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

Has antimitotic and antiproliferative effect. The mechanism of action is the interaction with DNA, the formation of free radicals and direct action on the membrane of cells with the suppression of the synthesis of nucleic acids. The cells are sensitive to the drug in the S- and G2-phases.

Pharmacokinetics:

Absorption is high, distribution is relatively uniform. Through the blood-brain barrier does not penetrate. The connection with plasma proteins is about 75%.

Metabolised in the liver with the formation of an active metabolite of doxorubicinol.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. After iv introduction quickly disappears from the blood, concentrating in the liver, kidneys, myocardium, spleen, lungs. The half-life is 20-48 h for doxorubicin and doxorubicinol.

Excretion: with bile - 40% unchanged for 7 days, with urine - 5-12% doxorubicin and its metabolites for 5 days.

Indications:Breast cancer, small cell lung cancer, mesothelioma, esophageal cancer, stomach cancer. primary hepatocellular carcinoma, insulinoma, carcinoid, malignant tumors of the head and neck, thyroid cancer, malignant thymoma, ovarian cancer, germ cell tumors of the testis, prostate cancer, bladder cancer (treatment and prevention of relapses after surgery), endometrial cancer, cervical cancer uterus, uterine sarcoma, soft tissue sarcoma, Ewing's sarcoma, osteogenic sarcoma, rhabdomyosarcoma, neuroblastoma, Wilms tumor, Kaloshi's sarcoma in AIDS, acute lymphoblastic leukemia, acute myeloblastic leukemia, hr nical lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma.

Contraindications:

Hypersensitivity to doxorubicin or other components of the drug, as well as to other anthracyclines and anthracenedions.

Pregnancy and lactation.

Intravenous administration is contraindicated when:

severe myelosuppression, severe hepatic insufficiency, severe heart failure and arrhythmias, recent myocardial infarction, previous therapy with other anthracyclines or anthracenedones in the maximum total doses, chicken pox, herpes zoster.

Introduction to the bladder is contraindicated when:

invasive tumors with penetration into the wall of the bladder, infection of the urinary tract, inflammation of the bladder.

Carefully:Stomach and duodenal ulcer, hyperbilirubinemia, previous radiation therapy or chemotherapy, urate nephrolithiasis (including history), heart disease (cardiotoxicity may occur at lower total doses), hepatic insufficiency, bone marrow infiltration by tumor cells .

Pregnancy and lactation:The drug is contraindicated during pregnancy and lactation.

Dosing and Administration:

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

- as a monotherapy, the recommended dose per cycle is 60-75 mg /m²every three weeks. Usually the drug is administered once during the cycle; however, the cyclic dose can be divided into several administrations (eg, administered for the first three consecutive days, or on the first and the eighth day of the cycle). The cycles are repeated every 3-4 weeks.

- to reduce the toxic effect of doxorubicin, especially cardiotoxicity, 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.

Violation of the function of the liver. In patients with hyperbilirubinemia, the doxorubicin dose should be reduced in accordance with the concentration of total bilirubin: by 50% at a serum bilirubin concentration of 12-30 mg / l; on 75% at a concentration of bilirubin in blood serum above 30 mg / l.

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

Intravenous administration of doxorubicin should be conducted with caution. 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.

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 more than 400 mg /m².

Before administration, the required dose of the drug should be dissolved in a 0.9% solution of sodium chloride or water for injection to a concentration of 2 mg / ml. The drug is injected intravenously slowly.

Introduction to 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 purpose of therapy - treatment or prevention. The recommended concentration of the solution is 1 mg / 1 ml of water for injection or 0.9% solution of sodium chloride. 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 fifteen minutes. As a rule, the drug should be in the bladder for 1-2 hours. At the end of instillation, the patient should empty the bladder.

To prevent excessive dilution of the drug with urine, patients should be warned that they should refrain from taking liquid 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 provide intensive local effects while reducing the total toxic effect doxorubicin can be injected intraarterially into the main hepatic artery at a dose of 30-150 mg / m² with 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, widespread necrosis of the tissue can occur, intraarterial administration can only be performed by physicians who are proficient in this technique.

Side effects:

On the part of the organs of hematopoiesis: dose-dependent, reversible leukopenia and neutropenia. Thrombocytopenia and anemia are also possible. Leukopenia usually reaches its lowest value 10-14 days after the administration of the drug, the restoration of the blood picture is usually observed on day 21.

From the cardiovascular system: the manifestation of early (acute) cardiotoxicity of doxorubicin is primarily sinus tachycardia and / or anomalies on the ECG (nonspecific changes in ST-T waves). There may also be tachyarrhythmias (including ventricular tachycardia), ventricular extrasystole, as well as bradycardia, atrioventricular blockade and Tisa blockade. The appearance of these phenomena is not always a prognostic factor in the development of subsequently delayed cardiotoxicity, they are rarely clinically significant, and do not require the abolition of doxorubicin therapy.

