· Breast carcinomas.

· Sarcoma of the bones and soft parts.

· Hodgkin's disease, non-Hodgkin's lymphoma.

· Solid tumors of the child.

· Lung cancers.

· Acute and chronic leukemias.

· Cancers of the bladder, ovary, stomach.

Dosage

Administration, intravenous

The total dose of doxorubicin per cycle may vary according to the therapeutic protocol (monotherapy or combination with other cytotoxic drugs) and therapeutic indication
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Initial Dose Recommended

In monotherapy, the recommended starting dose per cycle in adults is 60 to 90mg / m 2 body surface area.
The total dose per cycle may be administered as a single dose or over 3 consecutive days, or on D1 and D8. Under conditions where the patient normally recovers from the toxicity induced by the treatment (including depression, medullary and stomatitis), each cycle can be repeated every 3 to 4 weeks. The administration of doxorubicin in a weekly cycle of 10 to 20 mg / m 2 also showed its efficacy. If doxorubicin is used in combination with other cytotoxic drugs whose toxicity may be added, the recommended dose per cycle is 30 to 60 mg / m 2.

Dosage adjustment

Achievement of function, hepatic

The level of bilirubin should be monitored before each treatment. In case of liver function (see Warnings and precautions for use), dose reductions are recommended according to

Parameters of serum biochemistry

Dose to administer

(As a percentage of the theoretical dose)

Bilirubin: 20-51 μmol / l

Or

ASAT: 2 to 4 times the upper limit of the normal

50

Bilirubin> 51 μmol / l

Or

ASAT> 4 times the upper limit of the normal

25

Doxorubicin should not be administered to patients with severe impairment of liver function (see section Contraindications).


Mode of administration

Administration, intravenous

The dose of Adriblastin should be injected within 3 to 5 minutes and in a maximum of 10 minutes (to reduce the risk of thrombosis or extravasation) into the tubing of an intravenous infusion of sodium chloride solution 0.9% isotonic acid or 5% glucose solution.

Direct bolus injection is not recommended because of the risk of extravasation, which may occur even in the presence of a blood flow, suitable for aspiration.

ATTENTION

It is extremely important to ensure that the administration is intravenous. Any extravasation could produce necrosis of the surrounding tissues. In case of extravasation, the administration will be interrupted immediately.

Terms of use

The preparation of injectable cytotoxic solutions must be carried out by specialized and trained personnel with knowledge of the medicines used under conditions ensuring the protection of the environment and especially the protection of the personnel handling. Requires a preparation room reserved for this purpose. It is forbidden to smoke, to eat, to drink in this room. Handlers shall be provided with a set of equipment suitable for handling, including long-sleeved gowns, masks, protective goggles, protective goggles, gloves for use, single sterile, worktop protection areas, containers and Garbage collection bags. The excreta and vomit must be handled with care. Pregnant women should be warned and avoid the use of cytotoxic drugs. Any broken container shall be treated with the same precautions and considered as contaminated waste The disposal of the contaminated waste is carried out by incineration in rigid containers labeled for this purpose

These provisions may be considered within the framework of the Cancerology Network (Circular DGS / DH / 98 No. 98/188 of 24 March 1998) in collaboration with any suitable and meeting the requirements. >

No information in the marketing authorization.

Pharmacotherapeutic group: ANTHRACYCLINES AND RELATIVES

ATC code: L01DB01.

Antineoplastic cytostatic antibiotic of the family anthracyclines.

Basic studies have shown that doxorubicin rapidly binds to the nuclear structures of the cell, blocking the synthesis of A.D.N. And A.R.N. As an intercalating agent, at the level of the A.D.N.

On the basis of undesirable effects, patients should be warned not to drive and not to use machinery without the advice of a health professional. Br>
This medication is contraindicated in the following cases

· Hypersensitivity to doxorubicin or to any of the excipients, or to other anthracyclines or anthracenediones

· Persistent myelosuppression

· Severe hepatic impairment

· Severe myocardial insufficiency

· Recent myocardial infarction (less than 6 months)

· Severe arrhythmia

· Previous treatment with doxorubicin, daunorubicin, epirubicin, idarubicin and / or other anthracyclines or anthracenediones at the maximum cumulative dose (see section 4.4).

