicin with the administration of the drug in the maximum permissible cumulative dose.
Ulcerative stomatitis (may be preceded by a burning sensation in the mouth); repeated courses of treatment are not recommended if such symptoms are present.
Pregnancy and breastfeeding.
Hypersensitivity to doxorubicin, related substances or other ingredients of the drug.
Doxorubicin should not be used intravesically for the treatment of bladder cancer in patients with urethral stenosis who cannot undergo catheterization.
Doxorubicin should also not be used intravesically in patients with invasive tumors penetrating the bladder wall, urinary tract infections, or cystitis.
Side effects
Dose-limiting factors in doxorubicin therapy are myelosuppression and cardiotoxicity.
Hematological toxicity: Maximum bone marrow suppression (manifested as transient leukopenia, anemia, and thrombocytopenia) occurs 10-14 days after doxorubicin administration.
Cardiotoxicity: Cardiotoxicity of doxorubicin may manifest as arrhythmias immediately after administration of the drug. ECG changes (including T wave flattening, ST segment depression) may be observed up to 2 weeks after administration of doxorubicin.
The risk of cardiomyopathy increases progressively with increasing total dose. The cumulative dose of doxorubicin should not exceed 550 mg/m2 of body surface area. Irreversible congestive heart failure may develop even with a cumulative dose of 240 mg/m2. Signs of congestive cardiomyopathy may include shortness of breath and swelling of the feet and lower legs.
Age over 70 years or under 15 years should be considered as a risk factor. The likelihood of developing cardiomyopathy is also increased by previous or concurrent treatment with mitomycin C, cyclophosphamide or dacarbazine.
Cardiotoxic effects may occur several weeks or even months after discontinuation of doxorubicin therapy.
Gastrointestinal toxicity. Nausea, vomiting, and mucosal inflammation (stomatitis and proctitis) may occur 5-10 days after administration of doxorubicin. Gastrointestinal involvement may lead to ulceration, bleeding, and perforation. The first signs of mucosal inflammation are usually a burning sensation in the mouth and throat 5-10 days after administration of doxorubicin. Ulceration and secondary infection may occur later. Inflammation of the vaginal, rectal, and esophageal mucosa may also occur.
Dermatological toxicity. Reversible alopecia develops in most patients. Hyperpigmentation of nail beds and skin folds, onycholysis are possible. Doxorubicin, when extravasated, causes severe tissue irritation, with pain, inflammation, thrombophlebitis and even ulceration and tissue necrosis possible at the injection site.
There have been isolated reports of hypersensitivity reactions (manifested as rash, itching, urticaria, angioedema, fever and anaphylaxis).
Doxorubicin potentiates the response of normal tissues to radiation. If doxorubicin is used some time after the end of radiotherapy, late reactions (relapse of symptoms of radiation damage) are also possible.
Other effects: Conjunctivitis, lacrimation are possible.
Doxorubicin may potentiate toxic effects caused by radiotherapy or the use of other antineoplastic drugs (streptozocin, methotrexate, cyclophosphamide).
If administered too quickly, flushing of the face may occur.
There are reports of the development of thrombophlebitis during doxorubicin therapy.
Cases of slight transient increases in serum liver enzymes have been reported. If doxorubicin therapy is accompanied by radiotherapy to the liver, severe hepatotoxic effects are possible, which may lead to cirrhosis of the liver.
With intravesical use of doxorubicin, side effects such as hematuria, bladder and urethral irritation, stranguria, and pollakiuria are possible. They are usually mild and short-lived.
Intravesical administration of doxorubicin can sometimes cause the development of hemorrhagic cystitis, which can lead to a decrease in bladder capacity.
Special instructions
Doxorubicin treatment should be carried out under the supervision of a physician experienced in the use of chemotherapeutic agents. Treatment with cytotoxic drugs, especially in combination, suppresses the function of the immune system and increases the risk of developing secondary neoplastic diseases (such as secondary acute leukemia with or without a preleukemic phase).
It is recommended that at least the first phase of doxorubicin treatment be carried out in a hospital setting, as patients should be under medical supervision. Liver function tests and basic haematological parameters should be monitored before and during treatment with doxorubicin.
Nausea, vomiting and inflammation of the mucous membranes are often very severe and require appropriate treatment. Doxorubicin should not be administered IM or SC.
Cardiotoxicity. Doxorubicin is a cardiotoxic compound. Tachycardia and ECG changes may occur. Heart failure may develop suddenly without prior ECG signs either during treatment with doxorubicin or several weeks after the end of therapy. It may be refractory to therapy. The risk of cardiomyopathy gradually increases with increasing doses. The cumulative dose of doxorubicin that a patient receives during his lifetime should not exceed 450-550 mg/m2 of body surface area. Exceeding this dose significantly increases the risk of irreversible congestive heart failure. When determining the permissible cumulative dose of doxorubicin, previous or concomitant treatment with other cytotoxic drugs (high-dose cyclophosphamide, other anthracyclines) and radiotherapy to the mediastinum should be taken into account.
Age over 70 years or under 15 years, as well as concomitant cardiac pathology, should be considered as risk factors when determining the appropriateness of doxorubicin therapy.
During treatment with doxorubicin, ECG may show a decrease in the amplitude of the QRS complex, a prolongation of the systolic interval, and a decrease in the ejection fraction.
