DOXORUBICIN BAXTER PEGYLATED LIPOSOMAL

Doxorubicin Baxter pegylated liposomal should only be administered under the supervision of a qualified oncologist specialised in the administration of cytotoxic agents. Doxorubicin Baxter pegylated liposomal exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin hydrochloride.

Posology Breast cancer/Ovarian cancer Doxorubicin Baxter pegylated liposomal is administered intravenously at a dose of 50 mg/m2 once every 4 weeks for as long as the disease does not progress and the patient continues to tolerate treatment.

Multiple myeloma Doxorubicin Baxter pegylated liposomal is administered at 30 mg/m² on day 4 of the bortezomib 3 week regimen as a 1 hour infusion administered immediately after the bortezomib infusion. 3 mg/m² on days 1, 4, 8, and 11 every 3 weeks.

The dose should be repeated as long as patients respond satisfactorily and tolerate treatment. Day 4 dosing of both medicinal products may be delayed up to 48 hours as medically necessary. Doses of bortezomib should be at least 72 hours apart.

AIDS-related KS Doxorubicin Baxter pegylated liposomal is administered intravenously at 20 mg/m2 every two-to-three weeks. Avoid intervals shorter than 10 days as medicinal product accumulation and increased toxicity cannot be ruled out.

Treatment of patients for two-to-three months is recommended to achieve a therapeutic response. Continue treatment as needed to maintain a therapeutic response. 8), immediately discontinue the infusion, give appropriate premedications (antihistamine and/or short acting corticosteroid) and restart at a slower rate.

Guidelines for Doxorubicin Baxter pegylated liposomal dose modification To manage adverse events such as palmar-plantar erythrodysesthesia (PPE), stomatitis or haematological toxicity, the dose may be reduced or delayed. Guidelines for Doxorubicin Baxter pegylated liposomal 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). The tables for PPE (Table 1) and stomatitis (Table 2) provide the schedule followed for dose modification in clinical trials in the treatment of breast or ovarian cancer (modification of the recommended 4 week treatment cycle): if these toxicities occur in patients with AIDS-related KS, the recommended 2 to 3 week treatment cycle can be modified in a similar manner.

The table for haematological toxicity (Table 3) provides the schedule followed for dose modification in clinical trials in the treatment of patients with breast or ovarian cancer only. Dose modification in patients with AIDS-KS is provided following Table 4.

Table 1. Palmar–Plantar erythrodysesthesia Week after prior Doxorubicin Baxter pegylated liposomal dose Toxicity grade at current assessment Week 4 Week 5 Week 6 Grade 1 (mild erythema, swelling, or desquamation not interfering with daily activities) Redose unless patient has experienced a previous grade 3 or 4 skin toxicity, in which case wait an additional week Redose unless patient has experienced a previous grade 3 or 4 skin toxicity, in which case wait an additional week Decrease dose by 25%; return to 4 week interval Grade 2 (erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter) Wait an additional week Wait an additional week Decrease dose by 25%; return to 4 week interval Grade 3 (blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing) Wait an additional week Wait an additional week Withdraw patient Grade 4 (diffuse or local process causing infectious complications, or a bedridden state or hospitalisation) Wait an additional week Wait an additional week Withdraw patient Table 2.

Stomatitis Week after prior Doxorubicin Baxter pegylated liposomal dose Toxicity grade at current assessment Week 4 Week 5 Week 6 Grade 1 (painless ulcers, erythema, or mild soreness) Redose unless patient has experienced a previous grade 3 or 4 stomatitis in which case wait an additional week Redose unless patient has experienced a previous grade 3 or 4 stomatitis in which case wait an additional week Decrease dose by 25%; return to 4 week interval or withdraw patient per physician’s assessment Grade 2 (painful erythema, oedema, or ulcers, but can eat) Wait an additional week Wait an additional week Decrease dose by 25%; return to 4 week interval or withdraw patient per physician’s assessment Grade 3 (painful erythema, edema, or ulcers, but cannot eat) Wait an additional week Wait an additional week Withdraw patient Grade 4 (requires parenteral or enteral support) Wait an additional week Wait an additional week Withdraw patient Table 3.

