SUMMARY OF PRODUCT CHARACTERISTICS (SPC)

1.Name of the Medicinal Product: DOXOTIL 2.Qualitative and Quantitative composition in active ingredients: Doxorubicin Hydrochloride 10mg/5ml VIAL, 50mg/25m1 VIAL, 20mg/10ml VIAL, 100mg/50m1 VIAL 3. Dosage form: Solution for injection 4. CLINICAL PARTICULARS Delayed cardiotoxicity mainly develops during therapy with doxorubicin and up to two-three months thereafter, however late events (several months to years after treatment termination) have also been reported. Serious cardiac impairment may be prevented through

4.1 Therapeutic Indications. Doxorubicin has produced significant therapeutic response in a number of solid tumors and haematologic malignancies, and is commonly used in the treatment of the following neoplastic diseases: regular monitoring during treatment (see also Section 4.4). Sub-acute conditions, such as pericarditis and myocarditis, have also been reported. Gastrointestinal toxicity: Mucositis (mainly stomatitis, less often esophagitis) may occur in patientsundergoing doxorubicin

breast cancer lung cancer ovarian cancer transitional cell bladder cancer neuroblastoma Wilm's tumor soft tissue sarcomas osteosarcoma acute lymphocytic - lymphoblastic leukemia acute myelogenous leukemia non-Hodgkin's lymphomas Hodgkin's disease thyroid cancer therapy. Clinical manifestations of mucositis include pain or burning sensation, erythema, erosions-ulcertaions, bleeding and infections. Stomatitis generally appears almost instantly after drug administration and, if severe, may progress within a few days to mucosal

4.2 Posology and method of administration: Doxorubicin is a cytotoxic agent that is usually administered to cancer patients by intravenous injection and, when deemed advisable, by the intravesical or intra-arterial route. 4.2.1 Intravenous administration Dosage is usually calculated ulcerations; however, most patients recover from this adverse eect by the third week of therapy. Nausea, vomiting and, occasionally, diarrhea and abdominal pain may also occur. Severe vomiting and diarrhea may cause dehydration. Nausea and vomiting may be prevented

on the basis of body surface area (mg/m). The doxorubicin dosage schedule to be delivered may dier depending on the therapeutic indication (e.g. solid tumors or acute leukemias) as well as on its use within a specific regimen (e.g. as a single agent or in combination with other cytotoxic or alleviated by the administration of suitable antiemetic therapy. The doxorubicin-cytarabine combination has resulted in bleeding, ulceration and necrosis of the colon mucosa in patients with acute myelogenous leukemia. Skin Reactions and Hypersensitivity Reactions:

agents or as part of a multidisciplinary approach which includes combination with surgery and/or radiotherapy and/or hormone therapy). Intravenous administration of doxorubicin must be done with caution. It is recommended that doxorubicin be slowly administered into the tubing Alopecia, including the interruption of beard growth, occurs frequently. This adverse event is usually reversible and re-growth of all hair occurs within two-three months after termination of therapy. Flushes, skin and nail hyperpigmentation and hypersensitivity

of a freely running intravenous infusion (isotonic sodium chlorine or 5% glucose solution) over a period of 3 to 5 minutes. The purpose is to minimize the risk of thrombosis or perivenous extravasation that could lead to severe cellulites, vesication and tissue necrosis. A direct push injection to irradiated skin (radiation recall reaction) may also occur. Urticaria and anaphylaxis have been reported in patients treated with doxorubicin. Signs/symptoms of these reactions may vary from skin rash and pruritus to fever, chills and shock. The "hand-foot-syndrome"

is not recommended due to the risk of extravasation that may occur even in the presence of adequate blood return on needle aspiration.Treatment of solid tumors When doxorubicin is used as a single agent, the recommended dose per treatment cycle is 60-75 (palmar-plantar erythrodysestesia or acral erythema) has also been reported. Eects at the Injection Site: Erythematous streaking along the infused vein is not uncommon and may precede local phlebitis or thrombophlebitis. The risk of phlebitis/thrombophlebitis at the

