Doxorubicin Ebewe: Treatment cancer of the hematopoietic system, lymphatic system

2021-07-04 05:07 PM

Doxorubicin has been shown to have anti-neoplastic activity in several animal species and is effective in humans, but there is still no consensus on how doxorubicin and other anthracyclines exert antitumor effects.

Producer

Ebewe Pharma.

Ingredient

Per mL: Doxorubicin hydrochloride 2mg.

Pharmacodynamic

ATC code: L01D B01.

Doxorubicin has been shown to have anti-neoplastic activity in several animal species and is effective in humans, but there is still no consensus on how doxorubicin and other anthracyclines exert antitumor effects. Three main biochemical mechanisms have been proposed: action on DNA, binding to cell membranes and activation of metabolism through degradation.

An important cause of treatment failure with doxorubicin and other anthracyclines is the development of drug resistance. To overcome cellular resistance to doxorubicin, the use of calcium antagonists such as verapamil is considered since the primary target is the cell membrane; verapamil inhibits slow channel calcium transport and may increase cellular uptake of doxorubicin. Chang et al, 1989 showed that the cytotoxic effect of doxorubicin was enhanced by verapamil in vitro when administered to 3 pancreatic cancer cell lines.
 
A possible role in human plasma of doxorubicinol, the major degraded metabolite of doxorubicin, was also investigated, but was concluded not to be related to the accumulation of doxorubicin in cells. It should be noted that the combination of doxorubicin and verapamil has been shown to be associated with severe toxic effects in animals (Sridhar et al, 1992).

Pharmacokinetics

Following intravenous administration, doxorubicin has a rapid plasma clearance (t½ = 10 min) and is highly tissue bound. The terminal half-life is about 30 hours. Doxorubicin is partially metabolised, primarily to doxorubicinol and to a lesser extent to aglycones, and bound to glucuronide and sulfate. Excreted mainly via bile and feces. Approximately 10% of the dose is eliminated by the kidneys. Doxorubicin is about 50-85% bound to plasma proteins. The volume of distribution is 800-3,500 L/m2.

Doxorubicin is not absorbed orally; The drug does not cross the blood-brain barrier.

In patients with impaired liver function clearance of doxorubicin and its metabolites may be reduced.

Indications and uses

Solid tumors, cancers of the hematopoietic system and of the lymphatic system, including:

Acute myeloid and lymphoid leukemia, such as Hodgkin's and non-Hodgkin's lymphoma;

Breast cancer, bladder cancer, tracheal cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, adenocarcinoma thyroid tissue, testicular cancer, liver cancer; neuroblastoma;

Soft tissue connective tissue cancer, Ewing bone cancer Wilms tumor, head and neck cancer, bone marrow pain.

Doxorubicin can be injected directly into the bladder in the case of patients with superficial non-invasive bladder cancer - after laparoscopic resection (TUR) and for the prevention of cancer tissue.

Dosage and Administration

Doxorubicin can be given intravenously, intravenously, intravenously over 48-96 hours, or injected into the bladder. The drug is not allowed to be injected into the intraspinal cavity, intramuscularly, subcutaneously or orally. It is absolutely necessary to avoid injecting from the blood vessels because it can cause thromboembolism and local necrosis.

Prolonged drug infusion should only be indicated in special cases.

Intra-arterial injection achieves very high local drug concentrations. Extensive necrosis may occur in the affected tissue. Because this route of injection is dangerous, it should be considered with caution. Precise handling is required when direct injection (bolus injection) and/or short-term injection. Make sure the needle is in place by testing about 5 ml of standard infusion solution (isotonic saline) prior to infusion. The infusion lock should be clamped above the infusion line, then inject doxorubicin into the infusion line below the buckle to prevent doxorubicin from flowing upstream in the infusion line. Inject the entire amount of doxorubicin solution slowly into the vein (10-20 minutes). Then unlock the infusion line so that the infusion fluid pushes the drug into the vein to avoid the risk of embolism.