Haematological toxicity (ANC or platelets) – Management of patients with breast or ovarian cancer GRADE ANC PLATELETS MODIFICATION Grade 1 1,500 – 1,900 75,000 – 150,000 Resume treatment with no dose reduction. Grade 2 1,000 – < 1,500 50,000 – < 75,000 Wait until ANC ≥ 1,500 and platelets ≥ 75,000; redose with no dose reduction.

Grade 3 500 – < 1,000 25,000 – < 50,000 Wait until ANC ≥ 1,500 and platelets ≥ 75,000; redose with no dose reduction. Grade 4 < 500 < 25,000 Wait until ANC ≥ 1,500 and platelets ≥ 75,000; decrease dose by 25% or continue full dose with growth factor support.

For multiple myeloma patients treated with Doxorubicin Baxter pegylated liposomal in combination with bortezomib who experience PPE or stomatitis, the Doxorubicin Baxter pegylated liposomal dose should be modified as described in Table 1 and 2 above respectively.

Table 4, below provides the schedule followed for other dose modifications in the clinical trial in the treatment of patients with […]

Summary of the safety profile The most frequent adverse reactions (≥ 20%) were neutropaenia, nausea, leukopaenia, anaemia, and fatigue. Severe adverse reactions (Grade 3/4 adverse reactions occurring in ≥ 2% of patients) were neutropaenia, PPE, leukopaenia, lymphopaenia, 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.

Tabulated list of adverse reactions Table 5 summarises the adverse drug reactions that occurred in patients receiving Doxorubicin Baxter pegylated liposomal in 4,231 patients for the treatment of breast cancer, ovarian cancer, multiple myeloma, and AIDS-related KS.

Post-marketing adverse reactions are also included, as indicated by “b”. Frequencies are defined as very common (≥ 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) and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness.

Table 5:

Adverse reactions in patients treated with Doxorubicin Baxter pegylated liposomal System Organ Class Frequency All Grades Adverse Drug Reaction Sepsis Pneumonia Pneumocystis jirovecii pneumonia Cytomegalovirus infection including cytomegalovirus chorioretinitis Mycobacterium avium complex infection Candidiasis Herpes zoster Urinary tract infection Infection Upper respiratory tract infection Oral candidiasis Folliculitis Pharyngitis Common Nasopharyngitis Herpes simplexUncommon Fungal infection Infections and infestations Rare Opportunistic infection (including Aspergillus, Histoplasma, Isospora, Legionella, Microsporidium, Salmonella, Staphylococcus, Toxoplasma, Tuberculosis)a Acute myeloid leukaemiab Myelodysplastic syndromeb Neoplasms benign, malignant and unspecified (including cysts and polyps) Not known Oral neoplasmb Leukopaenia Neutropaenia Lymphopaenia Very common Anaemia (including hypochromic) ThrombocytopaeniaCommon Febrile neutropaenia PancytopaeniaUncommon Thrombocytosis Blood and lymphatic system disorders Rare Bone marrow failure HypersensitivityUncommon Anaphylactic reaction Immune system disorders Rare Anaphylactoid reaction Very common Decreased appetite Cachexia Dehydration Hypokalaemia Hyponatraemia Common Hypocalcaemia Hyperkalaemia Metabolism and nutrition disorders Uncommon Hypomagnesaemia Confusional state Anxiety Depression Psychiatric disorders Common Insomnia Neuropathy peripheral Peripheral sensory neuropathy Neuralgia Paraesthesia Hypoaesthesia Dysgeusia Headache Lethargy Common Dizziness Polyneuropathy Convulsion Syncope Dysaesthesia Nervous system disorders Uncommon Somnolence Common Conjunctivitis Vision blurredUncommon Lacrimation increased Eye disorders Rare Retinitis Common Tachycardia Palpitations Cardiac arrest Cardiac failure Cardiac failure congestive Cardiomyopathy Cardiac disordersa Uncommon Cardiotoxicity Ventricular arrhythmia Bundle branch block right Conduction disorder Atrioventricular block Rare Cyanosis Hypertension Hypotension Common Flushing Pulmonary embolism Infusion site necrosis (including soft tissue necrosis and skin necrosis) Phlebitis Uncommon Orthostatic hypotension Thrombophlebitis Venous thrombosis Vascular disorders Rare Vasodilatation Dyspnoea Dyspnoea exertional Epistaxis Common Cough AsthmaUncommon Chest discomfort Rare Throat tightness Respiratory, thoracic and mediastinal disorders Not Known Interstitial lung disease Stomatitis Nausea Vomiting Diarrhoea Very common Constipation Gastritis Aphthous stomatitis Mouth ulceration Dyspepsia Dysphagia Oesophagitis Abdominal pain Abdominal pain upper Oral pain Common Dry mouth FlatulenceUncommon Gingivitis Glossitis Gastrointestina l disorders Rare Lip ulceration Palmar plantar erythrodysaesthesia syndromea Rash (including erythematous, maculo-papular, and papular) Skin and subcutaneous tissue disorders Very common Alopecia Skin exfoliation Blister Dry skin Erythema Pruritus Hyperhidrosis Common Skin hyperpigmentation Dermatitis Dermatitis exfoliative Acne Skin ulcer Dermatitis allergic Urticaria Skin discolouration Petechiae Pigmentation disorder Uncommon Nail disorder Toxic epidermal necrolysis Erythema multiforme Dermatitis bullous Rare Lichenoid keratosis Not known Stevens-Johnson syndromeb Very common Musculoskeletal pain (including musculoskeletal chest pain, back pain, pain in extremity) Muscle spasms Myalgia Arthralgia Common Bone pain Musculoskelet al and connective tissue disorders Uncommon Muscular weakness Common DysuriaRenal and urinary disorders Not Known Renal-limited thrombotic microangiopathy Uncommon Breast pain Vaginal infection Reproductive disorders Rare Scrotal erythema PyrexiaVery common Fatigue Infusion-related reaction Pain Chest pain Influenza-like illness Chills Mucosal inflammation Asthenia Malaise Oedema General disorders and administration site conditions Common Oedema peripheral Administration site extravasation Injection site reaction Face oedema Uncommon Hyperthermia Rare Mucous membrane disorder Common Weight decreased Uncommon Ejection fraction decreased Liver function test abnormal (including Blood bilirubin increased, Alanine aminotransferase increased and Aspartate aminotransferase increased) Investigations Rare Blood creatinine increased Injury, poisoning and procedural complications Uncommon Radiation recall phenomenona a See Description of selected adverse reactions b Post-marketing adverse reaction Description of selected adverse reactions Palmar plantar […]

Given the difference in pharmacokinetic profiles and dosing schedules, Doxorubicin Baxter pegylated liposomal should not be used interchangeably with other formulations of doxorubicin hydrochloride. Cardiac toxicity It is recommended that all patients receiving Doxorubicin Baxter pegylated liposomal routinely undergo frequent ECG monitoring.

Transient ECG changes such as T-wave flattening, S-T segment depression and benign arrhythmias are not considered mandatory indications for the suspension of Doxorubicin Baxter pegylated liposomal therapy. However, reduction of the QRS complex is considered more indicative of cardiac toxicity.

, endomyocardial biopsy, must be considered. More specific methods for the evaluation and monitoring of cardiac functions as compared to ECG are a measurement of left ventricular ejection fraction by echocardiography or preferably by Multigated Angiography (MUGA).