mg/m2 of body surface area every three weeks. The drug is usually given in a single dose per cycle. However, the drug dosage per cycle may be given in divided doses (e.g. day 1 through day 3, or days 1 and 8). The administration of doxorubicin in injection site can be minimized by observing the administration procedure recommended in Section 4.4. Phlebosclerosis might also occur, especially if doxorubicin in repeatedly infused into a small vein. In the case of perivenous drug extravasation, local pain, sever

a weekly regimen has been proved to be as eective as the 3-week schedule. The recommended weekly dosage is 10-20mg/m2. This schedule of administration might be associated with reduced toxicity, especially with respect to the heart. When doxorubicin is cellulitis and tissue necrosis occurs (see also Section 4.4). Other Adverse Events: Other adverse events include malaise/fatigue, ocular toxicity (conjunctivitis, lacrimation) and hyperuricemia, which may occur as a consequence of the extensive purine catabolism that

used in combination with other anticancer agents with potentially overlapping toxicities, the recommended dose per cycle, ranges from 30 to 60 mg/m2. Given that doxorubicin is a myelosuppressive agent, the interval between cycles may have to be increased accompanies drug-induced rapid cell kill of highly chemosensitive neoplasms ("tumor lysis syndrome"). Hydration, urine alkalinization and allopurinol administration will help to prevent or minimize the adverse eects of hyperuricemia. Amenorrhea may also occur

or the drug dosage reduced, in the case of patients whose white blood cell counts (especially neutrophils) is below normal before any treatment cycle. Dosage may also need to be reduced in the case of pediatric or geriatric patients and in patients who and doxorubicin treatment may result in azoospermia in the seminal fluid. Administration of doxorubicin by the intravesical route may give rise to chemical cystitis and bladder constriction. 4.9 Overdosage Acute overdosage with doxorubicin results in severe

have already received therapy and their marrow reserve might be low. In the presence of impaired hepatic function, it is recommended to reduce the doxorubicin dosage (see section 4.4).Treatment of acute leukemia In the management of acute leukemia, myelosuppression (mainly leucopenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and acute cardiac alterations. The treatment of acute overdosage consists of hospitalization, intravenous antibiotics, granulocyte and platelet transfusions and

bone marrow aplasia is a therapeutic achievement and intensive combination chemotherapy schedules are applied. In such situations, the recommended doxorubicin dose is 2.4 mg/kg of body weight (corresponding to approximately 75-90 mg/m2 treatment of the gastrointestinal and cardiac toxic manifestations. The use of hematopoietic growth factors may be considered. Chronic overdosage, when total cumulative doses exceed 550 mg/m2, increases the risk of cardiomyopathy and could result in congestive

of body surface area) to be administered in divided doses over three consecutive days (one cycle). The time and dose for the second cycle must be dictated by the condition of both bone marrow and peripheral blood cells. The interval between cycles should be, heart failure (CHF); in such cases, treatment is that for CHF, consisting of digitalis preparations, diuretics, peripheral vasodilators and ACE inhibitors. 5. PHARMACOLOGY ATC Code: LO1DBO1 5.1 PharmacodynamicsEven though it is known that anthracyclines are able to

however, at least 10 days. 4.2.2 Intravesical Administration Doxorubicin administered intravesically can be used for treating superficial bladder tumors or as prophylaxis for reducing the risk of recurrence following transurethral resection. The recommended interfere with a number of biochemical and biological functions within eukaryotic cells, the precise mechanisms of doxorubicin cytotoxic properties have not been elucidated completely. The drug, once penetrated into a cell, mostly binds to chromatin. Experimental

doxorubicin dose for topical intravesical treatment of superficial bladder cancers is 30 to 50 mg in 25 - 50 mL of saline solution per instillation and the optimal concentration is about 1.0 mg/mL. Once instillation has been completed, the patient should be rotated evidence indicates that doxorubicin forms a complex with DNA by intercalation of its planar rings between nucleotide base pairs. The consequences of this intercalation are serious disturbances of DNA synthesis, DNA-dependent RNA synthesis and protein synthesis.