In case of injection into the bladder, the drug should be mixed in the urine. To reduce urine output to approximately 50 mL/hour the patient should not drink liquids for 12 hours prior to the procedure. Patients should change position every 15 minutes while the infusion of the drug into the bladder is in progress. Usually the transmission time is 1 hour. The patient should then urinate.

Before removing the drug from the vial and administering the injection, doxorubicin should be stored at room temperature. To dilute the doxorubicin solution, physiological saline should be used.

It is recommended to dissolve 50 ml of doxorubicin with 30-50 ml of physiological saline for bladder drip infusion.

If doxorubicin comes into contact with the skin or mucous membranes, wash the contact area with soap and water immediately.

Dosage

The dose of doxorubicin depends on the respective treatment cycle, the patient's general condition, and the patient's previous treatment. Therefore, the following figures are for guidance only:

Intermittent treatment with a dose of 75 mg/m2 body surface area every 3 weeks as a single dose or divided into several smaller doses injected over 2-3 consecutive days

Intermittent treatment with a dose of 60 mg/m2 body surface area every 3 weeks in patients with age-related decline in bone marrow function or a history of bone marrow failure or neoplasms invading the bone marrow .

Interval therapy of 25 mg/m2 body skin area per day (equivalent to 0.6 mg/kg body weight) for 3 days or 35 mg/m2 body skin area (equivalent to 0.8 mg /kg body weight) within 2 days for the treatment of cancer of the hematopoietic system, the withdrawal period should not be less than 10 days.

In children: 10-20 mg/m2 body skin, once weekly or every 2 weeks, total dose not to exceed 500 mg/m2 body skin.

For patients who cannot receive adequate dose for some reason (age, bone marrow suppression, immunosuppression, relative contraindications) the following cycle of therapy is recommended for monotherapy or multiple therapy).

Long-term infusion of 60 mg/m2 of skin over 48-96 hours.

20 mg/m2 body surface area for 3 consecutive days, once every 3 weeks.

20 mg/m2 body surface area once weekly, as an alternative to treatment with 60 mg/m2 body skin area every 3 weeks.

Because of the potential for adverse cardiac effects, the total cumulative dose should not exceed 500-550 mg/m2 body skin area.

The total dose should be reduced to 400 mg/m2 body skin area in the following cases: the patient has had previous mediastinal irradiation, has previously taken or is taking concomitant cardiotoxic drugs ( such as cyclophosphamide, mitoxantron) or related substances (daunorubicin).

In the case of stomatitis or mucositis, therapy should be continued only when the lesions have healed, with the dose reduced to approximately 50%.

If leukocytes are less than 2,000 and platelets are less than 50,000/mm3, doxorubicin should be discontinued.

In case of liver and kidney dysfunction the dose should be reduced accordingly as follows:

Bilirubin 1.2-3 mg/100 ml: 50% dose

Bilirubin > 3 mg/100 ml: 25% dose

Serum creatinine 1.2-2 mg/100 ml: 50% dose.

Warnings

Patients should recover from acute toxicity of previous cytotoxic therapy (eg, stomatitis, leukopenia, thrombocytopenia, and systemic infections) before initiating doxorubicin therapy. .

Careful monitoring of patients and laboratory results is required during treatment with doxorubicin. Liver and kidney function should be checked before and during treatment.

Blood uric acid levels should be monitored and appropriate treatment measures taken if hyperuricemia occurs.

Appropriate measures should be taken to control possible systemic infections prior to initiation of treatment. Doxorubicin injection should be adhered to according to the principle of safe intravascular injection because intravascular injection can lead to local necrosis and thrombophlebitis.

Clearance of doxorubicin is reduced in obese patients (>130% of ideal body weight).

Toxicity on the heart

The risk of mediastinal/pericardial toxicity may be increased after combination with radiation therapy or prior radiotherapy, or after treatment with other potentially cardiotoxic drugs or with other drugs. in patients with clinical conditions such as anemia, leukaemic pericarditis and/or myocarditis.

Cardiac function should be closely monitored prior to initiation and during treatment to minimize the risk of cardiotoxicity observed with anthracyclines.

