Doxopeg 2 mg Liposomal infusion.

Breast cancer: DOXOPEG is indicated as monotherapy for patients with metastatic breast cancer, where there is an increased cardiac risk. Ovarian cancer: DOXOPEG is indicated for the treatment of advanced ovarian cancer in women where a first line platinum-based chemotherapy regimen has failed. Multiple myeloma: DOXOPEG is indicated in combination with bortezomib, for the treatment of progressive multiple myeloma, in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplant. AIDS-related Kaposi sarcoma (KS): DOXOPEG is indicated for AIDS-related Kaposiu2019s sarcoma (KS) in patients with low CD 4 counts (< 200 CD 4 lymphocytes per mm 3 ) and extensive mucocutaneous or visceral disease.

Posology DOXOPEG must not be given by intramuscular or subcutaneous route. DOXOPEG should only be administered under the supervision of a qualified oncologist specialised in the administration of cytotoxic agents. DOXOPEG exhibits unique pharmacokinetic properties and should not be used interchangeably with other formulations of doxorubicin hydrochloride (see section 4.4). Treatment of breast cancer or ovarian cancer: DOXOPEG is administered intravenously at a dose of 50 mg/m 2 once every four weeks, for as long as the disease does not progress and the patient continues to tolerate treatment. Doses < 90 mg: dilute DOXOPEG in 250 ml dextrose 5 % in water. Doses u2265 90 mg: dilute DOXOPEG in 500 ml dextrose 5 % in water. The initial dose is administered at a rate < 1 mg/minute, in order to minimise the risk of infusion reactions. If no infusion reaction is observed, subsequent DOXOPEG infusions may be administered over a 60-minute period. If an infusion reaction occurs, the method of infusion should be modified as follows: 5 % of the total dose should be infused slowly over the first 15 minutes. If tolerated without a reaction, the infusion rate may then be doubled for the next 15 minutes. If tolerated, the infusion may then be completed over the next hour for a total infusion time of 90 minutes. Treatment of multiple myeloma: DOXOPEG is administered at 30 mg/m 2 on day 4 of the bortezomib 3-week regimen as a 1-hour infusion administered immediately after the bortezomib infusion. The bortezomib regimen consists of 1,3 mg/m 2 on days 1, 4, 8 and 11, every 3 weeks. The dose should be repeated as long as patients respond satisfactorily and tolerate treatment. Doses < 90 mg: dilute DOXOPEG in 250 ml of 5 % (50 mg/ml) glucose solution for infusion. Doses u2265 90 mg: dilute DOXOPEG in 500 ml of 5 % (50 mg/ml) glucose solution for infusion. The intravenous catheter and tubing should be flushed with 5 % glucose solution for infusion between administration of the 2 medicines. Day 4 dosing of both medicines may be delayed up to 48 hours as medically necessary. Doses of bortezomib should be at least 72 hours apart. The first infusion of DOXOPEG should be administered over 90 minutes as follows: u2022 10 ml over the first 10 minutes. u2022 20 ml over the next 10 minutes. u2022 40 ml over the next 10 minutes. u2022 Then complete the infusion over a total of 90 minutes. Subsequent doses of DOXOPEG will be administered over 1 hour, as tolerated. If an infusion reaction to DOXOPEG occurs, stop the infusion. After the symptoms have resolved, attempt to administer remaining DOXOPEG over 90 minutes as follows: u2022 10 ml over the first 10 minutes. u2022 20 ml over the next 10 minutes. u2022 40 ml over the next 10 minutes. u2022 Then complete the infusion over a total of 90 minutes. Infusion may be given through a peripheral vein or a central line. Treatment of AIDS-KS: DOXOPEG should be administered intravenously at 20 mg/m 2 every 2 - 3 weeks. Intervals shorter than 10 days should be avoided, as accumulation of DOXOPEG and increased toxicity cannot be ruled out. Patients should be treated for two to three months, to achieve a therapeutic response. Treatment should be continued as needed to maintain the therapeutic response. DOXOPEG, diluted in 250 ml dextrose 5 % in water, is administered by intravenous infusion over 30 minutes. All patients: If the patient experiences early symptoms or signs of infusion reaction, immediately discontinue the infusion, give appropriate pre-medication (antihistamine and/or short acting corticosteroid) and restart at a slower rate. Do not administer as a bolus injection or undiluted solution. It is recommended that the DOXOPEG infusion line be connected through the side port of an intravenous infusion of dextrose 5 % in water, to achieve further dilution and minimise the risk of thrombosis and extravasations. The infusion may be given through a peripheral vein. DOXOPEG must not be given by the intramuscular or subcutaneous route. Do not use with in-line filters. The dose of DOXOPEG may be reduced or delayed in order to manage adverse events such as palmar-plantar erythrodysaesthesia (PPE), stomatitis or haematological toxicity. Guidelines for DOXOPEG dose modification secondary to these adverse effects are provided in the tables below. The toxicity grading in these tables is based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC).

