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

Has antimitotic and antiproliferative effect. The mechanism of action consists in interaction with DNA, inhibition of topoisomerase II, 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, as well as direct cytotoxic action. The cells are sensitive to the drug in the S and G2 phases.

Pharmacokinetics:

After intravenous administration doxorubicin demonstrates a multiphase distribution: during the first five minutes, doxorubicin is rapidly captured by tissues and its concentration in plasma is decreased; a long half-life is due to the second phase - the phase of slow elimination from tissues. Concentrates in the liver, kidneys, myocardium, spleen, lungs. Through the blood-brain barrier does not penetrate. Penetrates through the placenta; excreted in breast milk with a maximum of 24 hours after reaching a maximum concentration of almost 4.4 times higher than in blood plasma.

The connection with plasma proteins is 74-76%. The volume of distribution is -20-30 l / kg. The clearance of the drug from the plasma is from 8 to 20 ml / min / kg.

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.

The final half-life of doxorubicinol is similar to that of doxorubicin and is 20-48 hours. Approximately 40% of the dose is excreted with bile in unchanged form for 5 days; about 5-12% of doxorubicin and its metabolites are found in the urine over the same period of time. Within 7 days in the form of doxorubicinol, less than 3% of the dose is excreted in the urine.The clearance of doxorubicin in children older than two years exceeds that of adults. The clearance in children younger than two years approaches the values of clearance in adults. Systemic clearance of doxorubicin is significantly reduced in obese women whose body weight is more than 130% of the optimal.

Indications:Breast cancer, small cell lung cancer, mesothelioma, esophageal cancer, stomach cancer, primary genotocellular carcinoma, insulinoma, carcinoid, malignant head and neck tumors, thyroid cancer, malignant thymoma, ovarian cancer, germ cell tumors of the testicle, prostate cancer, urinary cancer bladder (treatment of relapse prevention after surgery), endometrial cancer, cervical cancer, uterine sarcoma, Ewing's sarcoma, rhabdomyosarcoma, neuroblastoma, Wilms tumor, osteogenic sarcoma, soft tissue sarcoma, Arkom's sarcoma in AIDS, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic 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, the period of breastfeeding.

Intravenous administration is contraindicated in poi: pronounced myelosuppression (the number of leukocytes is less than 2000 cells / mm³. the number of platelets is less than 50,000 cells / mm³ ). hepatic insufficiency of severe severity, severe cardiovascular pathology (unstable angina pectoris, progressive heart failure, severe rhythm and conduction disorders, acute inflammatory heart diseases, myocardial infarction in the last six months, cardiomyopathy), previous therapy with other atracyclines and anthracenedions in terminal total doses, acute viral infections (including chicken pox, herpes zoster).

- Introduction to urinary bladder is contraindicated in: infections of the urinary tract, invasive tumors with penetration into the muscular wall of the bladder, inflammation of the bladder, hematuria.

Carefully:

- tumor bone marrow infiltration (it may be necessary to reduce the ready-made doses or increase the intervals between doses);

- heart disease (cardiotoxicity may occur at lower total doses);

- previous intensive chemotherapy;

- hepatic failure (mild and moderate severity);

- as part of combined antitumor therapy, as well as in combination with radiation or other antitumor therapy;

- urate nephrolithiasis (including in the anamnesis);

- children;

- elderly patients;

- patients with obesity;

- patients with peptic ulcer of the stomach and duodenum (with intra-arterial administration of doxorubicin);

- gout, including history;

- parasitic and infectious diseases of a viral, fungal or bacterial nature.

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

Dosing and Administration:

Intravenous, intraarterial, intravesical injection.

Doxorubicin can be used both as monotherapy and in combination with other cytostatic drugs at different doses, depending on the regimen. For individual dose selection, reference should be made to the literature.

Intravenous administration

Intravenous administration of doxorubicin should be conducted with caution.

The required dose of the drug is dissolved in a 0.9% solution of sodium chloride or water for injection to a concentration of not more than 1 mg / ml.