a quarter turn every fifteen minutes; overall, the solution must be retained in the bladder for a time period of 1-2 hours. To avoid undue dilution with urine, patients should be instructed not to drink any fluid in the twelve hours prior to instillation However, the doxorubicin concentrations required to exert the cytotoxic eects through these mechanisms appear to be somewhat greater than those achievable at the tumor site in the clinical setting. More recent experimental evidence seems to indicate that

(this shall limit urine production to approximately 50 mL/hour). Instillations can be repeated at intervals which can vary from one week to one month, depending on whether treatment is therapeutic or prophylactic. The systemic absorption of doxorubicin DNA intercalation triggers DNA cleavage by topoisomerase-II, yielding serious disturbances in the tertiary structure of DNA. This eect is observed with drug concentrations which have been found within the clinically therapeutic range. It is also known that doxorubicin

following intravesical instillation is very low. 4.2.3 Intra-arterial Administration Doxorubicin has also been used by the intra-arterial route in an attempt to produce intense local activitywith reduced general toxicity. Given that this technique is potentially is involved in oxidation/reduction reactions: a number of NADPH-dependent cellular reductases are able to reduce doxorubicin to semiquinone free radicals, which can in turn react with molecular oxygen to generate highly reactive cytotoxic compounds such as superoxide,

hazardous and can lead to widespread tissue necrosis, intra-arterial administration should only be attempted by physicians who are very experienced in this technique. 4.3 Contraindications Situations in which patients should not be treated with intravenous hydroxyl radicals and hydrogen peroxide. The formation of free radicals has been implicated in doxorubicin cardiotoxicity. A further site of action of doxorubicin may be at the cell membrane level: the drug can bind to cell membrane lipids and affect a variety of functions.

doxorubicin include: -persisting myelosuppression or severe stomatitis from previous cytotoxic treatments -Presence of generalized infections -Marked liver function impairment -Severe arrhythmias, myocardial insuciency, previous myocardial infarction Cytotoxic activity of doxorubicin may result as a consequence of any of the mechanisms mentioned or there may be others as well. Cell kinetics studies have shown that doxorubicin is active throughout the cell cycle, including the interphase. Rapidly proliferating tissues

-Prior treatment with anthracyclines up to their maximum cumulative dose - Hypersensitivity to doxorubicin, other anthracyclines or anthracenediones Contraindications for intravesical administration include:-Invasive tumors that have penetrated the bladder wall such as tumor tissues (but also bone marrow, gastrointestinal and oral mucosa, hair follicles) are therefore the most sensitive to the cytotoxic eects of doxorubicin. 5.2 Pharmacokinetics Absorption: Doxorubicin is not absorbed by the gastrointestinal tract.

-Urinary infections-Bladder inflammation -Catheterization problems (e.g. due to massive intravesical tumors) 4.4 Special warnings & precautions for use Treatment with doxorubicin should be carried out only by physicians experienced in chemotherapy and Given that the drug is extremely irritating to tissues, it has to be administered by intravascular routes (intravenous or intra-arterial). Intravesical administration has been shown as feasible; following such administration, drug passage to the systemic circulation is minimal.

must be conducted under strict supervision, with certain body functions being monitored. Complete blood count: This has to be performed with particular attention to total and dierential white blood cell counts. Doxorubicin-induced bone marrow depression, Distribution: Doxorubicin is quickly and widely distributed into the extravascular compartments, as indicated by a rapid (5 to 10 min) initial plasma half-life and by a steady-state distribution volume in excess of 20 to 30 L/kg. However, doxorubicin does

primarily of leucocytes, requires careful hematological monitoring given that persistent severe myelo-suppression may result in superinfections or haemorrhages. At the recommended doses and schedules for the treatment of solid tumors, marked leucopenia not cross the blood-brain barrier in detectable amounts. Binding of doxorubicin to plasma protein is about 75% and is not dependent on plasma concentrations up to 2M. Metabolism: Doxorubicin is metabolized to a significant extent, mainly by the liver.