· In association with yellow fever (yellow fever) vaccine (see section Interactions with other medicines and other forms of interaction)

· Breast-feeding (see section Pregnancy and lactation).

General

Doxorubicin should only be administered under the supervision of qualified physicians experienced in the use of cytotoxic treatments

Before initiating treatment with doxorubicin the patient should have recovered from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia and generalized infections) induced by prior cytotoxic treatment.
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Systemic clearance of doxorubicin is reduced in obese patients (ie, patients weighing 130% or more of the ideal body weight) (see Posology and Method of Administration).

Cardiac function

A risk of cardiotoxicity is associated with treatment with anthracyclines. It may manifest itself immediately or in a delayed manner.

Cardiotoxicity: consists mainly of sinus tachycardia, ventricular extrasystoles, ventricular tachycardia, and electrocardiogram abnormalities (changes in the T wave, atrioventricular conduction disorders, branch block) .

These rarely clinically important effects do not usually constitute a reason for discontinuation of therapy and are generally not predictive of the development of delayed cardiotoxicity. >

Cardiotoxicity: delayed: it may develop late in the course of treatment or within two to three months after the end of the treatment and more rarely several months or even several years after the end of treatment. >

Delayed cardiomyopathy is manifested by a reduction in left ventricular ejection fraction (LVEF) and / or signs and symptoms of congestive heart failure such as dyspnea, pulmonary edema, edema, cardiomegaly and hepatomegaly, oliguria; Ascites, pleural effusion and gallop rhythm. Subacute effects such as pericarditis / myocarditis have also been reported. Life-threatening congestive heart failure is the most severe form of cardiomyopathy induced by anthracyclines and represents cumulative toxicity, limiting the dose of this drug. >
Cardiac function should be evaluated before and throughout treatment to reduce the risk of heart failure, severe.

Prior to treatment, clinical evaluation (cardiac), ECG with either ventricular scintigraphy or echocardiography, especially in patients with increased risk factors for cardiac toxicity: active or latent cardiovascular disease, radiotherapy, prior Or concomitant mediastinal / pericardial, previous therapy with other anthracyclines or anthracenediones and concomitant use of other medicines that can alter contractility, cardiac or cardiotoxic drugs (eg, trastuzumab). Code>
During treatment: regular follow-up of LVEF evaluated by ventricular scintigraphy (MUGA) and / or echocardiography (ECHO), with immediate discontinuation, doxorubicin at the first signs, functional impairment. Repeated determinations of LVEF by MUGA or ECHO should be made especially in the use of high and cumulative doses of anthracyclines. The technique used for the evaluation must be reproducible throughout the follow-up.

The probability of developing congestive heart failure, estimated at about 1 to 2% for a cumulative dose of 300 mg / m², increases slowly to cumulative doses of doxorubicin of 450-550 mg / m². Beyond that, the risk of developing congestive heart failure increases rapidly and it is recommended not to exceed a maximum cumulative dose of 550 mg / m².
Anthracyclines, including doxorubicin, should be administered in combination with other cardiotoxic drugs only under close monitoring of the patient's cardiac function .; Patients receiving anthracyclines after discontinuation; Other cardiotoxic drugs, especially those with a long half-life, such as trastuzumab, may be at increased risk of cardiotoxicity. The half-life of trastuzumab is approximately 28.5 days, may persist in circulation for up to 24 weeks after discontinuation of therapy. As much as possible, the prescriber should avoid treatments containing an anthracycline for the next 24 weeks, stopping trastuzumab. If anthracyclines are used before the end of this period, close monitoring of cardiac function is then recommended.