Patients with a history of cardiovascular disease and previous anthracycline therapy with high cumulative doses or potentially cardiotoxic drugs are cofactors for the increased risk of cardiotoxicity of doxorubicin.

Cardiotoxicity has an increased risk in children and adolescents, especially late-onset toxicity.

This risk is higher in female patients than in male patients. Cardiac function monitoring is recommended to monitor this toxicity.

The risk/benefit balance of doxorubicin treatment should be weighed in each individual patient before initiating therapy.

Cardiotoxicity can present in two forms:

The early (acute) form is dose-dependent and characterized by nonspecific ECG changes (ST-T wave changes, sinus tachycardia, ventricular and supraventricular extrasystoles). Tachycardia, including premature ventricular contractions and ventricular tachycardia, bradycardia as well as atrioventricular conduction and bundle branch obstruction have also been reported. These symptoms usually do not represent late cardiotoxicity and are often of little clinical significance. Treatment can be continued in most cases.

The late (slow) form is dose-dependent and manifests cumulative organ toxicity with cardiomyopathy. These reactions usually develop late in the doxorubicin period or 2-3 months after stopping treatment. However, this toxicity may be noted even later (months to years after the end of treatment). Common symptoms include left ventricular failure with or with signs of congestive heart failure such as dyspnea, pulmonary edema, enlarged heart and hepatomegaly, oliguria, ascites, pleural effusion, and gallop. Subacute effects such as pericarditis or myocarditis have also been reported. Life-threatening congestive heart failure is the most severe form of anthracylin-induced cardiomyopathy and toxicity is limited by the cumulative dose of the drug.

Because there are no reliable methods to predict acute heart failure due to anthracycline-induced cardiomyopathy, manifested by a sustained decrease in QRS wave potential, prolongation of the systolic interval (PEP/LVEF) worldwide. normal and reduced left ventricular ejection fraction (LVEF) below baseline values ​​before treatment. Electrocardiogram, echocardiogram, MUGA scan before and during treatment and evaluation of left ventricular ejection fraction are required.

Early clinical diagnosis of anthracycline-induced myocardial injury plays an important role in determining the success of subsequent drug therapy. Cardiac glycosides, diuretics combined with salt restriction and rest regimen may be indicated.

The incidence of progressive congestive heart failure was about 1-2% of patients receiving a cumulative dose of 300 mg/m2 that increased slowly to a cumulative total dose of 450-550 mg/m2. At higher doses, the risk of congestive heart failure increases rapidly, so it is not recommended to exceed the maximum cumulative dose of 550 mg/m2.

Risk factors for cardiotoxicity include existing or latent cardiovascular disease, mediastinal or pericardial irradiation before or during chemotherapy, and prior therapy with derivatives. other anthracyclines or anthracendions or used concomitantly with inotropic drugs and age over 70 years. In these cases, the maximum cumulative dose of 400 mg/m2 should not be exceeded. Patients receiving high cumulative doses and patients at risk for cardiac function should be closely monitored. However, doxorubicin can also cause cardiotoxicity at low cumulative doses and even when risk factors are unpredictable.

The toxicity of doxorubicin and other anthracyclines or anthracendions is likely additive.

Marrow failure

Like other cytotoxic drugs, doxorubicin can cause myelosuppression. Hematologic parameters including white blood cell counts should be determined before and during each course of treatment.

Reversible leukopenia and/or dose-dependent neutropenia is the primary manifestation of doxorubicin hematological toxicity and reflects the most common dose-limiting toxicity of this drug.

Leukopenia and neutropenia are usually transient in nature, the most prominent manifestation of which is the maximal leukopenia to the lowest level when using high-dose regimens within 10-14 days after treatment that recovered on the 21st day.

There may also be thrombocytopenia and anemia. Clinical consequences of severe myelosuppression include fever, infection, infection/sepsis, septic shock, hemorrhage, hypoxia, or necrosis.