may occur (1000/mm3 or lower can be expected during treatment with full doses of doxorubicin), however such leucopenia is usually transient, reaching its nadir 10 to 14 days after treatment andwith recovery usually completed by the 21st day.Platelet and The major metabolite of doxorubicin is 13-OH-doxorubicinol, produced by aldo-keto reductases, possessing a certain degree of antitumor activity. Doxorubicin and 13-OH doxorubicinol predominate also in urine and in the bile. Other metabolites present in

erythrocyte levels should also be monitored. Haematologic toxicity may require dose reduction or suspension or delay of doxorubicin therapy. Assessment of liver function: Given that doxorubicin is primarily eliminated via the liver and bile, a delayed elimination detectable amounts in plasma are the aglycones of doxorubicin and 13-OH-doxorubicinol. Excretion: Following intravenous administration, plasma doxorubicin levels follow a multiphasicdecline, with a terminal half-life reported in the 20 to 48 hour range. The terminal

of the drug can occur in the case of reduced liver function or dicult bile outflow and serious secondary adverse eects can develop. Guidelines commonly used for dose reduction under conditions of impaired liver function are based on serum bilirubin half-life of 13-OH-doxorubicinol is similar to that of doxorubicin. Plasma clearance is in the range of 8 to 20 ml/min/kg, and is mainly due to metabolism and biliary excretion. This slow elimination from plasma might be further prolonged in patients with impaired

levels as follows: Serum bilirubin 1.2 - 3.0 mg/100mL 3.1 - 5.0 mg/100mL Dose reduction 50% 75% Assessment of liver function: Given that doxorubicin is primarily eliminated via the liver and bile, a delayed elimination of the drug can occur in the case of reduced liver function. The clearance of doxorubicin occurs to a substantial extent by metabolic conversion to a number of less active or inactive products. 40 to 50% of the administered dosage is recovered in the bile or in the feces in seven days. Renal excretion is minimal,

liver function or dicult bile outflow and serious secondary adverse eects can develop. Guidelines commonly used for dose reduction under conditions of impaired liver function are based on serum bilirubin levels as follows: Serum bilirubin 1.2 - 3.0 mg/100mL accounting for only 5% to 10% of the administered dose in 5 days. 5.3 Preclinical safety data The LD50 of doxorubicin was 21.9 and 12.5 mg/kg for mice and rats, respectively, and about 2.0 mg/kg for dogs. The main targets after a single dose of the drug were the

3.1 - 5.0 mg/100mL Dose reduction 50% 75% Cardiac Function: Cardiotoxicity is a known risk of anthracycline treatment. The most severe and typical form of such toxicity is represented by a delayed cardiomyopathy which occurs with increased frequency with hemolymphopoietic system and, especially in dogs, the gastrointestinal tract. The toxic effects following repeated administration were investigated in rats, rabbits and dogs. The main targets of doxorubicin in the said species were the hemolympopoietic system,

high cumulative doses of the drug and can result in congestive heart failure (CHF). Cardiac function should be assessed before undergoing treatment with doxorubicin and has to be monitored throughout therapy to minimize the risk of incurring severe cardiac the gastro-intestinal tract, the kidneys, the liver and both male and female reproductive organs. With respect to the heart, acute, subacute and cardiotoxicity studies have indicated that doxorubicin was cardiotoxic in all the laboratory animals studied. Doxorubicin was

impairment. Although endomyocardial biopsy is recognized as the most appropriate diagnostic tool to detect anthracycline-induced cardiomyopathy, this invasive examination may not be easily carried out on a routine basis. The routine assessment of cardiac genotoxic in most of the in vitro or in vivo mutagenicity tests performed, toxic to the reproductive organs, embryotoxic in rats and rabbits, and teratogenic in rats. There is no information available on the administration of doxorubicin in animals during the peri- and post-natal

function during doxorubicin treatment may include electrocardiogram (ECG) and the evaluation of the left ventricular ejection fraction (LVEF). ECG changes are generally indicative of a transient toxicity, but a reduction of the QRS voltage, or a prolongation periods. Doxorubicin, like other anthracyclines and many cytotoxic drugs, was carcinogenic in rats. A local safety study in dogs has shown that extravasation of the drug causes tissue necrosis.6. PHARMACEUTICAL PARTICULARS 6.1 List of excipientsSodium Chloride,

