Doxorubicin-Ebwee - instructions for use, dose, side effects, contraindications

Description:Transparent solution of red color, free from foreign particles. When stored in the refrigerator, the preparation can acquire a gel-like consistency that disappears when the drug is kept at a temperature of 15-25 ° C for 2-4 hours.

Pharmacotherapeutic group:Antitumor agent, antibiotic.

ATX: & nbsp

L.01.D.B.01 Doxorubicin

Pharmacodynamics:

Doxorubation - antitumor antibiotic of anthracycline, isolated from culture Streptomyces peucetius var. caesius. Has anti-mitotic and antiproliferative effect. Three main mechanisms of the action of doxorubicin are described: interaction with DNA, inhibition of topoisomerase I, DNA and RNA polymerases, formation of free radicals and direct action on cell membranes, which leads to suppression of DNA replication and nucleic acid synthesis, and direct cytotoxic action.The cells are sensitive to the drug in the S- and G2-phases of mitosis.

Pharmacokinetics:

After intravenous administration doxorubicin demonstrates a multiphase distribution: during the first five minutes, doxorubicin is rapidly captured by tissues and its concentration in the blood plasma decreases (the half-distribution period is about 12 min); long half life (T_1/₂) is associated with a slow elimination of doxorubicin from tissues. It concentrates in the liver, kidneys, myocardium, spleen, lungs. Penetrates through the placental barrier; excreted in breast milk. The connection with plasma proteins is about 75%. The volume of distribution is 500-2900 l / m². Partially metabolized in the liver with the formation of an active metabolite of doxorubicinol, to a lesser extent with the formation of aglycon, binds to glucuronides and sulfates. Enzymatic reduction of doxorubicin under the influence of oxidases, reductases and dehydrogenases leads to the formation of free radicals, which can contribute to the manifestation of cardiotoxic action. T_1/₂ - 20-48 h for doxorubicin and doxorubicinol.

The clearance of the drug from the blood plasma varies from 8 to 20 ml / min / kg.The clearance of doxorubicin is mainly due to metabolism and excretion of bile.

Excretion: with bile - 40% unchanged for 7 days, kidneys - 5-12% doxorubicin and its metabolites for 5 days. The rest of doxorubicin appears to be associated with tissues for a long time. Systemic clearance of doxorubicin is significantly reduced in patients with obesity, whose body weight is more than 130% of the optimal.

Pharmacokinetics in special groups

Children: the clearance of doxorubicin in children over 2 years old exceeds that of adults, in children less than 2 years old it approaches the values of clearance in adults.

Elderly patients: dose adjustment with age is not required.

Gender: The average clearance of doxorubicin in men is significantly higher than that of women. However, T_1/₂ Doxorubicin in men is longer than in women (54 and 35 hours, respectively).

Race: the effect of race on the pharmacokinetics of doxorubicin has not been studied.

Violation of liver function: in patients with impaired liver function, the clearance of doxorubicin and doxorubicinol decreases.

Indications:

- mammary cancer;

- lung cancer (small cell), mesothelioma;

- cancer of the esophagus, stomach cancer, primary hepatocellular carcinoma, pancreatic cancer (insulinoma), carcinoid;

- malignant tumors of the head and neck, thyroid cancer, malignant thymoma;

- ovarian cancer, germ cell testicular tumors, prostate cancer, bladder cancer (treatment and prevention of relapse after surgery), endometrial cancer, cervical cancer;

- sarcoma of the uterus, soft tissue sarcoma, Ewing's sarcoma, osteogenic sarcoma, rhabdomyosarcoma, neuroblastoma, Wilms tumor, Kaposi's sarcoma;

- acute lymphoblastic leukemia, acute myeloblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease and non-Hodgkin's lymphomas, multiple myeloma.

