Doxorubicin 10 Mg/5 Ml/50 Mg/25 Ml Solution

DOXORUBICIN FRESENIUS is indicated in:

• Acute leukaemias (Acute Lymphoblastic Leukaemia u2013 ALL and Acute Myelogenous Leukaemia u2013 AML), lymphomas and a number of solid tumours.
• Metastatic adenocarcinoma of the breast, carcinoma of the bladder, bronchogenic carcinoma and neuroblastoma.
• Metastatic thyroid carcinoma. Carcinoma of the endometrium, testes, prostate, cervix, head and neck and plasma-cell myeloma.
• It is active against carcinoma of the ovary when administered with cisplatin and cyclophosphamide.
• Concurrently with other cytotoxic medicines when administered for carcinoma of the breast and small (oat)-cell carcinoma of the lung.
• Wide range of sarcomas, including osteogenic, Ewingu2019s and soft-tissue sarcoma.
• In the ABVD (doxorubicin / bleomycin / vinblastine / dacarbazine) combination it is effective in Hodgkinu2019s disease.
• Concurrently in the BACOP combination in non-Hodgkinu2019s lymphoma.

Posology

Treatment of solid tumours: When doxorubicin is administered as monotherapy, the recommended dose per cycle is 60 - 90 mg/m2 of body surface area every 3 - 4 weeks. Administration of doxorubicin in a weekly regimen of 10 - 20 mg/m2 has also been shown to be effective. The medicine is generally given as a single dose per cycle; however, it is possible to give the medicine dosage per cycle in divided administrations:

• 0,6 mg/kg/day for 3 days (25 mg/m2 for 3 days) OR
• 0,8 mg/kg/day for 2 days (30 mg/m2 for 2 days) OR
• 1,6 mg/kg/day for 1 day (60 mg/m2 for 1 day).

If DOXORUBICIN FRESENIUS is used in combination with other antitumour medicines, the recommended dose per cycle is in the 30 - 60 mg/m2 range, repeated every 21 days. As doxorubicin is a myelosuppressive substance, the interval between cycles may need to be increased, or the dosage reduced in patients whose white blood cell (WBC) counts (particularly neutrophils) are below the range of normal values before any treatment cycle.

Treatment of acute leukaemias: In acute leukaemia the dosage schedule is based on the patientu2019s response. The recommended starting dose is 0,4 - 0,5 mg/kg/day for 3 days. According to the anti-leukaemia and myelosuppressive effect obtained, this course can be repeated a second or even a third time with an interval between courses of not less than 7 - 10 days.

Special populations: Dosage may also need to be reduced in children, in the elderly, obese patients and in pre-treated patients in whom the marrow reserve may be low. Hepatic dysfunction: In the presence of impaired hepatic function, it is suggested that doxorubicin dosage be reduced as follows:

DOXORUBICIN FRESENIUS should not be administered to patients with severe hepatic impairment (see section 4.3).

Method of administration: Precaution to be taken before manipulating or administering the product. See section 6.6 for instructions for preparation and handling. DOXORUBICIN FRESENIUS is administered by intravenous injection. DOXORUBICIN FRESENIUS should not be given orally, intramuscularly or subcutaneously. Intravenous administration: Intravenous administration of DOXORUBICIN FRESENIUS should be performed with caution (see section 6.6). It is recommended that the diluted solution of DOXORUBICIN FRESENIUS be administered into the tubing of a freely flowing intravenous infusion (isotonic sodium chloride or 5 % glucose solution) over a period of 3 to 5 minutes. This technique is intended to minimise the risk of thrombosis or perivenous extravasation.

• Hypersensitivity to doxorubicin or any other component of DOXORUBICIN FRESENIUS (listed in section 6.1).
• Hypersensitivity to other anthracyclines or anthracenediones.
• Persistent myelosuppression
• Hepatic impairment
• Myocardial insufficiency
• Recent myocardial infarction
• Severe dysrhythmias
• Previous treatment with maximum cumulative doses of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones (see section 4.4).
• Pregnancy and/or lactation (see section 4.6).