The occurrence of myeloid leukemia with or without a pre-leukemic phase has been reported rarely in patients treated with anthracyclines including doxorubicin. Secondary leukemia is more likely to occur when anthracyclines are combined with DNA-damaging antineoplastic agents or radiation therapy, in patients previously treated with high doses of cytotoxic drugs, or if other anthracyclines in very high doses. The latency period for cases of leukemia as above ranges from 1-3 years.

Digestive disorders

Doxorubicin is an emetic. Oral mucositis or stomatitis usually occurs shortly after initiation of treatment and in severe cases may progress to ulceration of the oral mucosa within a few days. Most patients regressed these side effects within the 3rd week of treatment.

Secondary oral cancer

Very rare cases of secondary oral cancer have been reported in patients with long-term (more than one year) exposure to doxorubicin or in patients receiving cumulative doses of doxorubicin >720 mg/m2. Cases of secondary oral cancer were diagnosed either during doxorubicin treatment or within 6 years after the last dose of doxorubicin. Check periodically for signs of mouth ulcers or any other mouth discomfort that may be related to secondary oral cancer.

Skin reactions at the injection site

Venous scleroderma may occur with intravenous infusion or repeated injections in the same vein. Strict adherence to the recommended use of the drug reduces the risk of phlebitis/thrombosis at the injection site.

Extravasation of doxorubicin during intravenous administration can cause local pain, severe tissue damage (blistering, severe cellulitis), necrosis, and thrombophlebitis. Extravasation presents with a stinging or burning sensation around the needle site. If extravasation occurs, the injection or infusion should be stopped immediately. After light aspiration, the catheter should be left in place for a while to remove all medication.

Intravenous infusion of dexrazoxan is recommended no later than 6 hours after extravasation occurs (for dose and other information see the dexrazoxan package insert). In cases where dexrazoxan is contraindicated, it is recommended to apply 99% DMSO over an area twice as large as the affected area (4 drops/10 cm2 of skin), repeated 3 times daily for 14 days. If necessary, consider excision of the lesion. It is recommended to cool the skin area for pain relief after DMSO (due to the antagonistic mechanism of vasoconstriction and vasodilation). Other therapeutic measures are currently not uniformly available in the literature and have not been identified.

Liver function

Doxorubicin is eliminated mainly via the biliary tract. Serum total bilirubin should be controlled before and during treatment. Patients with elevated bilirubin typically have decreased clearance and an increased incidence of toxicity. In these cases, the dose of doxorubicin should be reduced. Doxorubicin should not be used in patients with severe hepatic impairment.

Potentially carcinogenic, mutagenic and impaired fertility

Doxorubicin was toxic and mutagenic in in vitro and in vivo assays.

In women, doxorubicin can cause infertility during the treatment period. Doxorubicin can cause amenorrhea. Ovulation and menstruation reappear after the end of treatment, however early menopause may occur.

Doxorubicin is mutagenic and can cause chromosomal damage in human sperm. Reduced or lost sperm can be permanent; however, in some cases sperm counts have returned to normal a few years after stopping the drug. Men treated with doxorubicin should use effective contraception. Men treated with doxorubicin are advised not to father children for 6 months after treatment and to undergo genetic counseling to cryopreservate (or cryopreservate) sperm prior to treatment due to the potential for reversible infertility. may occur as a result of doxorubicin treatment. Women should not become pregnant during treatment and for 6 months after treatment.

Other toxicity

Doxorubicin may increase the toxicity of other anticancer drugs. Hemorrhagic cystitis with cyclophosphamide may be aggravated and the hepatotoxicity of 6-mercaptopurine may also be increased.

Toxic reactions (myocardial, mucosal, skin and liver) to radiation have also been reported. Isolated cases of thrombophlebitis, thromboembolic events including pulmonary embolism (sometimes fatal) have been reported.

Doxorubicin can cause hyperuricemia due to increased purine catabolism accompanied by rapid lysis of cancer cells (tumor lysis syndrome). Blood levels of uric acid, potassium, calcium phosphate and creatinine should be tested after initiation of therapy. Rehydration, alkalinization, and prophylaxis with allopurinol to avoid hyperuricemia may reduce the risk of complications of tumor lysis syndrome.