Contraindications:

- increased sensitivity to doxorubicin or other components of the preparation, as well as other anthracyclines and anthracenedions;

- pregnancy and the period of breastfeeding;

- Intravenous administration is contraindicated when: pronounced

myelosuppression (number of leukocytes <2000 cells / mm³, the number of platelets <50,000 cells / mm³), hepatic failure of severe severity,severe cardiovascular pathology (unstable angina, progressive heart failure, severe rhythm and conduction disorders, acute inflammatory diseases of the heart, myocardial infarction in the last 6 months, cardiomyopathy), previous therapy with other anthracyclines and anthracenedions in the maximum total doses, acute viral infections including chickenpox, herpes zoster);

- the introduction into the bladder is contraindicated in: invasive tumors with germination into the wall of the bladder (above the TN1 grade T1), urinary tract infections, inflammatory diseases of the bladder, hematuria.

Carefully:

In patients who received previously intensive chemotherapy; with heart diseases, with risk factors for cardiotoxicity; with obesity; with tumor infiltration of the bone marrow; urate nephrolithiasis (including in the anamnesis); as part of combined antitumor therapy, as well as in combination with radiation therapy; children under 18 years old, elderly patients; with peptic ulcer of the stomach and duodenum (with intra-arterial administration of doxorubicin); gout (incl.in the anamnesis); when oppression of bone marrow hematopoiesis; if the liver function is mild and moderate; parasitic and infectious diseases of a viral, fungal or bacterial nature.

Pregnancy and lactation:Controlled studies of doxorubicin in pregnant women have not been conducted. Studies in animals have shown embryotoxic, teratogenic and mutagenic effects of doxorubicin. therefore doxorubicin contraindicated in pregnancy. Because the doxorubicin penetrates into breast milk, in order to avoid the toxic effect of the drug on the baby during the period of treatment, it is necessary to stop breastfeeding.

Dosing and Administration:

Intravenous, intravesical or intra-arterial.

Doxorubicin can be used as a monotherapy or in combination with other cytostatics in different doses depending on the therapy scheme. For individual dose selection, reference should be made to the literature.

Intravenous administration:

The doxorubicin concentrate is diluted with 0.9% sodium chloride solution or 5% dextrose solution.To reduce the risk of developing thrombosis and extravasation, it is recommended that doxorubicin through the tube of the system for intravenous administration, during the infusion of 0.9% sodium chloride solution or 5% dextrose solution for 3-5 minutes. Duration of infusion should be at least 3 and not more than 20 minutes. Direct injection into the vein is not recommended because of the danger of extravasation.

- as a monotherapy the recommended dose per cycle is 60-75 mg / m²: every three weeks. Usually the drug is administered once during the cycle; however, the cyclic dose can be divided into several introductions (for example, administered during the first sin of consecutive days or on the first and eighth day of the cycle). The cycles are repeated every 3-4 weeks;

- to reduce the toxic effect of doxorubicin, especially on the heart, a weekly regimen of 10-20 mg /m²;

- in combination with other antineoplastic agents doxorubicin is administered at a cyclic dose of 30-60 mg /m²every 3-4 weeks.

Suppression of bone marrow function

In severe myelosuppression, dose reduction is recommended as follows:

Leukocytes, in 1 μl	Platelets, in 1 μl	Doxorubicin,%
more than 5000	more than 150,000	100
4000 - 5000	100000 - 150000	75
3000 -4000	75000 - 100000	50
2000 - 3000	50000 - 75000	25
less than 2000	less than 50000	0

Impaired liver function

In patients with hyperbilirubinemia, the doxorubicin dose should be reduced in accordance with the concentration of total serum bilirubin:

- a 50% reduction in the recommended dose at a serum bilirubin concentration of 1.2-3.0 mg / dL;

- a 75% reduction in the recommended dose at a serum bilirubin concentration above 3.0 mg / dl.

Other special patient groups

It is recommended to use lower doses or increase the intervals between cycles in patients who previously received massive antitumor therapy in children, elderly patients, obese patients (if body weight is more than 130% of the "ideal", there is a decrease in systemic clearance of doxorubicin), as well as in patients with bone marrow tumor infiltration.