DOXORUBICIN FRESENIUS should be administered only under the supervision of a doctor experienced in cancer chemotherapy. Patients should recover from the acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia and generalised infections) before beginning treatment with DOXORUBICIN FRESENIUS. DOXORUBICIN FRESENIUS is incompatible with heparin and should also not be mixed with other medicines (see section 6.2). DOXORUBICIN FRESENIUS should be given with great care, in reduced doses, to elderly patients and those with hepatic impairment. The systemic clearance of DOXORUBICIN FRESENIUS is reduced in obese patients (i.e. > 130 % ideal body weight) (see section 4.2).

Control of the left ventricular function: Analysis of left ventricular ejection fraction (LVEF) using ultrasound or heart scintigraphy should be performed in order to optimise the heart condition of the patient. This control should be made prior to the start of the treatment and after each accumulated dose of approximately 100 mg/m2.

Cardiac function: Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e. acute) or late (i.e. delayed) events. Early (i.e. acute) events: Early cardiotoxicity of doxorubicin consists mainly of sinus tachycardia and/or ECG abnormalities such as non-specific ST-T wave changes. Tachydysrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity and are generally not a consideration for discontinuation of DOXORUBICIN FRESENIUS treatment. Flattening and widening of the QRS-complex beyond normal limits may indicate doxorubicin hydrochloride-induced cardiomyopathy. As a rule, in patients with a normal LVEF baseline value (= 50 %), a 10 % decrease of absolute value or dropping below the 50 % threshold indicates cardiac dysfunction and in such situation treatment with DOXORUBICIN FRESENIUS should be carefully considered.

Late (i.e. delayed) events: Delayed cardiotoxicity usually develops late in the course of therapy with DOXORUBICIN FRESENIUS or within 2 to 3 months after treatment termination, but later events, several months to years after completion of treatment, have also been reported. Delayed cardiomyopathy is manifested by reduced LVEF and/or signs and symptoms of congestive heart failure (CHF) such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion and gallop rhythm. Subacute effects such as pericarditis/myocarditis have also been reported. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the medicine. Cardiac function should be assessed before patients undergo treatment with DOXORUBICIN FRESENIUS and should be monitored throughout therapy to minimise the risk of incurring severe cardiac impairment. The risk may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of DOXORUBICIN FRESENIUS at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up. If the patient has other potential risk factors of cardiotoxicity (history of cardiovascular disease, previous therapy with other anthracyclines or anthracenediones, prior or concomitant radiotherapy to the mediastinal/pericardial area, and concomitant use of medicines with the ability to suppress cardiac contractility, including cyclophosphamide and 5-fluoruracil), cardiotoxicity with DOXORUBICIN FRESENIUS may occur at lower cumulative doses and cardiac function should be carefully monitored. Children and adolescents are at an increased risk for developing delayed cardiotoxicity following DOXORUBICIN FRESENIUS administration. Females may be at greater risk than males. Follow-up cardiac evaluations are recommended periodically to monitor for this effect. It is probable that the toxicity of doxorubicin and other anthracyclines or anthracenediones is additive. To reduce the effects of cardiotoxicity the total cumulative dose of doxorubicin should not exceed 500 mg/m2 body surface area.

Haematologic toxicity: Blood counts and measurement of haemoglobin concentration should be carried out routinely. DOXORUBICIN FRESENIUS may produce myelosuppression (see section 4.8). Haematologic profiles should be assessed before and during each cycle of therapy with doxorubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leucopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of doxorubicin haematologic toxicity and is the most common acute dose-limiting toxicity of DOXORUBICIN FRESENIUS. Leukopenia and neutropenia generally reach the nadir between days 10 and 14 after medicine administration; the WBC/neutrophil counts return to normal values in most cases by day 21. Thrombocytopenia and anaemia may also occur. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia or death.

Secondary leukaemia: Secondary acute myeloid leukaemia with or without a preleukaemic phase, has been reported in patients concurrently treated with DOXORUBICIN FRESENIUS in combination with other DNA-damaging antineoplastic medicines. These leukaemias can have a 1 to 3 year latency period.

Fertility impairment: DOXORUBICIN FRESENIUS can have genotoxic effects. Doxorubicin may cause infertility during the time of medicine administration. In women, doxorubicin may cause amenorrhea. Although ovulation and menstruation appear to return after termination of therapy, premature menopause can occur. Women should not become pregnant during and up to 6 months after treatment. Doxorubicin is mutagenic and can induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia may be permanent; however, sperm counts have been reported to return to normospermic levels in some instances. This may occur several years after the end of therapy. Men undergoing doxorubicin treatment should use effective contraceptive measures. Also are advised not to father a child during and up to 6 months after treatment and to seek advice on cryo-conservation (or cryo-preservation) of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with doxorubicin.