beyond normal limits of the systolic time interval may be indicative - as is a decrease of the LVEF - of typical anthracycline-induced cardiomyopathy. The probability of developing CHF, estimated around 1% to 2%, at a cumulative dose of 300 mg/m2, Hydrochloric Acid, Water for Injection.6.2 Incompatibilities Contact with alkaline pH solutions should be avoided since this shall lead to hydrolysis of doxorubicin. Doxorubicin should not be mixed with heparin, cephalothin or sodium dexamethasone phosphate

slowly increases up to the total cumulative dose of 450-550 mg/m2. Above this level, the risk of developing CHF increases steeply, and it is recommended not to exceed the total cumulative dose of 550mg/m2. If any additional risk factor is present given that it has been reported that these drugs are chemically incompatible (formation of a precipitate). Its color changes from red to blue-purple when aminophyllin or 5-fluorouracil, this being a sign of decomposition. Doxorubicin should not be mixed with other cytotoxic

(active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous treatment with other anthracyclines-anthracenediones, concomitant use of other cardiotoxic drugs), cardiac toxicity might occur at lower drugs in the same syringe during the administration of combination chemotherapy regimens. 6.3 Shelf life: as mentioned on the inner and outer box 6.4 Special precautions for storage: Store the injection solution in the refrigerator between 2-8oC 6.5 Nature and contents

cumulative doses (e.g. total cumulative dose of 400 mg/m2 in patients irradiated to the mediastinum). Under these conditions, cardiac function monitoring should be very strict and the risk/benefit ratio for continuing treatment with doxorubicin in impaired of container: Carton box which contains 1 glass vial of 5ml or 10ml 0r 25ml or 50ml.6.6 Use and handling instructions:Intravenous administration: Doxorubicin is normally administered intravenously. The solution must be injected over a period of 3 to 5 minutes through the

cardiac function conditions must be carefully considered. Extravasation: Extravasation of doxorubicin during intravenous injection may result in severe tissue lesions and even necrosis. Venous sclerosis may result from injection into a small vessel or from tubing of a freely running saline intravenous infusion after checking that the needle is properly placed in the vein. This technique is applied in order to minimize the risk of thrombosis and peripheral extravasation of the drug, which may cause severe cellulitis and necrosis and

repeated injections into the same vein. To minimize the risk of drug extravasation and make sure that the vein is properly flushed after drug administration, it is recommended to give the drug via the tubing of a freely running saline infusion after checking ensures flushing of the vein following administration of the drug. Venous sclerosis may result from injection into a small vessel or from repeated injections into the same vein. Topical-area therapy: For intravesical as well as intra-arterial administration, see Section 4.2.

that the needle is properly placed in the vein. If signs or symptoms of exravasation occur during the intravenous administration of doxorubicin, the drug infusion should be immediately terminated. To manage extravasation, the interventions approved by Protective measures: Given the toxic nature of this substance, the following protection guidelines are provided: - Personnel should be trained in the appropriate techniques for drug reconstitution and handling; - Pregnant women should be excluded from work with this drug;

the physician and/or the hospital must be immediately implemented. Doxorubicin may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhanced hepatotoxicity of 6-mercaptopurine have - Personnel coming in contact with doxorubicin should wear protective clothing: special goggles, apron as well as gloves and mask, single use; - A designated area must be established for reconstitution (preferably under the laminar flow system). The surface of the work

been reported. An increase of radiation- induced toxicity (myocardium, mucosa, skin and liver) has also been reported. It has been found that the systemic clearance of doxorubicin is reduced in obese patients; such patients have to be carefully monitored bench must be protected with laminated, absorbent paper, single use; - All items to be used for reconstitution, administration or cleaning, including gloves, must be disposed of in bags intended for hazardous wastes for incineration at high temperatures.

if undergoing treatment with full doses of the drug. Doxorubicin may impart a red color to the urine for one or two days following administration. Patients should be advised that this event is not cause for alarm 4.5 Interactions with other drugs and substances Accidental contact with the skin or the eyes must be treated immediately by copious washing with large amounts of water, or soap and water, or sodium bicarbonate solution; medical attention should then be sought. Any spill or leakage should be immediately treated with