Cardiac function monitoring should be particularly strict in patients who receive high cumulative doses and in those with risk factors Nevertheless, the associated cardiac toxicity to doxorubicin may occur with cumulative doses; Risk factors are present or not.

The risk of developing delayed cardiotoxicity following administration of doxorubicin is greater in children and adolescents. The risk is also greater in women than in men. It is therefore advisable to carry out a regular cardiac follow-up.

It is likely that the toxicity of doxorubicin and other anthracyclines or anthracenediones is additive.
Hematological toxicity

Like other cytotoxic drugs, doxorubicin may cause myelosuppression. The hematological parameters, including the white blood cell count, should be evaluated before and during each treatment cycle. The main hematological abnormality of doxorubicin is leukopenia, and / or granulocytopenia (neutropenia), dose-dependent and reversible, this is also the most acute, dose-limiting toxicity. Leukopenia and neutropenia usually reach nadir between the 10th and 14th day of treatment, with leukocyte / neutrophil values ​​normalizing in most cases around the 21st day. Thrombocytopenia and anemia may also occur. The clinical consequences of severe myelosuppression include: fever, infection, sepsis / septicemia, septic shock, haemorrhage, tissue hypoxia or death

Secondary leukemias

A secondary leukemia, preceded or not by a phase, preleukemic has been reported, in patients treated with anthracyclines, including doxorubicin.

Secondary leukemia is more common when such drugs are administered

· In association with antineoplastic agents acting on DNA

· In association with radiotherapy

· In patients heavily pretreated with cytotoxic drugs

· Or when doses of anthracyclines have been successively increased

These leukemias may have a latency period of 1 to 3 years.
Gastrointestinal toxicity

Doxorubicin is emetogenic. Mucositis and / or stomatitis usually occur at the beginning of treatment. In case of severity, it may evolve in a few days towards ulceration of the mucous membrane. Most patients heal towards the third week of treatment.

Liver function

The elimination being mainly hepatobiliary, the levels of total bilirubin, total serum and ASAT must be determined before and during treatment. Patients with high bilirubin or ASAT levels may show decreased clearance of doxorubicin combined with an increase in overall toxicity. Therefore, a dose adjustment is recommended (see Dosage and Administration). In patients with severe hepatic impairment, doxorubicin should not be administered (see Contraindications).


Injection into a small vessel or repeated injections into the vein may cause phlebosclerosis. Adherence to administration modalities (see section 4.2) may minimize the risk of phlebitis / thrombophlebitis at the site of injection.
Extravasation

Extravasation of doxorubicin during intravenous injection may cause local pain, severe tissue damage (vesication, severe cellulitis) and necrosis. If signs or symptoms of extravasation occur during the intravenous administration of doxorubicin, infusion of the product should be discontinued immediately.

Tumor lysis syndrome: Doxorubicin can cause hyperuricemia due to a significant catabolism of the purines resulting from the rapid lysis of the cancer cells induced by the cytotoxic treatment (tumor lysis syndrome). >

Blood levels of uric acid, potassium, phosphate and calcium, as well as creatinine should be checked regularly after the initiation of treatment. >
Hydrolysis, very careful alkalization of urine, and prophylactic treatment with allopurinol (1st intent) or other agent, hypouricemic to prevent hyperuricemia, may minimize the potential complications of tumor lysis syndrome

Other

Doxorubicin may potentiate the toxicity of other cancer treatments. Exacerbation of hemorrhagic cystitis induced by cyclophosphamide and an increase in hepatotoxicity induced by 6-mercaptopurine have been reported.
The use of doxorubicin with a live attenuated (except antiamaril) or phenytoin (and by extrapolation of fosphenytoin) vaccine is not recommended (see section Interactions with other medicinal products and other forms of interaction). >

Immunosuppressive effects - increased susceptibility to infections

The administration of live or attenuated live vaccines in patients immunosuppressed by their treatment with doxorubicin may lead to severe or fatal infections

Vaccination with a live vaccine should be avoided in patients receiving doxorubicin. Killed or inactivated vaccines may be administered. However, the response to such vaccines may be diminished.