Gastrointestinal: Doxorubicin is emetogenic. Mucositis/stomatitis generally appears early after medicine administration and, if severe, may progress over a few days to mucosal ulcerations. Most patients recover from this adverse event by the third week of therapy. An antiemetic prophylaxis is recommended. DOXORUBICIN FRESENIUS should not be used in the presence of inflammation, ulceration or diarrhoea.

Liver function: Before starting the treatment, it is recommended to measure the liver function by using conventional tests such as AST, ALT, ALP and bilirubin as well as the renal function. The major route of elimination of doxorubicin is the hepatobiliary system. Serum total bilirubin should be evaluated before and during treatment with DOXORUBICIN FRESENIUS. Patients with elevated bilirubin may experience slower clearance of medicine with an increase in overall toxicity. Lower doses are recommended in these patients (see section 4.2). Patients with severe hepatic impairment should not receive DOXORUBICIN FRESENIUS (see section 4.3).

Effects at site of injection: Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimise the risk of phlebitis/thrombophlebitis at the injection site (see section 4.2 and 6.6).

Extravasation: Extravasation of doxorubicin during intravenous injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of DOXORUBICIN FRESENIUS, the infusion should be stopped immediately; the needle should be left in place for a short time and then be removed after short aspiration. If extravasation is suspected or occurs, the injection should be discontinued and restarted in a different blood vessel. Cooling the area for 24 hours can reduce the discomfort. The patient should be carefully monitored for several weeks. Surgical measures might be necessary.

Radiotherapy: Radiation-induced toxicities (myocardium, mucosa, skin and liver) have also been reported. Special caution is mandatory for patients who have had radiotherapy previously, are having radiotherapy concurrently or are planning to have radiotherapy. These patients are at special risk of local reactions in the radiation field (recall phenomenon) if DOXORUBICIN FRESENIUS is used. Severe, sometimes fatal, hepatotoxicity (liver damage) has been reported in this connection. Prior radiation to the mediastinum increases the cardiotoxicity of doxorubicin. The cumulative dose of 400 mg/m2 must not be exceeded especially in this case.

Anticancer therapies: DOXORUBICIN FRESENIUS may potentiate the toxicity of other anticancer therapies (see section 4.5). Exacerbation of cyclophosphamide-induced haemorrhagic cystitis and enhanced hepatotoxicity of 6-mercaptopurine have been reported, as with other cytotoxic medicines, thrombophlebitis and thromboembolic phenomena including pulmonary embolism (in some cases fatal) have been coincidentally reported with the use of doxorubicin (see section 4.8).

Vaccines: DOXORUBICIN FRESENIUS is not recommended in combination with live, attenuated vaccines. Contact to persons recently vaccinated against polio should be avoided. Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic medicines including DOXORUBICIN FRESENIUS, may result in serious or fatal infections. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Tumour lysis syndrome: DOXORUBICIN FRESENIUS may induce hyperuricaemia as a consequence of the extensive purine catabolism that accompanies medicine-induced rapid lysis of neoplastic cells (tumour lysis syndrome) (see section 4.8). Blood uric acid levels, potassium, calcium phosphate and creatinine should be evaluated after initial treatment. Hydration, urine alkalinisation, and prophylaxis with allopurinol to prevent hyperuricaemia may minimise potential complications of tumour lysis syndrome.

Other: DOXORUBICIN FRESENIUS may impart a red colour to the urine. Patients should be cautioned that this does not pose any health hazards. Dosage should not be repeated in the presence or development of bone marrow depression or buccal ulceration. The latter may be preceded by premonitory buccal burning sensations and repetition in the presence of this symptom is not advised.

DOXORUBICIN FRESENIUS contains 0,15 mmol (3,5 mg) sodium per mL. This should be taken into account by patients on a controlled sodium diet.