Doxorubicin may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced haemorrhagic cystitis and enhanced hepatotoxicity of 6-mercaptopurine have been reported. An increase of radiation-induced toxicity dilute sodium hypochlorite (1% available chlorine), preferably by absorption and then flushing with water. Following use, all cleaning items must be incinerated as above described. 6.7. Marketing Authorisation Holder GENEPHARM S.A., 18 km Marathon Av. 15351 Pallini,

(myocardium, mucosa, skin and liver) has also been reported. Doxorubicin is mainly used in combination with other cytotoxic drugs and additive toxicity may occur especially with regard to bone marrow/hemato logical and gastro-intestinal eects. Attiki- Greece 7. MARKETING AUTHORISATION NUMBER Doxotil 10mg/5ml: 42331/11/30-05-2012, Doxotil 20mg/10ml: 42332/11/30-05-2012 Doxotil 50mg/25ml: 42333/11/30-05-2012, Doxotil 100mg/50ml: 42334/11/30-05-2012 8. DATE OF FIRST MARKETING:

Furthermore, concomitant use of doxorubicin with other anticancer drugs that have been reported as potentially cardiotoxic (e.g. 5-fluorouracil, cyclophosphamide, cisplatin, taxanes), as well as the concomitant use of other cardioactive compounds Doxotil 10mg/5ml: 80347/19-12-2006, Doxotil 20mg/10ml: 80348/19-12-2006 Doxotil 50mg/25ml: 80349/19-12-2006, Doxotil 100mg/50ml: 80350/19-12-2006 9. DATE OF TEXT REVISION: December 2012

(e.g. calcium channel blockers) requires close monitoring of cardiac function throughout treatment. Doxorubicin is extensively metabolized by the liver. Changes in liver function induced by concomitant therapies may aect doxorubicin metabolism,
pharmacokinetics, therapeutic ecacy and/or toxicity. The doxorubicin-cytarabine combination has caused hemorrhage, ulceration and necrosis of colon mucosa in patients with acute myelogenous leukemia.4.6 Use during pregnancy and lactation
The safe use of doxorubicin in pregnancy has not been established. Doxorubicin is embryotoxic and teratogenic in rats. It is embryotoxic and may induce abortion in rabbits. Women of child-bearing potential who are to undergo doxorubicin therapy should be informed
of the potential risk to the fetus and should be urged to avoid becoming pregnant during treatment. If doxorubicin has to be used during pregnancy, the potential benefits of the treatment must be weighed carefully against possible risks to the fetus. Given the mutageni

IMPORTANT THERAPEUTIC
c potential of doxorubicin, the drug could induce chromosomal damage in human spermatozoa - therefore, men but also women undergoing treatment should employ contraceptive measures. Doxorubicin is excreted into breast milk; therefore women undergoing
doxorubicin treatment should not breast-feed due to the potential for serious harm to nursing infants. 4.7 Eects on the ability to driving and to operate machinery No particular adverse events relating to eects of doxorubicin treatment on the ability to drive or operate
machinery have been reported. 4.8 Adverse eects Bone marrow/Hematological Toxicity: A dose-dependent, reversible leucopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of doxorubicin bone marrow/hematological toxicity and represents
the acute dose-limiting toxicity of this drug. During the most commonly used 3-4 week administration schedule, the nadir of leucocytes/granulocytes is generally reached 10 to 14 days after drug administration. In patients with normal bone marrow regeneration capacity,