Radiation-induced toxicities (on myocardium, mucous membranes, skin and liver) have also been reported.
As with other cytotoxic agents, thrombophlebitis and thromboembolic events, including pulmonary embolism (in some cases, fatal) have been reported when taking doxorubicin.

Women of childbearing potential treated with pregnant women (see Pregnancy and lactation): Women of childbearing potential treated with doxorubicin should use an effective means of contraception during treatment and during the month following treatment discontinuation .

Men treated (see section Pregnancy and lactation): It is desirable that men treated with doxorubicin or their partner use a contraceptive method so as to avoid conception during the treatment of the patient and within 4 months after the end Of the processing.

Treated patients should be advised of the need to consult for preservation of semen prior to treatment because of the possibility of impairment of fertility.

This medicinal product contains sodium, which contains 3.54 mg sodium per ml of solution, to be taken into account in patients on a strict diet. >
Doxorubicin-Related Interactions

Doxorubicin is mainly used in combination with other cytotoxic drugs.
Additive toxicity may occur, especially for medullary / haematological, and gastrointestinal (see Warnings and Precautions for Use). The use of doxorubicin in chemotherapy combining other potentially cardiotoxic products (eg cyclophosphamide), as well as the concomitant use of other cardiac products (eg, calcium channel blockers); Require cardiac function monitoring throughout the treatment.

Changes in hepatic function induced by concomitant therapies may affect the metabolism, pharmacokinetics, efficacy and / or toxicity of doxorubicin.

When paclitaxel is administered, prior to doxorubicin, it may increase plasma levels of doxorubicin and / or its metabolites. Some data indicate that this effect is minor when anthracycline is administered before paclitaxel.
Associations to be taken into account

+; Sorafénib

If combined with sorafenib, risk of increased plasma concentrations of doxorubicin

+; Verapamil

Risk of increased toxicity of doxorubicin by increasing its plasma concentrations

Common interactions with all cytotoxic drugs

Associations contraindicated (see section Contraindications)

+ Yellow fever vaccine

Risk of vaccine disease, generalized fatal.

Associations, not recommended (see Warnings and precautions for use)

+, Phenytoin (and, by extrapolation, fosphenytoin)

Risk of convulsions occurring by decreased digestive absorption of phenytoin alone by cytotoxic, or increased risk of toxicity or loss of efficacy, cytotoxic by increased metabolism, hepatic by phenytoin Or fosphenytoin.

+ Live attenuated vaccines except yellow fever

Risk of illness, generalized vaccination possibly fatal. This risk is increased in subjects already immunocompromised by the underlying disease

Use an inactivated vaccine when it exists (poliomyelitis).

Associations to be taken into account

+ Antivitamins K (AVK)

The high variability of coagulability and increased thrombotic and haemorrhagic risks in tumor affections, coupled with the potential for interaction between AVK and anticancer chemotherapy, Is decided to treat the patient by AVK, increase the frequency of INR checks.

+ Immunosuppressants (ciclosporin, everolimus, sirolimus, tacrolimus)

Excessive immunodepression with, risk of syndrome, lymphoproliferative.

In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products (eg, heparin or alkaline solutions), except those specified in Dosage and Mode of Administration , Sodium chloride solution, 0.9% isotonic solution or 5% glucose solution.

Doxorubicin should not be mixed with fluorouracil (eg in the same infusion bag or the Y-injection site of IV infusion tubing) since it has been reported that these drugs are Incompatible because a precipitate can form. If a combination of doxorubicin with fluorouracil is required, it is advisable to rinse the IV tubing between the administration of these two drugs.
Hemodialysis is unnecessary, as doxorubicin is excreted mainly by the biliary and intestinal route.
Overdosage includes a risk of acute and delayed myocardial toxicity and increased myelosuppression (mainly leukopenia and thrombocytopenia) and other side effects, including toxicity, gastrointestinal (mainly mucositis).