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

In patients who received previous radiation therapy in the lung and mediastinal region or who were treated with other cardiotoxic drugs, the total dose of doxorubicin should not be> 400 mg /m².

Intravesical administration:

Introduction to the bladder is used to treat superficial bladder tumors, as well as prevent relapse after transurethral resection. Introduction to the bladder is not used to treat invasive tumors with germination into the muscular wall of the bladder.

The recommended dose for intravesical administration is 30-50 mg for instillation (drip administration), with intervals between administrations from 1 week to 1 month, depending on the purpose of therapy - treatment or prevention. The recommended concentration of the solution is 1 mg / ml water for injection or 0.9% sodium chloride solution. After the instillation is completed, to ensure a uniform effect of the drug on the bladder mucosa, patients should flip from side to side every 15 minutes. Typically, the drug should be in the bladder for 1-2 hours. At the end of instillation, the patient should empty the bladder.

To avoid excessive dilution of the drug with urine, patients should be warned that they should refrain from taking liquids for 12 hours before instillation.The systemic absorption of doxorubicin during instillation into the bladder is very low. When the manifestations of local toxic effects (chemical cystitis, which can manifest dysuria, polyuria, nicture, painful urination, hematuria, discomfort in the bladder, necrosis of the bladder wall), the dose to be instillated should be dissolved in 50-100 ml of 0.9 % solution of sodium chloride. Particular attention should be paid to problems associated with catheterization (for example, with obstruction of the urethra caused by massive intravesical tumors).

Intraarterial administration:

Patients with hepatocellular carcinoma to ensure intensive local effects while reducing the overall toxic effect doxorubicin can be injected intraarterially into the main hepatic artery at a dose of 30-150 mg / m²with an interval of 3 weeks to 3 months. Higher doses should be used only in those cases when the extracorporeal elimination of the drug is simultaneously carried out. Since this method is potentially dangerous,and when it is used, air embolism and / or arterial thrombosis can result, leading to widespread necrosis of the tissue, intraarterial administration can only be performed by physicians who are proficient in this technique.

Side effects:According to the World Health Organization (WHO), undesirable effects are classified according to their frequency of development as follows:

very often (> 1/10),

often (from> 1/100 to <1/10),

infrequently (from> 1/1000 to <1/100),

rarely (from> 1/10000 to <1/1000),

very rarely (<1/10000);

frequency unknown - According to available data to establish the frequency of occurrence was not possible.

Infectious and parasitic diseases

very often: infectious complications;

often: sepsis / septicemia; infrequently: septic shock.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

infrequently: acute lymphoblastic leukemia, acute myeloblastic leukemia (including secondary forms).

Violations of the blood and lymphatic system

very often: dose-dependent reversible myelosuppression (leukopenia,

neutropenia, thrombocytopenia, anemia), leukopenia usually reaches a minimum value 10-14 days after drug administration,restoration of the blood picture is usually observed on day 21, febrile neutropenia, tissue hypoxia or necrotic changes.

Immune system disorders

rarely: angioedema of the eyelids and tongue with impaired breathing;

very rarely: anaphylaxis;

frequency unknown: anaphylactic reactions.

Disorders from the metabolism and nutrition

very often: anorexia;

often: dehydration;

very rarely: hyperuricemia;

frequency is unknown: tumor disintegration syndrome.

Impaired vision is often: conjunctivitis;

frequency unknown: keratitis, lachrymation.

Heart Disease

often: early (acute) cardiotoxicity: nonspecific changes on the ECG (location of the ST segment above / below the isoline, sinus tachycardia, supraventricular and ventricular extrasystoles), tachyarrhythmia, including premature ventricular contraction and ventricular tachycardia, bradyarrhythmia; late (delayed) cardiotoxicity: cardiomyopathy, left ventricular failure with or without signs of congestive heart failure (such as dyspnea, pulmonary edema, peripheral edema, cardiomegaly, hepatomegaly, oliguria, ascites, exudative pleurisy, gallop rhythm, pericarditis, myocarditis);

rarely: atrioventricular block and blockade of the legs of the bundle.