Additional warnings and cautions with other routes of administration

Injecting medicine into the bladder

Injecting doxorubicin into the bladder can cause symptoms of chemical cystitis (eg, dysuria, polyuria, dysuria, hematuria, bladder discomfort, bladder wall necrosis) and bladder spasms. Particular attention is needed in case of problems with the catheter (obstruction of the urethra caused by tumor invasion in the bladder).

Effects on ability to drive and use machinery

Doxorubicin may impair the ability to drive and use machines, so caution should be exercised if these activities are performed while taking this medicine.

Overdose

Very high doses of doxorubicin can cause myocardial failure including angina pectoris and myocardial infarction within 24 hours, marked myelosuppression (especially leukopenia and thrombocytopenia) within 10-14 days, and systemic toxicity. gastrointestinal (mainly mucositis). If myocardial failure occurs, doxorubicin should be discontinued.

In cases of marked myelosuppression, necessary measures are often applied such as blood transfusion, antibiotic therapy, and transfer of the patient to a sterile room.

Doxorubicin is not removed through dialysis.

There is no specific antibody for doxorubicin.

Chronic toxicity with cumulative doses >550 mg/m2 increases the risk of cardiomyopathies and may lead to heart failure requiring conventional therapeutic measures. Delayed heart failure may appear up to 6 months after overdose.

Contraindications

Hypersensitivity to doxorubicin, anthracyclines or anthracendions or any of the excipients.

Doxorubicin is contraindicated in pregnancy and lactation (See also section Use in pregnancy and lactation).

Contraindications for intravenous infusion

Contraindications to the use of doxorubicin:

In patients with marked myelosuppression (including those with an increased tendency to bleed).

In patients with a history of cardiac disease (unstable angina, progressive heart failure, stage IV heart failure, conduction disturbances and severe arrhythmias, myocardial infarction within the previous 6 months, cardiomyopathy).

In patients with severe liver damage.

Use in pregnant and lactating women

Pregnancy: Doxorubicin should not be used during pregnancy. In general, antineoplastic agents should only be used for very limited indications and the benefit of the drug to the mother should be weighed against the risk of harm to the fetus. In animal studies, doxorubicin has been shown to cause fetal harm, fetal harm and teratogenicity.

Men and women should use effective contraception during and for up to 6 months after treatment.

Lactation: Doxorubicin has been reported to be excreted in human milk. A risk to the nursing infant cannot be excluded. Because of contraindications to the use of doxorubicin during lactation, breastfeeding should be discontinued during doxorubicin therapy.

Fertility: In women, doxorubicin may cause amenorrhea and infertility during treatment. Ovulation and menstruation reappeared after discontinuation of treatment, however early menopause has been reported.

In animal studies, effects of doxorubicin on the male reproductive organs (testicular atrophy, diffuse degeneration of the seminiferous tubules, and hypospermia) were noted. Doxorubicin is mutagenic and can cause chromosomal damage in sperm. Decreased sperm count or loss of sperm may be permanent; however, in some cases, sperm counts have been reported to return to normal levels. This phenomenon may occur several years after the end of treatment.

Interactive

Concomitant use with other antineoplastic agents, such as anthracyclines (daunorubicin, epirubicin, idarubicin), cisplatin, cyclophosphamide, ciclosporin, cytarabin, dacarbazine, dactinomycin, fluorouracil, mitomycin C and taxanes may increase the risk of renal failure. congestive heart failure induced by doxorubicin. The pharmacokinetics of doxorubicin were significantly altered when administered immediately following a short intravenous infusion of paclitaxel. Concomitant use of paclitaxel reduces the clearance of doxorubicin and has been reported to increase the occurrence of leukopenia and stomatitis.

Increased cardiotoxicity has also been reported with concomitant administration of cardioactive drugs such as calcium channel blockers and verapamil (with increased peak concentrations, half-life and volume of distribution of doxorubicin). Cardiac function should be closely monitored when these combination regimens are used.

Using trastuzumab in combination with anthracyclines (such as doxorubicin) increases the risk of cardiotoxicity.