DOXORUBICIN FRESENIUS is mainly used in combination with other cytotoxic medicines. Additive toxicity may occur, especially bone marrow/haematologic and gastrointestinal effects (see section 4.4). The use of DOXORUBICIN FRESENIUS in combination chemotherapy with other potentially cardiotoxic medicines, as well as the concomitant use of other cardioactive compounds (e.g. calcium channel blockers), requires monitoring of cardiac function throughout treatment. The use of trastuzumab in combination with anthracyclines (such as DOXORUBICIN FRESENIUS) is associated with a high cardiotoxic risk. Trastuzumab and anthracyclines should not be used in combination for the time being, except in well controlled clinical studies where the cardiac function is monitored. When anthracyclines are used after the end of a therapy with trastuzumab, an elevated risk of cardiotoxicity may result. The half-life of trastuzumab is approximately 28 - 38 days and may persist in the circulation for up to 27 weeks. If possible, there should be a sufficiently long interval (up to 27 weeks) between the end of a therapy with trastuzumab and the beginning of the anthracycline (DOXORUBICIN FRESENIUS) therapy. Careful monitoring of the cardiac function is imperative. Changes in hepatic function induced by concomitant therapies may affect doxorubicin metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity.

DOXORUBICIN hepatotoxicity may be enhanced by other hepatotoxic treatment modalities (e.g. 6-mercaptopurine). Doxorubicin undergoes metabolism via cytochrome P450 (CYP450) and is a substrate for the Pgp transporter. Concomitant administration of inhibitors of CYP450 and/or Pgp might lead to increased plasma concentrations of doxorubicin and thereby increased toxicity. Conversely, concomitant administration of inducers of CYP450, such as rifampicin and barbiturates, might decrease plasma concentrations of doxorubicin and reduce efficacy. Concomitant administration of phenytoin may result in lower plasma phenytoin levels. Paclitaxel administered shortly before doxorubicin may decrease clearance and increase plasma concentrations of doxorubicin. Some data indicate that this interaction is less pronounced when doxorubicin is administered before paclitaxel. Ciclosporin, an inhibitor of CYP3A4 and Pgp, increased the AUC of doxorubicin and doxorubicinol by 55 % and 350 %, respectively. The combination might require dose adjustment. Cimetidine has also been shown to reduce the plasma clearance and increase the AUC of doxorubicin. As doxorubicin is rapidly metabolised and predominantly eliminated by the biliary system, the concomitant administration of known hepatotoxic chemotherapeutic medicines (e.g. mercaptopurine, methotrexate, streptozocin) could potentially increase the toxicity of doxorubicin as a result of reduced hepatic clearance of the medicines. Dosing of DOXORUBICIN FRESENIUS must be modified if concomitant therapy with hepatotoxic medicines is mandatory.

Marked nephrotoxicity of amphotericin B can occur during DOXORUBICIN FRESENIUS therapy. Elevated serum doxorubicin concentrations were reported after the concomitant administration of doxorubicin and ritonavir. The toxic effects of DOXORUBICIN FRESENIUS therapy may be increased in a combination with other cytostatics (e.g. cytarabine, cisplatin, cyclophosphamide). Necroses of the large intestine with massive haemorrhage and severe infections in connection with combination therapies with cytarabine have been reported. Clozapine may increase the risk and severity of the haematologic toxicity of DOXORUBICIN FRESENIUS. Doxorubicin is a potent, radiosensitising substance (u201cradiosensitizeru201d), and recall phenomena induced by it may be life-threatening. Any preceding, concomitant or subsequent radiation therapy may increase the cardiotoxicity or hepatotoxicity of doxorubicin. If DOXORUBICIN FRESENIUS therapy is followed by administration of cyclophosphamide, an increased rate of haemorrhagic cystitis has been reported. DOXORUBICIN FRESENIUS therapy may lead to increased serum uric acid; therefore, dose adjustment of uric acid lowering medicines may be necessary. DOXORUBICIN FRESENIUS may reduce oral bioavailability of digoxin.

The use of DOXORUBICIN FRESENIUS during pregnancy or lactation is contraindicated. Women of childbearing potential should avoid pregnancy during treatment and 7 months thereafter. Women of childbearing potential must use effective contraception during DOXORUBICIN FRESENIUS therapy. Pregnancy: DOXORUBICIN FRESENIUS crosses the placenta. It can cause foetal harm when administered during pregnancy. Breastfeeding: DOXORUBICIN FRESENIUS is distributed into breastmilk. Mothers should discontinue breastfeeding prior to taking DOXORUBICIN FRESENIUS. Fertility: For safety reasons, men wanting a baby should preserve unexposed sperm prior to treatment with doxorubicin and abstain from fathering a child during and 6 months after therapy (see section 4.4). Male or female patients intending to have a child are advised to seek genetic counselling after treatment with DOXORUBICIN FRESENIUS.