RESPONSE
white blood cell counts usually recover by the end of the third week. If sever myelosuppression occurs, bone marrow support may be used (e.g. peripheral blood progenitor cells or growth factors). Thrombocytopenia and anemia may also occur. The clinical consequences
of doxorubicin bone marrow/hematological toxicity may include fever, infections, sepsis/ septicemia, septic shock, hemorrhages, tissue hypoxia or death. Intravenous antibiotics should be given if febrile neutropenia occurs. The occurrence of secondary acute myelogenous
leukemia, with or without a pre-leukemic phase, has been reported rarely in patients treated concurrently with doxorubicin in combination with DNA-damaging antineoplastic agents. These leukemias can have a short latency period (1-3 years). Cardiac
Toxicity: Anthracycline-induced cardiac toxicity may be manifested by early (acute) or delayed events. The early cardiac toxicity of doxorubicin consists mainly of sinus tachycardia and/or ECG abnormalities, e.g. non-specific ST-T wave changes, however,
tachyarrhythmias such as premature ventricular contractions, ventricular tachycardia, bradycardia as well as atrioventricular and bundle-branch block have also been reported. With the exception of malignant cardiac dysrhythmias, these eects are usually not predictive
of subsequent development of delayed cardiotoxicity, they are rarely of clinical importance and generally they are not considered an indication for the suspension of doxorubicin treatment. Delayed cardiac toxicity is represented by a characteristic cardiomyopathy which is
manifested clinically by symptoms/signs of ventricular dysfunction/congestive heart failure (such as dyspnea, pulmonary edema, dependent edema (e.g. at the ankle), hepatomegaly, ascites, pleural eusion, gallop rhythm). This toxicity appears to be dependent on the
cumulative dose of doxorubicin and represents the cumulative dose-limiting toxicity of the drug. A number of studies have assessed that the risk of developing CHF increases steeply, in absence of other cardiac risk factors, after having reached a doxorubicin cumulative
dose of 550 mg/m2. If any additional risk factor for cardiac toxicity is present(active or dormant cardiovascular disease, previous mediastinal radiotherapy, previous/concomitant use of other cardiotoxic drugs), cardiac toxicity might occur at lower cumulative doses.
 Documented efficacy in The administration every three Significant therapeutic response for recession
a wide range of indications weeks is more effective. of the following neoplastic diseases (1, SPC).

Doxorubicin is widely used in chemotherapy due to its efficacy The administration of 60mg/m2 Doxorubicin every 3 weeks is more effective
breast cancer osteosarcoma
in fighting a wide range of cancers such as: than 15mg/m2 weekly in patients with
lung cancer acute lymphocytic -
carcinomas, sarcomas and hematological cancers medullary thyroid carcinoma
lymphoblastic leukemia
(% ) ovarian cancer
100
acute myelogenous leukemia
90
transitional cell bladder cancer
80
non-Hodgkin's lymphomas
Effective combination with
70
60
neuroblastoma
numerous other antineoplastic drugs 50 Hodgkin's disease
40 Wilm's tumor
30 thyroid cancer
20 soft tissue sarcomas

The combination of doxorubicin 60mg/m2 followed by trabectedin1.1mg/m2 every 100
90
10
80 0
21days is safe and active in patients with soft-tissue sarcoma. 70
60mg/m2 15mg/m2
60
50
every 3 weeks (n=4) weekly (n=5)
40

Packaging
30
20

Proven safety (7)

10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
solution for injection 10mg/5ml

Doxo 01/03-2013/1.000
- all treatments
o Censored observations - all treatments
100 100
o Censored observations solution for injection 50mg/25ml
Doxorubicin
90 90
80 80
70 70
was well-tolerated by most patients. None of the patients
Patients%

Patients%

60 60

50
40
50
40
developed a doxorubicin-induced cardiomyopathy.(7)
30 30

20 20

10
0
10
0
Hair loss 42%
Nausea 23%
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

number of months from first treatment date number of months from first treatment date
100
Respiratory infection 10%
90
80
pneumonia 7%
70
Kaplan-Meier curve for Progression-free survival B Kaplan-Meier curve for Overall
60
for all treatment groups. Survival for all treatment groups. References
50
40
1. Product S.P.C. 2. C. Carvalho et all:.Current Medicinal Chemistry, 2009,16,3267-3285. 3. J.Edmonson et all:. Gynecologic Ongology 85, 507- 510(2002).
4. A.Musolino et all:.CANCER 2011;117:964-973.
30
5. S.Kupeli & S.Bilisi J.Pediatr. Hematol. Ongology 2012;34: e 106-e109.6. J.Blay et all:.Clin. Cancer Rew. 2008:14(20) October 15,2008.
7. Matuszczyk et all:.Horm. Metab. Res. 2008;40:210-213.8. H.A. Azim
20 et all:.Annals of Oncology 21:1064-1071,2010
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28