With intravenous administration, the drug is injected for 3-5 minutes - preferably through the tube of the system for intravenous administration during the drip of 5% dextrose or 0.9% sodium chloride solution (to reduce the risk of thrombosis and extravasation).

- As a monotherapy the recommended dose per cycle is 60-75 mg / sq. M with an interval of 3-4 weeks. Usually the drug is administered once during the cycle; however, the cyclic dose can be divided into several administrations (for example, 25-30 mg / m 2 / day for the first three consecutive days).

- To reduce the toxic effect of doxorubicin, especially cardiotoxicity, a weekly regimen of administration of the drug but 10-20 mg / m 2 is applied.

- In combination with other antitumor drugs doxorubicin is prescribed in a cyclic dose of 30-60 mg / m2 every 3-4 weeks.

Repeated administration of the drug is possible only with the disappearance of all signs of toxicity (especially gastrointestinal and hematological).

The total dose of doxorubicin should not exceed 550 mg / m 2.

In patients who received previous radiotherapy for the mediastinal / pericardial region or who took other cardiotoxic drugs, the total dose of doxorubicin should not exceed 400 mg / m 2.

Violation of the function of the liver. In patients with hyperbilirubinemia, doxorubicin dose should be reduced in accordance with the concentration of total bilirubin:

- if the serum bilirubin level is 1.2-3 mg / dL, then the administered dose should be reduced by 50% of the recommended dose; if the serum bilirubin level is more than 3 mg / dl, the administered dose should be reduced by 75% of the recommended dose.

Suppression of bone marrow function.

In severe myelosuppression, a decrease in the doxorubicin dose is recommended as follows:

Leukocytes	Platelets	Doksorub-n,%
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%

Other special patient groups. It is recommended that lower doses be given or longer intervals between cycles in patients who previously received massive antitumor therapy; in children; in elderly patients; in patients with obesity (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.

Intraarterial administration

Patients with hepatocellular carcinoma to provide intensive local effects while reducing the total toxic effect doxorubicin can be administered intraarterially to the main hepatic artery at a dose of 30-150 mg / m2 at intervals 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 be performed only by doctors who perfectly know this technique.

Introduction to the bladder

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 suitable for the treatment of invasive tumors with penetration into the muscular wall of the bladder.

The recommended dose for intravesical administration is 30-50 mg per instillation, with intervals between 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 mucous membrane of the bladder, patients should flip from side to side every 15 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. 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 intended for repeated instillation should be further dissolved in 50-100 ml 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).

Side effects:

From the hematopoiesis:

dose-dependent reversible leukopenia and neutropenia, infections and bleeding. 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 pathological changes in the electrocardiogram (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 chronic heart failure (CHS) (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 caused by anthracyclines of cardiomyopathy is a life-threatening chronic heart failure (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, mucositis, stomatitis or esophagitis (in severe cases ulceration of the mucous membranes of the gastrointestinal tract), hyperpigmentation of the oral mucosa, abdominal pain, gastrointestinal bleeding, diarrhea, colitis, necrotic colitis , dehydration, increased activity of "liver" enzymes, hyperbilirubinemia.

From the urinary system:

staining the urine in red for 1-2 days after the administration of doxorubicin, hyperuricemia. acute renal failure.

On the part of the organs of vision: 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 some cases the number of spermatozoa is restored to a normal level; this can happen in a few 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, urticaria, skin rash, itching, acne erythema, palmar-plantar erythrodysesthesia (tingling sensation in the hands and feet, followed by pain, redness and swelling), onycholysis may 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.

From the nervous system:

peripheral neuropathy in the form of regional sensory and / or motor disorders was noted in patients with intravenous administration of doxorubicin, mainly in combination with cisplatin.

Seizures and coma were noted in patients who received doxorubicin in combination with cisplatin and vincristine.

Allergic reactions:

dermatitis, urticaria, angioedema, hyperemia of the skin of the palms and soles, bronchospasm, anaphylaxis (rarely).

Local reactions:

with intravenous administration, erythematous striation along the vein in which the infusion was performed is often detected, 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.

In children, the development of late neoplastic diseases.