Due to the frequent occurrence of nausea and vomiting, driving cars and operation of machinery should be discouraged.

System organ class/ Frequency Undesirable effect

Infections and infestations: Frequent: sepsis, septicaemia

Neoplasms benign and malignant: Less frequent: secondary acute myeloid leukaemia when in combination with antineoplastic medicines which damage the DNA. (see section 4.4), tumour lysis syndrome Frequency unknown: acute lymphocytic leukaemia and acute myelogenous leukaemia

Blood and lymphatic system disorders: Frequent: bone marrow depression, leukopenia and neutropenia Less frequent: anaemia, thrombocytopenia, bleeding, immunosuppressant effect

Immune system disorders: Less frequent: hypersensitivity reactions, anaphylactic reactions

Metabolism and nutrition disorders: Frequent: anorexia Less frequent: dehydration, uric acid nephropathy. This occurs most commonly during initial treatment of patients with leukaemia or lymphoma as a result of rapid cell breakdown that leads to elevated serum uric acid concentrations.

Nervous system disorders: Less frequent: headache

Eye disorders: Less frequent: conjunctivitis, lachrymation Frequency unknown: keratitis

Cardiac disorders: Frequent: cardiomyopathy (2 %: e.g. decrease of LVEF, dyspnoea) Less frequent: dysrhythmias, congestive heart failure Frequency unknown: asymptomatic reduction in LVEF and congestive heart failure. Cardiotoxicity may be manifested in tachycardia including supraventricular tachycardia and ECG changes. (e.g. sinus tachycardia, tachydysrhythmia, ventricular tachycardia, bradycardia, atrioventricular and bundle-branch block). See section 4.4.

Vascular disorders: Less frequent: hypotension, phlebitis Frequency unknown: thrombophlebitis, thromboembolism, hot flushes, shock

Respiratory, thoracic and mediastinal disorders: Frequency unknown: bronchospasm, radiation pneumonitis

Gastrointestinal disorders: Frequent: nausea, vomiting, mucositis/stomatitis, diarrhoea Less frequent: oesophagitis, abdominal pain, intestinal ulceration and perforation, buccal ulceration Frequency unknown: colitis, hyperpigmentation of oral mucosa

Hepato-biliary disorders: Frequency unknown: hepatotoxicity, transient increase of liver enzymes

Skin and subcutaneous tissue disorders: Frequent: alopecia, facial flushing Less frequent: itching, local hypersensitivity reaction of the field of radiation (recall phenomenon), urticaria, exanthema, local erythematous reactions along the vein which was used for the injection, hyperpigmentation of skin and nails, onycholysis Frequency unknown: tissue hypoxia, acral erythema and plantar-palmar dysaesthesia, photosensitivity

Renal and urinary disorders: Less frequent: urine discolouration, hyperuricaemia, acute renal failure, nephrotoxicity, hyperphosphataemia Frequency unknown: acute renal failure

Reproductive system and breast disorders: Less frequent: amenorrhoea, inhibition of spermatogenesis, gynaecomastia Frequency unknown: azoospermia (see section 4.4)

General disorders and administrative site conditions: Less frequent: fever, malaise, weakness, shivering, dizziness Frequency unknown: thrombophlebitis, streaking of the skin, stinging or burning sensation at the injection site (see section 4.4), asthenia

Investigations: Frequency unknown: ECG abnormalities

Surgical and medical procedures: Frequency unknown: extravasation can lead to severe cellulitis, vesication and local tissue necrosis (see section 4.4)

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Healthcare providers are asked to report any suspected adverse drug reactions to the Holder of the Certificate of Registration at the following email address: [email protected] and to the relevant medicineu2019s regulatory authority in the country where the product is marketed.

Acute overdosage may cause gastrointestinal symptoms, buccal ulceration and bone marrow depression. Should these symptoms occur therapy should be stopped. A cumulative dosage above 500 mg/m2 may cause irreversible cardiac failure. Treatment is supportive and symptomatic.