Later (delayed) myocardial damage is manifested by a decrease in the left ventricular ejection fraction without clinical symptoms and / or symptoms of congestive heart failure (dyspnea, pulmonary edema, peripheral edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy, gallop rhythm). Also subacute phenomena (pericarditis / myocarditis) can be noted. The most severe form of anthracycline-induced cardiomyopathy is the life-threatening CHF, which is a toxicity that limits the cumulative dose of the drug.Phlebitis, thrombophlebitis, thromboembolic complications, including pulmonary embolism (in some cases, with a fatal outcome).

From the digestive system:

anorexia, nausea, vomiting, stomatitis or esophagitis (in severe cases ulceration of the mucous membranes of the gastrointestinal tract), hyperpigmentation of the oral mucosa, abdominal pain, bleeding from the gastrointestinal tract, diarrhea, colitis. Increase the concentration of total bilirubin and the activity of "liver" transaminases in the blood serum.

From the urinary system:

staining the urine in red for 1-2 days after the administration of doxorubicin.

From the sense organs:

conjunctivitis, keratitis, lachrymation.

On the part of the reproductive system:

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 normal level, this can happen several years after the end of therapy).

From the skin and skin appendages:

in most cases, reversible complete alopecia develops. The resumption of hair growth usually begins 2-3 months after the drug is discontinued. Hyperpigmentation of the skin and nails, photosensitivity, hives, rash, itching may also occur. Some patients who received radiation therapy after doxorubicin administration (usually after 4-7 days) showed hypersensitivity of the irritated skin, erythema with the formation of vesicles, edema, severe pain, wet epidermitis in places corresponding to irradiation fields.

Allergic reactions:

skin rash, dermatitis, urticaria, flushing of the skin of the palms and soles, bronchospasm, anaphylaxis (rarely).

Local reactions:

Often there is erythematous striation along the vein into which the infusion was made, then local phlebitis or thrombophlebitis may occur. Also, phlebosclerosis may develop, especially if doxorubicin is reentered into a small vein. In the event of a drug falling into the surrounding tissues, local soreness, severe inflammation of the subcutaneous tissue and necrosis of the tissues may occur.

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.

With intravesical injection:

cystitis, staining the urine in red.

Other:

malaise, asthenia, fever, chills, hot flushes to the face, hyperuricemia or nephropathy associated with increased uric acid formation, development of acute lymphocytic or myelocytic leukemia.

Overdose:

Acute overdose of doxorubicin can lead to severe myelosuppression (mainly to leukopenia and thrombocytopenia), to toxic effects from the gastrointestinal tract, to cause acute heart damage.

Antidote to doxorubicin is unknown. In case of overdose, symptomatic therapy is recommended.

Interaction:

When doxorubicin is used in combination with other cytotoxic agents, additive

toxicity, especially with regard to bone marrow / hemopoietic system and gastrointestinal tract.The cardiotoxicity of doxorubicin is enhanced by the preceding or concomitant

introduction of other cytotoxic drugs (for example, fluorouracil and / or cyclophosphamide), which requires careful monitoring of heart function throughout the course of therapy.

The administration of paclitaxel to doxorubicin can lead to an increase in plasma concentrations of doxorubicin and / or its metabolites in plasma. This effect is minimal when doxorubicin

apply to paclitaxel. The risk of cardiotoxicity increases with the appointment of bevacizumab together or after doxorubicin. On the background of doxorubicin therapy, it is possible to intensify the phenomena of hemorrhagic cystitis caused by cyclophosphamide and increase the hepatotoxicity of mercaptopurine.

Simultaneous or previous administration of other cytostatics. sulfonamide, chloramphenicol, phenytoin, arbitrary amiloride, antiretroviral agents can lead to severe hematopoietic disorders.

Radiotherapy enhances the cardiotoxic or hepatotoxic effects of doxorubicin.

Rifampicin, barbiturates and other inducers of cytochrome P450 accelerate the metabolism of doxorubicin and reduce its effectiveness.

Inhibitors of cytochrome P450 increase the toxicity of doxorubicin.Simultaneous use of cyclosporine and doxorubicin slows metabolism and decreases the clearance of both drugs, which

leads to an increase in their concentration in the blood plasma, and, as a consequence, to the prolongation and intensification of the toxic effects of doxorubicin.

Doxorubicin reduces the concentration of phenytoin in blood plasma with simultaneous administration.