Co-administration of trastuzumab and anthracyclines is not currently recommended except in closely controlled clinical studies with cardiac function monitoring. Patients treated with anthracyclines are at increased risk of cardiotoxicity that persists after discontinuation of other cardiotoxic agents, particularly those with long half-lives such as trastuzumab. The half-life of trastuzumab has been reported to range from 28-38 days and the drug remains in the body for up to 27 weeks. Therefore, physicians should avoid anthracycline treatment until 27 weeks after stopping trastuzumab. In cases where anthracycline use is still prior to this time, close monitoring of cardiac function is recommended.

Doxorubicin is mediated by cytochrome P450 (CYP450) and is a substrate of the Pgp transmembrane transport system. Co-administration of doxorubicin with inhibitors of CYP450 and/or Pgp may increase plasma concentrations of doxorubicin and thereby increase toxicity. Conversely, co-administration of CYP450 inducers such as rifampicin and barbiturates may decrease plasma concentrations of doxorubicin and decrease its efficacy.

Ciclosporin, an inhibitor of CYP3A4 and Pgp, increased the AUC of doxorubicin and doxorubicinol by 55% and 350%, respectively. Therefore, dose adjustment is required when combining these two drugs.

Cimetidine also decreased plasma clearance and increased AUC of doxorubicin.

An increased incidence of hemorrhagic cystitis has been observed if doxorubicin is used after cyclophosphamide administration.

In patients treated with anthracycline drugs (epirubicin, idarubicin, daunorubicin) up to the respective maximum cumulative dose.

Acute infection.

Inflammation of the oral mucosa.

Contraindications for direct intravesical pump

Tumor invades the bladder wall (outside T1).

Urinary tract infections and cystitis.

Blood in urine.

Absorption of antiepileptic drugs (eg, carbamazepine, phenytoin, valproate) is decreased when co-administered with doxorubicin.

Because doxorubicin is rapidly metabolised and eliminated primarily via the biliary tract, concomitant use of chemotherapeutic agents with known hepatotoxicity (eg, mercaptopurine, methotrexate, streptozocin) may increase the toxicity of doxorubicin by reducing the toxicity of doxorubicin. drug clearance in the liver. Doxorubicin dose must be changed if co-administered with hepatotoxic drugs.

Hematopoietic system disorders have been reported following concomitant administration of doxorubicin with drugs affecting bone marrow function (eg, amidopyrin derivatives, antiretrovirals, chloramphenicol, phenytoin, sulphonamides).

An increased incidence of leukopenia and thrombocytopenia has been reported following concomitant administration of progesterone.

Nephrotoxicity of amphotericin B may become apparent during treatment with doxorubicin. Increased serum doxorubicin concentrations have been observed with co-administration of doxorubicin and ritonavir.

The toxicity of doxorubicin may be increased when combined with other antineoplastic agents (eg, cytarabine, cisplatin, cyclophosphamide). Colonic necrosis with massive bleeding and severe infection has been reported in combination with cytarabine.

Clozapine may increase the risk and severity of hematological toxicity of doxorubicin.

Doxorubicin is a potent radiosensitizer, so that reoccurrence associated with drug exposure can be life-threatening.

Radiation therapy before, concurrently, or after treatment with doxorubicin may increase the cardiotoxicity and hepatotoxicity of the drug.

Doxorubicin may precipitate hemorrhagic cystitis caused by previous treatment with cyclophosphamide.

Doxorubicin may decrease the oral bioavailability of digoxin.

Treatment with doxorubicin may increase serum uric acid; Therefore, dose adjustment of uric acid-lowering drugs may be necessary.

Live vaccines should not be used while patients are being treated with doxorubicin because of the risk of systemic illness that can lead to death. The risk is increased for patients who are immunocompromised due to the patient's underlying illness. Patients on treatment with doxorubicin should avoid contact with people who have recently received a polio vaccine.

Concomitant use of heparin and doxorubicin may increase the clearance of doxorubicin. Furthermore, precipitates may be formed that lead to inactivation of both drugs.