These methods must be applied routinely before the initiation of Doxorubicin Baxter pegylated liposomal therapy and repeated periodically during treatment. The evaluation of left ventricular function is considered to be mandatory before each additional administration of Doxorubicin Baxter pegylated liposomal that exceeds a lifetime cumulative anthracycline dose of 450 mg/m2.

The evaluation tests and methods mentioned above concerning the monitoring of cardiac performance during anthracycline therapy are to be employed in the following order: ECG monitoring, measurement of left ventricular ejection fraction, endomyocardial biopsy.

If a test result indicates possible cardiac injury associated with Doxorubicin Baxter pegylated liposomal therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury. In patients with cardiac disease requiring treatment, administer Doxorubicin Baxter pegylated liposomal only when the benefit outweighs the risk to the patient.

Exercise caution in patients with impaired cardiac function who receive Doxorubicin Baxter pegylated liposomal. , < 45%), endomyocardial biopsy may be considered and the benefit of continued therapy must be carefully evaluated against the risk of developing irreversible cardiac damage.

Congestive heart failure due to cardiomyopathy may occur suddenly, without prior ECG changes and may also be encountered several weeks after discontinuation of therapy. Caution must be observed in patients who have received other anthracyclines.

, 5-fluorouracil. Cardiac toxicity also may occur at cumulative anthracycline doses lower than 450 mg/m2 in patients with prior mediastinal irradiation or in those receiving concurrent cyclophosphamide therapy. 8). Myelosuppression Many patients treated with Doxorubicin Baxter pegylated liposomal have baseline myelosuppression due to such factors as their pre-existing HIV disease or numerous concomitant or previous medications, or tumours involving bone marrow.

In the pivotal trial in patients with ovarian cancer treated at a dose of 50 mg/m2, myelosuppression was generally mild to moderate, reversible, and was not associated with episodes of neutropaenic infection or sepsis. Moreover, in a controlled clinical trial of Doxorubicin Baxter pegylated liposomal vs.

topotecan, the incidence of treatment related sepsis was substantially less in the Doxorubicin Baxter pegylated liposomal-treated ovarian cancer patients as compared to the topotecan treatment group. A similar low incidence of myelosuppression was seen in patients with metastatic breast cancer receiving Doxorubicin Baxter pegylated liposomal in a first-line clinical trial.

8). Because of the potential for bone marrow suppression, periodic blood counts must be performed frequently during the course of Doxorubicin Baxter pegylated liposomal therapy, and at a minimum, prior to each dose of Doxorubicin Baxter pegylated liposomal.

Persistent severe myelosuppression may result in superinfection or haemorrhage. In controlled clinical studies in patients with AIDS-KS against a bleomycin/vincristine regimen, opportunistic infections were apparently more frequent during treatment with Doxorubicin Baxter pegylated liposomal.

Patients and doctors must be aware of this higher incidence and take action as appropriate. 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 doxorubicin 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 Doxorubicin Baxter pegylated liposomal or those receiving a cumulative Doxorubicin Baxter pegylated liposomal dose greater than 720 mg/m2.

Cases of secondary oral cancer were diagnosed both, during treatment with Doxorubicin Baxter pegylated liposomal, 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 […]

3. 1. 3 PHARMACEUTICAL FORM Concentrate for solution for infusion (sterile concentrate) The dispersion is sterile, translucent and red. 1 Therapeutic indications Doxorubicin Baxter pegylated liposomal is indicated: - As monotherapy for patients with metastatic breast cancer, where there is an increased cardiac risk.

- For treatment of advanced ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen. - 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.

- For treatment of AIDS-related Kaposi’s sarcoma (KS) in patients with low CD4 counts (< 200 CD4 lymphocytes/mm3) and extensive mucocutaneous or visceral disease. Doxorubicin Baxter pegylated liposomal may be used as first-line systemic chemotherapy, or as second line chemotherapy in AIDS-KS patients with disease that has progressed with, or in patients intolerant to, prior combination systemic chemotherapy comprising at least two of the following agents: a vinca alkaloid, bleomycin and standard doxorubicin (or other anthracycline).