Vascular disorders

very often: thrombophlebitis; often: phlebitis, bleeding;

infrequently: thromboembolic complications, including pulmonary embolism (in some cases with fatal outcome), shock; the frequency is unknown: the tides of blood to the face.

Disturbances from the respiratory system, chest and mediastinal organs

rarely: respiratory insufficiency, edema of the nasal mucosa, dyspnea,

tachypnea, exudative pleurisy, bronchospasm, radiation pneumonia.

Disorders from the gastrointestinal tract.

very often: nausea, vomiting, ulceration of the mucous membranes of the gastrointestinal tract (stomatitis, ulcerative colitis, usually 5-10 days after the initiation of treatment and may progress with repeated therapeutic cycles), diarrhea;

often: esophagitis, pain in the abdomen, heartburn;

infrequently: bleeding from the gastrointestinal tract, colitis, erosive gastritis, necrotic colitis;

very rarely: erosion and impaired pigmentation of the oral mucosa.

Disturbances from the liver and bile ducts

often: hepatotoxicity, transient increase in activity

"hepatic" transaminases, increasing the concentration of total bilirubin.

Disturbances from the skin and subcutaneous tissues

very often: onycholysis, erythema, photosensitivity, rash (enanthema, exanthema), reversible complete alopecia (hair growth resumption usually begins 2-3 months after discontinuation of drug administration); often: itching, hypersensitivity of the skin in the area of irradiation, hyperpigmentation of the skin and nails, urticaria;

very rarely: erythema;

frequency unknown: palmar-plantar erythrodysesthesia.

Disturbances from musculoskeletal and connective tissue

very rarely: generalized myasthenia gravis;

frequency unknown: arthralgia.

Disorders from the kidneys and urinary tract

rarely: nephropathy associated with increased uric acid formation;

frequency is unknown: staining the urine in red for 1-2 days after drug administration, acute renal failure.

Violations of the genitals and mammary gland

very rarely: amenorrhea (at the end of therapy, ovulation recovers, but premature menopause may occur), oligospermia,azoospermia (in a number of cases the number of spermatozoa is restored to a normal level, this can happen a few years after the end of therapy);

Laboratory and instrumental data

Often: asymptomatic reduction of the left ventricular ejection fraction, ECG change, weight gain (in women with early breast cancer receiving adjuvant therapy with doxorubicin).

General disorders and disorders at the site of administration

very often: fever, asthenia, chills;

often: pain or redness at the injection site;

infrequently: Erythematous striation along the vein, which

infusion, local phlebitis or thrombophlebitis, phlebosclerosis (if doxorubicin is reentered into a small vein). In the event of a drug getting into the surrounding tissue, soreness, inflammation of the subcutaneous tissue and tissue necrosis may occur;

rarely: drowsiness;

very rarely: general malaise, weakness.

With intra-arterial administration:

in addition to systemic toxicity, gastric and duodenal ulcers can be observed (probably due to reflux of drugs in the gastric artery); narrowing of the bile duct due to drug-induced sclerosing cholangitis; widespread necrosis of perfused tissue.

With intravesical injection:

cystitis, incl. hemorrhagic, dysuria, hematuria (blood in the urine), polyuria, pollakiuria (frequent urination), stranguria (painful urination), necrosis and spasms of the bladder.

The adverse events that arise during treatment are usually reversible upon cancellation of the drug.

Adverse reactions identified during post-marketing research

Benign, malignant and unspecified neoplasms (including cysts and polyps)

rarely: secondary neoplasms of the oral cavity.

Overdose:

Symptoms: severe myelosuppression (mainly leukopenia,

thrombocytopenia), toxic lesions of the gastrointestinal tract (nausea, vomiting, stomatitis, enteritis, diarrhea), acute heart damage (lowering blood pressure, palpitations, rhythm disturbance, pain in the heart, acute heart failure), coronary heart disease (CHD) ) (angina pectoris, myocardial infarction, heart failure).