Adverse Effects (ADRs)

The following adverse reactions have been reported with doxorubicin and are listed below by MedDRA system organ class and frequency. To assess adverse effects, the following frequency conventions will be used:

Very popular: 1/10

Common: 1/100 to <1/10

Uncommon: 1/1,000 to <1/100

Rare: 1/10,000 to <1/1,000

Very rare: <1/10,000

Unknown: not estimated from available data.

Infections and parasitic infections

Very common: Infection. Common: Infection/sepsis. Uncommon: septic shock.

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

Uncommon: Acute lymphocytic leukemia, acute myeloid leukemia.

Blood and lymphatic system disorders

Very common: Myelosuppression, leukopenia, neutropenia, anemia, thrombocytopenia, tissue hypoxia or necrosis, febrile neutropenia. Uncommon: Secondary myeloid leukemia.

Immune system disorder

Rare: Angioedema of the eyes, lips and tongue with respiratory failure. Very rare: Anaphylaxis. Not known: Anaphylactic reaction.

Metabolic and nutritional disorders

Very common: Anorexia. Common: Dehydration. Very rare: Hyperuricemia. Not known: Tumor lysis syndrome.

Visual disturbances

Common: Conjunctivitis. Not known: Keratitis, lacrimation.

Disorders on the heart

Common: Cardiotoxicity, such as cardiomyopathy, sinus tachycardia, tachyarrhythmias, bradycardia, congestive heart failure. Very rare: atrioventricular block, bundle-branch block.

Vascular disorder

Very common: Thrombophlebitis. Common: Phlebitis, hemorrhage. Uncommon: Thrombosis. Very rare: Shock. Unknown: Hot flashes.

Respiratory, thoracic and mediastinal disorders

Rare: Respiratory depression, swelling of the nasal mucosa, tachypnea, dyspnea, radiation pneumonia.

Digestive disorders

Very common: Nausea/vomiting, stomatitis/mucositis, diarrhea. Common: Esophagitis, abdominal pain or burning sensation. Uncommon: Gastrointestinal bleeding, colitis, erosive gastritis, necrotizing colitis, sometimes serious infections in case of concomitant use of doxorubicin and cytarabine. Very rare: Ulcers, discolouration of oral mucosa.

Hepatobiliary disorders

Not known: Hepatotoxicity, transient elevation of liver enzymes.

Skin and subcutaneous tissue disorders

Very common: Local toxicity, nail peeling, rash, erythema, photosensitivity, alopecia. Common: Pruritus, sensitization of the irradiated area (“relapse syndrome”), skin and nail hyperpigmentation, urticaria. Very rare: Erythema acral. Not known: Palmar-feet sensory syndrome.

Musculoskeletal and connective tissue disorders

Very rare: Generalized myasthenia gravis. Not known: Joint pain.

Urinary disorders

Common: after injection into the bladder: cystitis with dysuria, dysuria, hematuria, polyuria, nocturia, burning urine, necrosis, bladder spasm. Not known: Red urine color change 1-2 days after taking the drug, acute renal failure.

Reproductive system and mammary gland disorders

Very rare: Amenorrhea, decreased sperm count, loss of sperm.

General disorders and at the injection position

Very common: Fever, weakness, chills. Common: Reactions at the infusion site. Very rare: Fatigue/Weakness. Not known: Venous sclerosis.

Tests

Very common: asymptomatic decrease in LVEF, abnormal electrocardiogram, abnormal transaminase value levels, weight gaina.

aIn women with early breast cancer receiving adjuvant doxorubicin (NSABP Study B-15).

Side effects reported with doxorubicin treatment are usually reversible.

Experience after bringing the drug to market

Benign, malignant and non-specific tumors (including cysts and polyps)

Very rare: Secondary oral tumor.

Preservation

Store at 2-8°C and protect from light. Do not freeze.

Stability after dilution is 28 days if refrigerated and 4 days at room temperature.

Presentation and packaging

Concentrated solution for infusion: box of 1 vial of 5mL, box of 1 vial of 25mL.