2 Posology and method of administration Doxorubicin Baxter pegylated liposomal should only be administered under the supervision of a qualified oncologist specialised in the administration of cytotoxic agents. Doxorubicin Baxter pegylated liposomal exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin hydrochloride.

Posology Breast cancer/Ovarian cancer Doxorubicin Baxter pegylated liposomal is administered intravenously at a dose of 50 mg/m2 once every 4 weeks for as long as the disease does not progress and the patient continues to tolerate treatment.

Multiple myeloma Doxorubicin Baxter pegylated liposomal is administered at 30 mg/m² on day 4 of the bortezomib 3 week regimen as a 1 hour infusion administered immediately after the bortezomib infusion. 3 mg/m² on days 1, 4, 8, and 11 every 3 weeks.

The dose should be repeated as long as patients respond satisfactorily and tolerate treatment. Day 4 dosing of both medicinal products may be delayed up to 48 hours as medically necessary. Doses of bortezomib should be at least 72 hours apart.

AIDS-related KS Doxorubicin Baxter pegylated liposomal is administered intravenously at 20 mg/m2 every two-to-three weeks. Avoid intervals shorter than 10 days as medicinal product accumulation and increased toxicity cannot be ruled out.

Treatment of patients for two-to-three months is recommended to achieve a therapeutic response. Continue treatment as needed to maintain a therapeutic response. 8), immediately discontinue the infusion, give appropriate premedications (antihistamine and/or short acting corticosteroid) and restart at a slower rate.

Guidelines for Doxorubicin Baxter pegylated liposomal dose modification To manage adverse events such as palmar-plantar erythrodysesthesia (PPE), stomatitis or haematological toxicity, the dose may be reduced or delayed. Guidelines for Doxorubicin Baxter pegylated liposomal 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). The tables for PPE (Table 1) and stomatitis (Table 2) provide the schedule followed for dose modification in clinical trials in the treatment of breast or ovarian cancer (modification of the recommended 4 week treatment cycle): if these toxicities occur in patients with AIDS-related KS, the recommended 2 to 3 week treatment cycle can be modified in a similar manner.

The table for haematological toxicity (Table 3) provides the schedule followed for dose modification in clinical trials in the treatment of patients with breast or ovarian cancer only. Dose modification in patients with AIDS-KS is provided following Table 4.

Table 1. Palmar–Plantar erythrodysesthesia Week after prior Doxorubicin Baxter pegylated liposomal dose Toxicity grade at current assessment Week 4 Week 5 Week 6 Grade 1 (mild erythema, swelling, or desquamation not interfering with daily activities) Redose unless patient has experienced a previous grade 3 or 4 skin toxicity, in which case wait an additional week Redose unless patient has experienced a previous grade 3 or 4 skin toxicity, in which case wait an additional week Decrease dose by 25%; return to 4 week interval Grade 2 (erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter) Wait an additional week Wait an additional week Decrease dose by 25%; return to 4 week interval Grade 3 (blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing) Wait an additional week Wait an additional week Withdraw patient Grade 4 (diffuse or local process causing infectious complications, or a bedridden state or hospitalisation) Wait an additional week Wait an additional week Withdraw patient Table 2.

Stomatitis Week after prior Doxorubicin Baxter pegylated liposomal dose Toxicity grade at current assessment Week 4 Week 5 Week 6 Grade 1 (painless ulcers, erythema, or mild soreness) Redose unless patient has experienced a previous grade 3 or 4 stomatitis in which case wait an additional week Redose unless patient has experienced a previous grade 3 or 4 stomatitis in which case wait an additional week Decrease dose by 25%; return to 4 week interval or withdraw patient per physician’s assessment Grade 2 (painful erythema, oedema, or ulcers, but can eat) Wait an additional week Wait an additional week Decrease dose by 25%; […]