With intra-arterial administration of doxorubicin, in addition to systemic toxicity, gastric and duodenal ulcers can be observed (probably,due to reflux drugs in the gastric artery); narrowing of the bile ducts due to drug-induced sclerosing cholangitis, widespread necrosis of perforated tissue.

With intravesical administration, symptoms of chemical cystitis may appear (dysuria, polyuria, nocturia, painful urination, hematuria, discomfort in the bladder, necrosis of the bladder wall), constriction of the bladder, staining the urine in red.

Other: malaise, asthenia, fever, chills, weight gain, hyperuricemia or nephropathy associated with increased uric acid formation, development of acute lymphoblastic or myeloblastic leukemia, radiation pneumonia, secondary infections, sepsis / septicemia, bleeding, septic shock.

Overdose:

Symptoms: severe myelosuppression (mainly leukopenia and thrombocytopenia), toxic effects from the gastrointestinal tract, acute myocardial damage.

Antidote to doxorubicin is unknown.

Treatment: Symptomatic therapy, accompanied by hospitalization.

Interaction:

When doxorubicin is used in combination with other cytotoxic agents, additive toxicity is possible, especially with respect to the bone marrow / hematopoietic system and gastrointestinal tract.

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

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

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

Streptozocin increases the half-life of doxorubicin.

Urikozuric drugs increase the risk of developing nephropathy.

Cytarabine when used with doxorubicin enhances (mutually) the frequency and severity of side effects.

With simultaneous use with cyclosporin, an increase in doxorubicin concentration in plasma and an increase in myelotoxic effect are observed.

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.

When combined with dactinomycin. daunorubicin, mitomycin, cardiotoxic effect may be increased. The recommended dose of doxorubicin is no more than 400 mg / m 2. The use of doxorubicin in patients who received complete cumulative doses of daunorubicin or doxorubicin (in the anamnesis) is not recommended.

Simultaneous use with verapamil increases the concentrations of doxorubicin in blood plasma and increases its effectiveness.

Inhibitors of the enzymes of the cytochrome P450 system (eg, cimetidine, ranitidine) can reduce the metabolism of doxorubicin. as a result, increasing the risk of developing its toxic effects.

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

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

Doxorubicin reduces the absorption of antiepileptic drugs (eg, carbamazepine, phenytoin, valproic acid) and reduces their content in blood plasma.

Doxorubicin may reduce the bioavailability of digoxin when administered orally. Therefore, during treatment with doxorubicin it is necessary to regularly check the concentration of digoxin in the blood plasma.

The use of trastuzumab in combination with doxorubicin (and other anthracyclines) is associated with a high cardiotoxic risk. therefore trastuzumab should not be used in combination with anthracyclines. If it is necessary to use anthracyclines. cardiac function should be carefully monitored. 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 (up to 24 weeks) should be maintained. In any case, it is necessary to carefully monitor the state of cardiac activity.

Combinations of doxorubicin with amphotericin B should be avoided because it can lead to severe nephrotoxicity.

With simultaneous use of doxorubicin and sorafenib 400 mg twice daily, both the increase in AUC (area under the (pharmacokinetic concentration-time curve)) of doxorubicin by 21-47% and the absence of changes in this indicator were noted.

Against the background of using blockers of "slow" calcium channels, the risk of cardiotoxicity of doxorubicin increases; with simultaneous application requires monitoring of heart functions.

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

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, fluorouracil, hydrocortisone, sodium succinate, aminophylline, cephalothin, other antitumor drugs.

In the treatment with doxorubicin, the suppression of natural defense mechanisms is possible, therefore, with simultaneous administration with live viral vaccines, it is possible to intensify the replication process of the vaccine virus,increasing its adverse / adverse effects and / or reducing the production of antibodies in the patient's body in response to the introduction of the vaccine. Vaccination is recommended to be carried out some time after the end of treatment: the interval varies from 3 months. up to 1 year.