• Hypersensitivity to doxorubicin hydrochloride, or to any of the excipients (see section 6.1).
• Pregnancy and/or lactation (see section 4.6).
• DOXOPEG should not be used to treat AIDS-related KS that may be treated effectively with local therapy or systemic alpha-interferon.
• The safety and efficacy in patients under the age of 18 years have not been established (see section 4.4).

DOXOPEG should not be given by the intramuscular or subcutaneous route. Myelosuppression: DOXOPEG causes pronounced bone marrow depression, which may be dose limiting. White cell counts reach a nadir 10 to 15 days after a dose and usually recovers by about 21 days. In the presence of bone-marrow depression or ulceration of the mouth, blood counts should be monitored and doses should not be repeated. DOXOPEG should be given with great care in reduced doses to patients with hepatic impairment. Baseline myelosuppression is observed in many patients with AIDS-KS treated with DOXOPEG, due to factors such as their HIV disease, numerous concomitant medicines or tumours involving bone marrow. Myelosuppression appears to be a dose-limiting adverse event in patients with AIDS-KS (see section 4.8). Because of the potential for bone marrow suppression, periodic blood counts should be performed frequently during the course of DOXOPEG therapy, and at a minimum, prior to each dose of DOXOPEG. Superinfection or haemorrhage may be the result of persistent severe myelosuppression. DOXOPEG should not be used interchangeably with other formulations of doxorubicin hydrochloride, although the difference in pharmacokinetic profiles and dosing schedules are known. The efficacy of DOXOPEG combination chemotherapy has not been established in the treatment of ovarian cancer. Cardiac risk: The anthracyclines, such as DOXOPEG, may produce cardiotoxicity, such as electrocardiogram (ECG) abnormalities, dysrhythmias or congestive heart failure, which may be fatal. All patients receiving DOXOPEG should routinely undergo frequent ECG monitoring. Transient ECG changes, such as T-wave flattening, S-T segment depression and benign dysrhythmias, are not considered mandatory indications for the suspension of DOXOPEG therapy. However, reduction of the QRS complex is considered more indicative of cardiotoxicity. In the event of this change, the most definitive test for anthracycline myocardial injury, i.e. endomyocardial biopsy, should be considered. Patients are at increased risk of thromboembolic disease. Thrombophlebitis and venous thrombosis, as well as pulmonary embolism, may occur less frequently. More specific methods for the evaluation and monitoring of cardiac function, as compared to ECG, are measurement of left ventricular ejection fraction by echocardiography or preferably by Multiple Gated Arteriography (MUGA). These methods should be applied routinely before the initiation of DOXOPEG therapy and should be repeated periodically during treatment. The evaluation of the left ventricular function is considered to be mandatory before each additional administration of DOXOPEG which exceeds a cumulative dose of 450 mg/m 2. Whenever cardiomyopathy is suspected, i.e. the left ventricular ejection fraction has decreased relatively as compared to pre-treatment values and/or (at the same time) left ventricular ejection are lower than prognostically relevant value (e.g. < 45 %), endomyocardial biopsies should be performed and the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage. Congestive heart failure (CHF) due to cardiomyopathy may occur suddenly, without prior ECG changes, and may also be encountered several weeks after discontinuation of therapy. The CHF may be irreversible and sometimes fatal. The evaluation tests and methods above, concerning the monitoring of cardiac performance during anthracycline therapy, should be employed in the following order: ECG monitoring, measurement of left ventricular ejection fraction and endomyocardial biopsy. If a test result indicates possible cardiac injury associated with DOXOPEG therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury. Patients with a history of cardiovascular disease should receive DOXOPEG only when the benefit outweighs the risk to the patient. Caution should be exercised in patients with impaired cardiac function who receive DOXOPEG. The most important determinant of cardiotoxicity occurred with total doses greater than 450 to 550 mg/m 2 and may occur months or even years after use. Care should be taken in patients who have received other anthracyclines. The total cumulative dose should be limited and cardiac function should be monitored during treatment. The total cumulative dose of DOXOPEG should also take into account any previous (or concomitant) therapy with cardiotoxic compounds, such as other anthracyclines/anthraquinones or 5-fluorouracil. Cardiotoxicity may also occur at cumulative anthracycline doses lower than 450 mg/m 2 in patients with prior mediastinal irradiation or in patients receiving concurrent cyclophosphamide, trastuzumab or other antineoplastic therapy. CHF has been reported, even with doses of 240 to 300 mg/m 2. Cardiotoxicity is more likely to occur in children, elderly patients and in patients with liver disease or trisomy 21. High single doses are more toxic than lower, more frequent doses. Palmar-plantar erythrodysaesthesia (PPE): The symptoms of PPE include painful, macular reddening skin eruptions. It is generally seen after 2 u2013 3 cycles of treatment in patients experiencing these symptoms. In most patients it clears in 1 or 2 weeks, with or without treatment of corticosteroids. For the prophylaxis and treatment of PPE, 50 - 150 mg pyridoxine per day can be used. Other strategies to prevent and treat PPE, which may be initiated 4 to 7 days after treatment with DOXOPEG, include keeping hands and feet cool by exposing them to cold water (soaks, baths or swimming), avoiding excessive heat/hot water and keeping them unrestricted (no socks, gloves, or shoes that are tight fitting). PPE appears to be dose and schedule-related and can be reduced by extending the dose interval 1 to 2 weeks or by reducing the dose. This reaction can be severe and debilitating in some patients and may require discontinuation of treatment. Patients with AIDS-KS: Haematological events may occur early in treatment with DOXOPEG. Haematological toxicity may require dose reduction, suspension or delay of therapy. DOXOPEG treatment should be temporarily suspended in patients when the absolute neutrophil count (ANC) is < 1 000/m 3 and/or the platelet count is < 50 000/mm 3. G-CSF (or GM-CSF) may be given as concomitant therapy to support the blood count when the ANC is < 1 000/mm 3 in subsequent cycles. The haematological toxicity for ovarian cancer patients is less severe than in AIDS-KS setting (see section 4.8). Respiratory side effects occurred frequently in the AIDS population during treatment with DOXOPEG and may be related to opportunistic infections (see section 4.8). Secondary haematological malignancies: As with other DNA-damaging antineoplastic agents, secondary acute myeloid leukemias and myelodysplasias have been reported in patients having received combined treatment with doxorubicin. Therefore, any patient treated with DOXOPEG should be kept under haematological supervision. Secondary oral neoplasms: Very rare cases of secondary oral cancer have been reported in patients with long-term (more than one year) exposure to DOXOPEG pegylated liposomal or those receiving a cumulative DOXOPEG dose greater than 720 mg/m 2. Cases of secondary oral cancer were diagnosed both, during treatment with DOXOPEG, and up to 6 years after the last dose. Patients should be examined at regular intervals for the presence of oral ulceration or any oral discomfort that may be indicative of secondary oral cancer.