Treatment: antidote is unknown. With the development of IHD, the drug should be discontinued. In case of overdose, symptomatic therapy is recommended (blood transfusion, antibacterial treatment).Hemodialysis is not effective.

Interaction:

Doxorubicin is used mainly in combination with other cytostatic agents. At the same time, their myelotoxicity may increase. Combination therapy with cytostatic agents (such as, daunorubicin, dactipomycin, cystplatin, fluorouracil, mitomycin, cyclophosphamide) potentiate the risk of developing congestive heart failure.

Simultaneous use of cardioactive drugs (for example, blockers of "slow" calcium channels) requires careful monitoring of cardiac activity throughout the treatment period.

Against the background of treatment with doxorubicin, it is possible to intensify the phenomena of hemorrhagic cystitis caused by cyclophosphamide. Necrotic colitis, sometimes accompanied by infections, can be noted with a combination of doxorubicin with cytarabine, cisplatin, cyclophosphamide.

Concomitant treatment with chemotherapeutic hepatotoxic drugs (for example, mercaptopurine, methotrexate, streptozocin) may increase toxicity of doxorubicin as a result of an increase in the half-life of the latter and a decrease in liver function.

If before applying doxorubicin, enter paclitaxel, in the serum can increase the concentration of doxorubicin and its metabolites. This effect is negligible if doxorubicin apply to paclitaxel. Joint use of these drugs increases the frequency of neutropenia and stomatitis.

The use of trastuzumab in combination with doxorubicin (and other anthracyclines) is associated with a high cardiotoxic risk. Therefore for today trastuzumab should not be used in combination with anthracyclines, except in reliably controlled clinical studies with monitoring of cardiac activity. The use of anthracyclines after the end of trastuzumab therapy may have an increased risk of cardiac toxicity. If possible, between the end of therapy with trastuzumab and the initiation of treatment with anthracyclines, a sufficient time interval (at least 27 weeks) should be maintained. In any case, it is necessary to carefully monitor the state of cardiac activity.

Doxorubicin is metabolized by cytochrome P450 (CYP3A4 and CYP2D6) and is a substrate for the P-glycoprotein carrier.

With simultaneous administration of cyclosporine (inhibitor of CYP3A4 and P-glycoprotein) and doxorubicin and there may be a decrease in the intensity of metabolism, a decrease in the clearance of both substances and, as a consequence, an increase in their level in the blood serum. If possible, dose adjustment should be performed with simultaneous use of doxorubicin and cyclosporine. Adding cyclosporine to doxorubicin can lead to an increase in the area under the concentration-time curve (AUC) for doxorubicin and doxorubicinol, possibly due to a decrease in the clearance of the starting material and a decrease in the intensity of doxorubicinol metabolism. The literature data indicate that when cyclosporine is added to doxorubicin, more severe and prolonged toxic changes are observed on the part of the blood picture than with doxorubicin alone. In addition, with the simultaneous use of cyclosporine and doxorubicin mentioned the occurrence of coma and seizures.

With the simultaneous use of doxorubicin and 400 mg sorafenib 2 times a day, there have been cases of augmentation of doxorubicin AUC by 21-47%, and cases without AUC changes.The clinical significance of these results is not known.

Inhibitors of the enzymes of the cytochrome P450 system (eg, cimetidine, ranitidine, verapamil) can reduce the metabolism of doxorubicin, thereby increasing the risk of developing its toxic effects. Cimetidine reduces plasma clearance of doxorubicin and promotes an increase in AUC.

Inductors of enzymes of the cytochrome P450 system (for example, rifampicin, barbiturates) can increase the rate of doxorubicin metabolism, thereby reducing its effectiveness.

Absorption of antiepileptic drugs (eg, carbamazepine, phenytoin, valproate) with simultaneous use of doxorubicin decreases.