Doxorubicin reduces the oral bioavailability of digoxia. When doxorubicin is used in combination with cardiovascular drugs (for example, calcium channel blockers), it is necessary to monitor myocardial function.

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

Pharmaceutically incompatible with heparin, dexamethasone, hydrocortisone, sodium succinate, aminophylline, cephalothin, 5-fluorouracil and other antitumor drugs.

With simultaneous administration with live viral vaccines, it is possible to intensify the process of replication of the vaccine virus, increase its side / adverse effects and / or reduce the production of antibodies in the patient's body in response to the introduction of the vaccine.

Simultaneous use with progesterone enhances doxorubicin - induced neutro- and thrombocytopenia.

Special instructions:

Treatment with doxorubicin should be carried out under the supervision of physicians with experience in the use of antitumor drugs.

- To reduce the risk of toxic cardiac damage, it is recommended that a regular check of its function be performed before the initiation of therapy with doxorubicin, including assessment of the left ventricular ejection fraction from echocardiography or multichannel radioisotope angiography and ECG monitoring. An early clinical diagnosis of heart failure due to the use of the drug is very important for its successful treatment. If signs of chronic cardiotoxicity are detected, treatment with doxorubicin is immediately stopped.

- Acute cardiotoxicity in most cases is transient (reversible), and usually it is not considered as an indication for the abolition of doxorubicin therapy. Late (delayed) cardiotoxicity (cardiomyopathy) depends on the total dose. 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 slowly increases at a total cumulative dose of 450-550 mg /m². Then the risk of developing congestive heart failure increases dramatically, so it is recommended not to exceed the total total dose of 550 mg /m². If the patient has any additional risk of cardiotoxicity (for example, history of heart disease, prior therapy with anthracyclines or anthracenedions, previous radiotherapy of the mediastinum, simultaneous use of other potentially cardiotoxic drugs such as cyclophosphamide and 5-fluorouracil), then toxic effects can occur at lower cumulative doses, and cardiac function monitoring should be particularly stringent. Doxorubicin-induced cardiotoxicity 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).

- During treatment with doxorubicin, it is necessary to evaluate hematological parameters before and during each cycle of therapy, including the determination of the number of leukocytes,thrombocytes, hemoglobin, blood elements and liver function tests.

- When the first signs of doxorubia extravasation appear (burning or soreness 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. It is advisable to use ice packs.

- If possible, avoid insertion into the veins over the joints or into the veins of the extremities with disturbed venous or lymphatic drainage.

- With the use of doxorubicin due to the rapid lysis of tumor cells, hyperuricemia can occur, and therefore it is recommended that patients determine the concentration of uric acid, potassium, calcium and creatinine during therapy. Such measures as increased hydration, alkalinization of urine and prophylactic appointment of allopurinol to prevent hyperuricemia allow to minimize the risk of complications associated with tumor lysis syndrome. In the treatment of hyperuricemia and gout, it may be necessary to adjust the doses of antidotal drugs as a result of an increase in the concentration of uric acid against the background of drug treatment.

- Patients with advanced neutropenia / leukopenia should be carefully monitored to identify signs of infection.

- Refusal from immunization, 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; Avoid contact with people who received a polio vaccine, or wear a face mask covering the nose and mouth.

- Men and women of childbearing age, during treatment with doxorubicin and at least 3 months afterwards, should use reliable contraceptive methods.

- When working with doxorubicin, the rules for handling cytotoxic substances must be observed. Contaminated surface is recommended

treated with dilute sodium hypochlorite solution (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, pull eyelids and rinse eyes (eyes) with plenty of water for at least 15 minutes.

Effect on the ability to drive transp. cf. and fur:

Although the drug does not directly affect the ability to drive a car, nevertheless, some patients may experience dizziness, drowsiness. Therefore, during the treatment period, these patients should refrain from driving the car and controlling the mechanisms.

Form release / dosage:Lyophilized powder for the preparation of injection of 10 mg and 50 mg in glass bottles.

Packaging:Bottles are corked chlorobutyl plugs and crimped aluminum caps with a plastic insert. For 1 bottle of the drug with the attached instructions for use in a cardboard pack or 10 bottles of the drug together with instructions for use in a foam box.

Packing for hospitals: 36 bottles of 50 mg each and 36 instructions for use in a foam box.

Storage conditions:

At a temperature of 15 to 25 ° C.

Keep out of the reach of children.

Shelf life:

5 years.

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

Terms of leave from pharmacies:On prescription

Registration number:П N015001 / 01

Date of registration:20.05.2009 / 22.11.2011

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

PHARMACHEMIE, B.V. Netherlands

Information update date: & nbsp18.01.2016

Illustrated instructions

Instructions

Doxorubicin-Teva (Doxorubicin-Teva)