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. If the amplitude of the QRS complex decreases by 30% of the initial value, the QRS complex is extended to the ECG, or the fraction of the left ventricular shortening is reduced by 5% according to the echocardiogram. it is recommended to stop treatment with doxorubicin. 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 risk of developing myocardial dysfunction is approximately 1-2% with a total dose of 300 mg / m 2; The probability of this slowly increases with a total cumulative dose of 450-550 mg / m 2. After that, the development of chronic heart failure increases dramatically, so it is recommended not to exceed the total total dose of 550 mg / sq. M. If the patient has any additional risk of cardiotoxicity (for example, history of heart disease, prior therapy with anthracyclines or anthracenedion, previous mediastinal medication, simultaneous use of other potentially cardiotoxic drugs, such as cyclophosphamide and fluorouracil), then the toxic effect can manifest itself at lower cumulative doses, and the control of heart function should be particularly strict, and the total cumulative dose should not exceed 400 mg / m 2.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 after the end of therapy).

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

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

Doxorubicin is excreted mainly with bile. Before and during treatment, the total bilirubin in serum should be monitored. Patients with elevated bilirubin values tend to have slower clearance and a higher percentage of toxic effects. In such cases, a dose reduction is recommended. Patients with severe hepatic impairment doxorubicin can not be applied.

In patients who received doxorubicin, cases of secondary leukemia with or without preleukemic phase are described. Secondary leukemia often develops with doxorubicin in combination with other antitumour agents that affect DNA synthesis, radiation therapy, as well as in patients who have previously received intensive cytotoxic therapy or anthracyclines at high doses. Secondary leukemia can have a latent period of 1-3 years.

When the first signs of doxorubicin extravasation appear (burning or soreness at the injection site), the infusion should be stopped immediately and then resumed infusion into another vein until the full dose is given. Locally conduct an event to eliminate the consequences of extravasation. It is advisable to use ice packs.

If possible, vein over the joints, small veins or veins of the extremities with impaired venous or lymphatic drainage should be avoided.

the consequence of injection into a shallow vein or in connection with the repeated administration of the drug in the same vein, may develop phlebosclerosis.

When doxorubicin is used due to rapid lysis of tumor cells, hyperuricemia can be observed.Therefore, patients during therapy are recommended to determine the concentration of uric acid, potassium, calcium and creatinine. 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, correction of doses of antihypertensive drugs may be required 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.

Mucositis / stomatitis usually develops soon after administration of the drug and in severe cases for several days can lead to ulceration of the mucosa. In most cases, these undesirable phenomena are resolved by the third week from therapy.

It is not recommended immunization, if it is not approved by a doctor, in the interval from 3 months. year after taking the drug; other members of the patient's family living with him should not be immunized with oral polio vaccine; It is necessary to run contacts with people,who received a vaccine against poliomyelitis, or wear a protective mask covering the nose and mouth.

Men and women of childbearing age during treatment with doxorubicin and at least 3 months after should be taken reliable methods of contraception.

When working with doxorubicin, the rules for handling cytotoxic substances must be observed. Contaminated surface of the drug is recommended to work diluted sodium hypochlorite solution (containing 1% chlorine). If the product falls on the skin, immediately flush the skin with soap and water or a solution of sodium bicarbonate; When doxorubicin gets into the eyes - pull the eyelids and wash the eyes with plenty of water for at least 15 minutes.

Effect on the ability to drive transp. cf. and fur:Considering that nausea, vomiting, lacrimation and other symptoms affecting the general condition can develop in patients with doxorubicin, it is recommended to abstain from driving the car and working with other mechanisms during treatment.

Form release / dosage:Liofilizate for the preparation of solution for injection 10 mg and 50 mg.

Packaging:

For 60 mg or 300 mg of the drug (corresponding to 10 mg or 50 mg of doxorubicin hydrochloride) in glass vials sealed with rubber stoppers or freeze-dried cork days and crimped with aluminum or combined caps.

1 bottle with instructions for use in an individual pack of cardboard.

10 bottles with instructions for use in a cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-003190

Date of registration:11.09.2015

Date of cancellation:2020-09-11

The owner of the registration certificate:Company DEKO, LLC Company DEKO, LLC Russia

Information update date: & nbsp10.01.2016

Illustrated instructions

Instructions

Doxorubicin-DECO (Doxorubicin-Deko)