Doxorubicin enhances the effect of radiation therapy. Doxorubicin is a radiosensitizer, and the anamnestic radiation phenomenon caused by it can be life-threatening. Any previous, simultaneous or subsequent radiotherapy can enhance the cardiotoxicity and hepatotoxicity of doxorubicin.

Progesterone enhances doxorubicin-induced neutropenia and thrombocytopenia.

In the interaction of doxorubicin and drugs that affect bone marrow function (such as, amidopyrine derivatives, antiretroviral drugs, chloramphenicol, phenytoin, sulfonamides), there may be a violation of hemopoiesis.

Clozapine may increase the risk of development and severity of hematologic complications with doxorubicin. Doxorubicin binds to heparin. As a consequence, precipitation and loss of efficacy of both active substances are possible. Doxorubicin can reduce the bioavailability of digoxin when administered orally. Therefore, during treatment with doxorubicin, the concentration of digoxin in the blood plasma must be checked regularly.

Treatment with doxorubicin sometimes leads to an increase in the level of uric acid in the blood, so a dose adjustment of uricosuric drugs is necessary, which increases the risk of developing nephropathy.

Combinations of doxorubicin with Amphotericin B should be avoided, as it can lead to severe nephrotoxicity.

With the simultaneous use of doxorubicin and ritonavir, an increase in the level of doxorubicin in serum was reported.

Pharmaceutically incompatible with dexamethasone, fluorouracil, hydrocortisone, sodium succinate, amyophylline, cephalothin. The introduction of live (or attenuated) vaccines to patients whose immunity is impaired by chemotherapy,including doxorubicin, may lead to the development of generalized potentially lethal infections. Therefore, patients receiving doxorubicin, vaccination of live vaccines should be avoided. During treatment with doxorubicin, patients should also avoid contact with people newly vaccinated with live polio vaccines. Vaccination is recommended after some time (from 3 months to 1 year) after the end of treatment.

Doxorubicin should not be mixed with other drugs. Do not allow contact with alkaline solutions, as this can lead to hydrolysis of the drug.

Special instructions:

- Treatment with Doxorubicin-Ebove should be performed under the supervision of physicians with experience in the use of antitumor drugs. Prior to and during therapy with doxorubicin, regular monitoring of cardiac function (ECG, Echo-CG, scintigraphy), liver and kidneys (biochemical blood test, control of glomerular filtration rate, urinalysis) and blood state (clinical blood test) are required to prevent complications of treatment .

- Before starting treatment with doxorubicin, the patient should be excluded from the presence of toxic effects fromprevious courses of chemotherapy (such as stomatitis, neutropenia, thrombocytopenia, generalized infections).

- Doxorubicin must be administered only intravenously, as the introduction into surrounding tissues leads to the development of local necrosis and thrombophlebitis. When working with doxorubicin, the rules for handling cytotoxic substances must be observed. It is recommended to treat the contaminated surface with a dilute solution of sodium hypochlorite (containing 1% chlorine). If the product gets on the skin, immediately flush the skin with soap and water or a solution of sodium bicarbonate; In case of contact with eyes, remove eyelids and rinse eyes (eyes) with plenty of water for 15 minutes.

- Cardiotoxicity. The risk of cardiotoxicity increases with preliminary or concomitant radiotherapy in the mediastinum area, the use of potentially cardiotoxic drugs, previous therapy with anthracyclines or anthracenedion, in patients with anemia or leukemic pericarditis / myocarditis, under the age of 15 years (more often late cardiotoxicity) and over 70 years of age .Women have a higher risk of cardiotoxicity than men. In the above-mentioned groups of patients, the benefit-risk of treatment should be carefully evaluated before the initiation of therapy with doxorubicin.

Cardiotoxicity can manifest itself in two forms:

Early (acute) cardiac toxicity is a dose-independent form, in most cases is reversible and is not considered an indication for the abolition of doxorubicin therapy.

