Doxorubicin-LENS - 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 to 48 hours 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, lung cancer (small cell lung), mesothelioma, esophageal cancer, gastric cancer, primary hepatocellular carcinoma, pancreatic cancer, insulinoma, carcinoid cancer, head and neck. thyroid cancer, malignant thymoma, ovarian cancer, germ cell testicular tumors, trophoblastic tumors, prostate cancer, bladder cancer (treatment and relapse prophylaxis after surgery), endometrial cancer, cervical cancer, uterine sarcoma, Ewing's sarcoma, rhabdomyosarcoma, neuroblastoma , Wilm's tumor, osteogenic sarcoma, soft tissue sarcoma, Kaposi's sarcoma, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, Hodgkin's disease and non-Hodgkin's lymphoma, a plurality of th myeloma.

Contraindications:

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

- Pregnancy and the period of breastfeeding;

- Intravenous administration is contraindicated in: severe myelosuppression, severe hepatic impairment, severe heart failure and arrhythmias, recent myocardial infarction, previous therapy with other anthracyclines or anthracenedones in the maximum total doses, varicella zoster, herpes zoster;

Introduction to the bladder is contraindicated in: invasive tumors with penetration into the wall of the bladder, urinary tract infection, 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:Application during pregnancy and lactation of the drug is contraindicated.

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

Intravenous administration

The drug is injected intravenously slowly.

- 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 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 /m² every 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.

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 local manifestations of toxic action (chemical cystitis, which can manifest dysuria, polyuria, nocturia, painful urination, hematuria, discomfort in the bladder, the bladder wall necrosis), the dose intended for instillation, 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:

From the 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 bundle bundle 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 not known. In case of overdose, symptomatic therapy is recommended

Interaction:

Doxorubicin may increase the toxicity of other antitumour agents, especially myelotoxicity and toxic effects on the gastrointestinal tract.

With the simultaneous use of doxorubicin and other cytotoxic drugs that have potential cardiotoxicity (eg, 5-fluorouracil and / or cyclophosphamide) requires careful monitoring of heart function throughout the course of therapy.

Against the background of doxorubicin, it is possible to intensify the phenomena of hemorrhagic cystitis,caused by cyclophosphamide and increased hepatotoxicity of 6-mercaptopurine.

Streptozotocin increases the half-life of doxorubicin.

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

Urikozuric antidotal drugs increase the risk of developing nephropathy. Hepatotoxic drugs, worsening the function of the liver, can lead to an increase in the toxicity of doxorubicin.

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.

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 monitoring of its function be performed before starting therapy with doxorubicin, including an 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 likelihood of myocardial dysfunction is approximately 1-2% with a total dose of 300 mg / m²; The probability of this increases slowly 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, a history of heart disease, previous therapy with anthracyclines or anthracenedions, previous radiotherapy of the mediastinum region, 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 the treatment with doxorubicin, it is necessary to evaluate hematological parameters before and during each cycle of therapy, including determination of the number of leukocytes, platelets, hemoglobin, blood elements and liver function tests.

- When the first signs of extravasation of doxorubation occur (burning or soreness at the injection site), the infusion should be stopped immediately,and then resume the infusion into another vein until the full dose is given. 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; otherthe family members of the patient living with it should refuse immunization 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. 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, pull eyelids and rinse eyes (eyes) with plenty of water for at least 15 minutes.

Form release / dosage:

Solution for intravascular and intravesical administration 2 mg / ml (10 mg / 5 ml, 25 mg / 12.5 ml, 50 mg / 25 ml, 75 mg / 37.5 ml or 150 mg / 75 ml).

Packaging:

For 5 ml, 12.5 ml, 25 ml, 37.5 ml or 75 ml in neutral glass bottles,hermetically sealed with rubber stoppers, with caps covered with aluminum or aluminum-plastic caps.

1 bottle with instructions for use in a pack of cardboard.

5 bottles of 5 ml each, along with instructions for use in a pack with partitions or special cardboard sockets.

By 10, 25, 50, 85 or 100 bottles with an equal number of instructions for use in a cardboard box (for hospitals).

Storage conditions:

In the dark place at a temperature of no higher than 8 ° C.

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:LS-002609

Date of registration:21.03.2012 / 13.01.2015

The owner of the registration certificate:LENS-PHARM, LLC LENS-PHARM, LLC Russia

Manufacturer: & nbsp

LENS-PHARM, LLC Russia

Information update date: & nbsp13.01.2016

Illustrated instructions

Instructions

Doxorubicin-LENS® (Doxorubicin-LANS)