• Although not formally studied, DOXOPEG may potentiate the toxicity of other anti-cancer therapies.
• In patients with solid tumours (including ovarian cancer), who have received concomitant cyclophosphamide or taxanes, no new additive toxicities were noted.
• In patients with AIDS-KS, exacerbation of cyclophosphamide-induced haemorrhagic cystitis and enhancement of the hepatotoxicity of 6- mercaptopurine have been reported with DOXOPEG.
• Caution must be exercised when giving any other cytotoxic agents, especially myelotoxic agents, at the same time.

The use of DOXOPEG during pregnancy or lactation is contraindicated (see section 4.3). Women of child-bearing potential/contraception in men and women: Due to the genotoxic potential of doxorubicin hydrochloride, women of child-bearing potential should use effective contraceptive measures while being treated with DOXOPEG pegylated liposomal and for 8 months following completion of treatment. Men are recommended to use effective contraceptive measures and to not father a child while receiving DOXOPEG pegylated liposomal and for 6 months following completion of treatment. Pregnancy: DOXOPEG is teratogenic in animals and should therefore not be administered during pregnancy. DOXOPEG can cause foetal harm when administered during pregnancy. Lactation: Safety and efficacy have not been established. DOXOPEG has a potential risk of causing adverse reactions in the infant as anthracyclines are distributed in breast milk. Mothers should discontinue breastfeeding prior to the administration of DOXOPEG.

Dizziness and somnolence are infrequently associated with DOXOPEG administration. Patients suffering from these effects should avoid driving motor vehicles and/or operating machinery.

a) Summary of adverse effects The most frequent adverse reactions (u2265 20 %) were neutropenia, nausea, leukopenia, anaemia, and fatigue. Severe adverse reactions (Grade 3/4 adverse reactions occurring in u2265 2 % of patients) were neutropenia, PPE, leukopenia, lymphopenia, anaemia, thrombocytopaenia, stomatitis, fatigue, diarrhoea, vomiting, nausea, pyrexia, dyspnoea, and pneumonia. Less frequently reported severe adverse reactions included Pneumocystis jirovecii pneumonia, abdominal pain, cytomegalovirus infection including cytomegalovirus chorioretinitis, asthenia, cardiac arrest, cardiac failure, cardiac failure congestive, pulmonary embolism, thrombophlebitis, venous thrombosis, anaphylactic reaction, anaphylactoid reaction, toxic epidermal necrolysis, and Stevens-Johnson syndrome. b) Tabulated list of adverse reactions The following side effects have been reported in patients receiving DOXOPEG in patients for the treatment of breast cancer, ovarian cancer, multiple myeloma, and AIDS-related KS. Post-marketing adverse reactions are also included.

See section 4.8. Acute overdosage with DOXOPEG worsens the toxic effect of mucositis, leukopenia and thrombocytopenia. Treatment of acute overdosage of the severely myelosuppressed patient consists of hospitalisation, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.