Late (delayed) cardiotoxicity depends on the total dose and manifests as cardiomyopathy. It develops primarily during the course of therapy or within two months after its termination, however, delayed side effects may occur (several months or even years after the end of therapy). The probability of developing a violation of myocardial function is approximately 1-2% at a total dose of 300 mg /m²; The probability of this increases slowly at a total cumulative dose of 450-550 mg / m². If this dose is exceeded, the risk of developing congestive heart failure increases dramatically, and therefore treatment with doxorubicin is recommended to stop after reaching a total dose of 550 mg / m^2. If the patient has any additional risk of cardiotoxicity, then toxic effects may occur at lower cumulative doses, and cardiac function monitoring should be particularly careful, and the total cumulative dose for adults should not exceed 400 mg / m². Life-threatening congestive heart failure is the most severe form of cardiomyopathy caused by anthracyclines, and is the result of the toxic effect of the substance, which limits its cumulative dose.

While there are no reliable methods to predict the development of acute heart failure, anthracycline-induced cardiomyopathy is determined by a steady decrease in the amplitude of the QRS complex, an increase in systolic time intervals (PEP / LVET, PEP - pre-ejection period, LVET - left ventricular ejection fraction) and a decrease in LVET in comparison with baseline values before treatment. Timely clinical diagnosis of doxorubicin-induced myocardial damage is very important for the application of pharmacological treatment.It shows the treatment of cardiac glycosides, diuretics, as well as sodium restriction and bed rest.

- Myelosupressnia. During the treatment with doxorubicin, it is necessary to evaluate the parameters of the clinical blood test and liver function tests before and during each therapy cycle. Patients with advanced neutropenia / leukopenia should be carefully monitored to identify signs of superinfection.

- Doxorubicin causes a vomitive reflex. Mucositis or stomatitis usually occurs soon after the beginning of treatment and in severe cases for several days can lead to the formation of ulcers on the mucous membrane. In most patients, these side effects occur at the third week of treatment.

- In patients with an overweight (> 130% of ideal weight), the systemic clearance of doxorubicin decreases.

- If possible, vein over the joints, small veins or veins of the extremities with impaired venous or lymphatic drainage should be avoided. Due to injection into a shallow vein or due to repeated administration of the drug in the same vein, phlebosclerosis may form.

- Intravenous administration of doxorubicin should be conducted with caution. When the first signs of doxorubicin extravasation appear (burning or pain at the injection site), the infusion should be stopped immediately and then resumed infusion into another vein before the full dose is administered. Local activities to eliminate the consequences of extravasation. You do not need to remove the cannula immediately, but remove it after a brief aspiration. No later than 6 hours after extravasation, intravenous infusion of dexrazoxane is recommended. In those cases where dexrazoxane is contra-indicated, it is recommended to apply 99% dimethylsulfoxide (4 drops per 10 cm² surface of the skin), repeating this procedure three times a day for at least 14 days. If necessary, the possibility of surgical cleaning should be weighed. On the affected area to reduce pain alternately with the use of dimethyl sulfoxide should be applied cold.

It is advisable to use ice packs.

- Doxorubicin is excreted mainly with bile. Before and during treatment, the total bilirubin in the serum should be monitored.Patients with elevated bilirubin values tend to have a slower clearance and a higher percentage

toxic effects. In such cases, a dose reduction is recommended. Patients with severe hepatic impairment doxorubicin can not be applied.

- Doxorubicin can cause urine to turn red.

- With the use of doxorubicin due to the rapid lysis of tumor cells, hyperuricemia can be observed, and therefore it is recommended that patients during therapy determine the concentration of uric acid, potassium, calcium and creatinine in the serum. Such measures as increased hydration, alkalinization of urine and preventive prescription of allopurinol to prevent hyperuricemia, allow to minimize the risk of complications associated with the tumor disintegration syndrome. In the treatment of hyperuricemia and gout, correction of doses of anti-gouty drugs may be required as a result of an increase in the concentration of uric acid on the background of drug treatment.