In patients previously treated with other anthracyclines or cyclophosphamide, mitomycin C or dacarbazine, and also receiving radiotherapy to the mediastinum, cardiotoxic effects may occur when using the drug in doses lower than the recommended maximum cumulative.
There have been reports of acute severe arrhythmias occurring during or within a few hours after doxorubicin administration.
Particular caution is required when treating patients with doxorubicin with cardiac disease (recent myocardial infarction, heart failure, cardiomyopathy, pericarditis or arrhythmia), as well as patients who have been treated with other cardiotoxic drugs, such as cyclophosphamide.
Cardiac function should be monitored (by ECG, echocardiography and measurement of ejection fraction) before, during and after administration of doxorubicin.
Myelosuppression. Since bone marrow suppression is often observed during doxorubicin therapy, regular monitoring of hematological parameters is necessary. Most often, patients develop neutropenia, less often thrombocytopenia and anemia. The number of formed blood elements reaches a minimum 10-14 days after the administration of doxorubicin. Hematological parameters usually return to normal 21 days after the administration of the drug. Doxorubicin therapy should not be started or continued if the number of polynuclear granulocytes is less than 2000 cells / mm 3. In the treatment of acute leukemia, this limit may be lower, taking into account the circumstances.
Severe myelosuppression may result in bleeding or superinfection, requiring dose reduction or discontinuation of doxorubicin therapy.
Since doxorubicin acts as an immunosuppressant, measures should be taken to prevent secondary infections during treatment with the drug.
Hyperuricemia. As with other antineoplastic agents, tumor lysis during doxorubicin therapy may cause hyperuricemia with the development of acute gout or urate nephropathy.
Hepatic impairment Since doxorubicin is excreted mainly in the bile, in cases of impaired liver function or hepatic insufficiency, the elimination of doxorubicin may be delayed and toxic effects may be increased. Therefore, it is recommended to perform liver function tests (to determine the levels of ALT and AST, LF and bilirubin) before and during therapy.
Blood uric acid levels should be monitored. Patients should drink sufficient fluids (at least 3 l/m2 of body surface area daily). Xanthine oxidase inhibitors (allopurinol) may be used if necessary.
Both men and women should use effective contraceptive measures during and for at least 3 months after completing doxorubicin therapy.
Discoloration of urine: Patients should be advised that doxorubicin may discolor the urine red, especially shortly after administration. This phenomenon is of no clinical significance.
Intravesical administration. Doxorubicin should not be administered intravesically in the presence of invasive tumors that have grown through the bladder wall, as well as in the presence of urinary tract infections and cystitis.
Pregnancy and lactation. Animal reproductive toxicity studies have shown that doxorubicin is teratogenic and embryotoxic. It is excreted in breast milk. Doxorubicin should not be used during pregnancy and lactation.
Effects on ability to drive and use machines: Depending on individual sensitivity, doxorubicin may adversely affect the ability to drive and use machines.
Interactions
Caution is required when using doxorubicin after or simultaneously with other cardiotoxic or antitumor (especially myelotoxic) drugs.
Maximum tissue concentrations of doxorubicin, the duration of the terminal half-life and the volume of distribution may be increased by concomitant use of verapamil.
Since doxorubicin is rapidly metabolized in the liver and excreted primarily in the bile, concomitant use of hepatotoxic chemotherapeutic agents (e.g. methotrexate) may potentially increase the toxicity of doxorubicin due to decreased hepatic clearance of the drug.
When high-dose cyclophosphamide is used in combination with doxorubicin, serum concentrations of both compounds are increased. This may lead to excessive myelosuppression and immunosuppression and increased side effects.
Inhibitors of P450 enzymes (e.g. cimetidine and ranitidine) may slow down the metabolism of doxorubicin, leading to increased toxic effects. Inducers of cytochrome P450 enzymes may accelerate the metabolism of doxorubicin, reducing the effectiveness of therapy.
Doxorubicin potentiates the effects of radiation therapy and can, even some time after the end of the radiation course, cause severe symptoms in the irradiated area.
Do not allow the drug to come into contact with any alkaline solutions, as this causes hydrolysis of doxorubicin. Doxorubicin should not be mixed with heparin and fluorouracil, as a precipitate may form. Mixing doxorubicin with other drugs is not recommended.
Overdose
Overdose symptoms are the same as those seen with therapeutic use of doxorubicin, but their intensity is higher. A single dose of doxorubicin of 250-500 mg is fatal. Acute myocardial degeneration may develop within 24 hours after overdose. Severe myelosuppression is possible with a decrease in the number of formed blood elements to a minimum 10-15 days after administration of doxorubicin. Heart failure may develop within 6 months after overdose. In case of overdose, symptomatic and supportive therapy should be carried out. Cardiac glycosides and diuretics should be prescribed as early as possible. Since severe myelo- and immunosuppression may cause bleeding and infections, appropriate preventive measures should be taken. Blood transfusion and isolation of patients in sterile hospital boxes may be required.
Hemodialysis is ineffective in case of doxorubicin overdose.
Storage conditions
At 2-8 °C in the original packaging (to protect from light). The solution should be withdrawn from the vials immediately before use. From a microbiological point of view, the diluted solution should be used immediately. If the solution for infusion is not used immediately, the storage time and conditions should be monitored by the responsible person. The storage period of the solution should normally not exceed 24 hours at 2-8 °C. Tests have shown that there is no significant change in the diluted doxorubicin solution after storage for 24 hours at 2-8 °C in a place protected from light or not.