Cases of delayed cardiac failure were observed several months after the overdose in anthracyclines. Therefore, cardiac function should be monitored very strictly and blood counts should be performed daily.

In case of overdose, the treatment is based on the maintenance of vital functions in special care units, this period includes measures, such as blood transfusions and nursing, palliative care.
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Pregnancy

Women of childbearing potential should use an effective contraceptive during the course of treatment and during the month following cessation of treatment Due to the availability of data doxorubicin will be administered during pregnancy only if the pathology Involves the vital prognosis of the mother. Indeed, clinical data on the use of doxorubicin during pregnancy are few and a malformative effect has been demonstrated in animals (see). If doxorubicin is used during pregnancy or if the patient becomes pregnant during treatment, it is necessary to inform her of the potential risks to the fetus. In the case of treatment with doxorubicin at the end of pregnancy, it is necessary to take into account the neonatal management of the cardiac and hematological profile in the newborn.

Breastfeeding

Doxorubicin is excreted in breast milk. Women treated with doxorubicin should not breast-feed while taking doxorubicin.

Fertility

In women, treatment with doxorubicin combined with other antimitotics may result in transient or more amenorrhea, rarely definitive. Ovulation and menstruation usually reappear after cessation of treatment but early menopause is possible

In humans, oligospermia or azoospermia may appear and be permanent. However, a return to normal of the spermogram, which may take several years, is possible.
Men treated should be advised of the need to consult for preservation of semen prior to treatment because of the possibility of impairment of fertility.

Doxorubicin is mutagenic and may induce chromosomal damage of spermatozoa Men who are treated with doxorubicin should avoid conception during treatment and within 4 months of the end of treatment. Br>

The following adverse reactions have been reported following treatment with doxorubicin

Infections and infestations

Infection, sepsis / septicemia.

Tumors, benign, malignant

Acute lymphocytic leukemia, acute myeloid leukemia

Hematologic and system disorders,

Leukopenia, neutropenia, anemia, thrombocytopenia.

Immune system disorders

Anaphylaxis.
Metabolism and nutrition disorders

Anorexia, dehydration, hyperuricemia

Eye disorders

Conjunctivitis / keratitis, lacrimations.

Cardiac disorders

Sinus tachycardia, tachyarrhythmia, block, atrioventricular and branch block, congestive heart failure,

Affections, vascular

Hemorrhage, flushing of heat, phlebitis, thrombophlebitis, thromboembolism, shock.

Gastrointestinal disorders

Nausea / vomiting, mucositis / stomatitis, hyperpigmentation of the buccal mucosa, oesophagitis, abdominal pain, gastric erosions, gastrointestinal tract haemorrhage, diarrhea, colitis >
Skin and subcutaneous tissue disorders

Alopecia, local toxicity, rash / itching, skin changes, skin and nail hyperpigmentation, photosensitivity, skin hypersensitivity, irradiation, urticaria, erythema acral, palmoplantar erythrodysesthesia
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Kidney and urinary tract disorders

Coloring in urine red 1 to 2 days after administration.

Breast and reproductive organs

Amenorrhea, oligospermia, azoospermia.

Disorders, General and Site Anomalies, Administration

Malaise / asthenia, fever, chills

Investigations

ECG abnormalities, asymptomatic fall, left ventricular ejection fraction, variation in transaminase levels

In NSABP B-15, according to doxorubicin-treated patients in adjuvant breast cancer, the most relevant adverse effects reported were similar to the toxicity profile of doxorubicin. An additional adverse reaction has been reported

Investigations: weight gain.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization of the drug is important. It permits continuous monitoring of the benefit / risk ratio of the drug. Health professionals report any suspected adverse reactions via the national reporting system: National Agency for the Safety of Medicines and Health Products (Ansm) and network of Regional Pharmacovigilance Centers -
· Hodgkin's disease, non-Hodgkin's lymphoma · Solid tumors of the child · Lung cancers · Acute leukemias And Chronic Cancers of the bladder, ovary, stomach.