- In women, treatment with doxorubicin can cause amenorrhea and infertility. As a rule, ovulation and menstruation normalize after the end of therapy, but there were reports of premature menopause.In animal experiments toxic effects of doxorubicin were also observed with respect to male genital organs (testicular atrophy, diffuse degeneration of the vas deferens and hypospermia). Doxorubicin demonstrates a mutagenic effect and can cause damage to chromosomes in human spermatozoa. Oligospermia or azoospermia can be irreversible. In some cases, it was also reported about the normalization of the relevant indicators, sometimes years after the end of therapy.

Men and women with childbearing potential during treatment with doxorubicin and at least 6 months afterwards should use reliable contraceptive methods.

- In some patients who received radiation therapy, after the administration of doxorubicin (usually after 4-7 days), the hypersensitivity of the irritated skin, the appearance of erythema with the formation of vesicles, edema, severe pain at the injection site, wet epidermitis in places corresponding to irradiation fields were noted.

- In patients treated with anthracyclines (including doxorubicin), secondary myeloid leukemia with or without preleukemic phase was observed.The risk of secondary leukemia increases with doxorubicin in combination with DNA damaging anti-tumor drugs or with radiation therapy, as well as in patients who previously received high doses of cytotoxic drugs, or if the dose of anthracyclines was very high. This type of leukemia can have a latent period of about 1 to 3 years.

- With prolonged (more than a year) treatment with doxorubicin or its cumulation, more than 720 mg /m² in very rare cases, secondary cancer of the oral cavity can develop, including 6 years after the end of therapy. It is necessary to regularly check the oral cavity for the presence of ulcers and if there is any discomfort immediately contact a specialist.

- Immunization is not recommended, if it is not approved by the doctor, in the interval from 3 months to 1 year after taking the drug; other members of the patient's family living with him should not be immunized with oral polio vaccine; should avoid contact with people who received a polio vaccine, or wear a face mask covering the nose and mouth.

- This drug contains 9 mg of sodium chloride in 1 ml.If the patient adheres to a diet with restriction of consumption of table salt, this circumstance should be taken into account.

Special precautions for the destruction of unused medicinal product

Remains of the preparation, all instruments and materials used for the preparation of solutions for intravascular and intravesical administration of doxorubicin should be destroyed in accordance with the standard hospital procedure for the disposal of cytotoxic substances, taking into account existing regulatory acts on the destruction of hazardous waste.

Effect on the ability to drive transp. cf. and fur:Because of the likelihood of side effects such as nausea, vomiting, drowsiness, lacrimation and other symptoms affecting the general condition, from driving the car and working with other mechanisms during treatment should be avoided.

Form release / dosage:

Concentrate for the preparation of a solution for intravascular and intraperitoneal administration of 2 mg / ml (10 mg / 5 ml, 20 mg / 10 ml, 50 mg / 25 ml, 100 mg / 50 ml and 200 mg / 100 ml).

Packaging:

5 ml, 10 ml, 25 ml, 50 ml and 100 ml in brown bottles (glass type 1, Hearth.Pharm.), Sealed with rubber stoppers under aluminum rolling and closed with a protective plastic cover.

One bottle with the drug, along with instructions for use, is placed in a cardboard box.

Storage conditions:

In the dark place at a temperature of 2 to 8 ° C.

Note: When stored in the refrigerator, the preparation may acquire a gel-like consistency that disappears when the preparation is kept at a temperature of 15-25 ° C for 2-4 hours.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015188 / 01

Date of registration:11.08.2008 / 18.05.2015

The owner of the registration certificate:Ebewe Pharma Gesmb.b. Nfg. KGEbewe Pharma Gesmb.b. Nfg. KG Austria

Manufacturer: & nbsp

EBEWE PHARMA, Ges.m.b.H.Nfg.KG Austria

Information update date: & nbsp18.01.2016

Illustrated instructions

Instructions

Doxorubicin-Ebove (Doxorubicin-Ebewe)