Sopilcin 20 Mg/10 Ml/50 Mg/25 Ml Infusion

SOPILCIN is indicated:

• As monotherapy for patients with metastatic breast cancer, where there is an increased cardiac risk.
• For the 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 AIDS-related Kaposiu2019s sarcoma (KS) in patients with low CD4 counts (< 200 CD4 lymphocytes/mm3) and extensive mucocutaneous or visceral disease.

SOPILCIN should only be administered under the supervision of a qualified oncologist specialised in the administration of cytotoxic medicines. SOPILCIN exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin hydrochloride (see sections 4.4 and 5.2).

Posology

Breast cancer/ Ovarian cancer: SOPILCIN 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: SOPILCIN 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. The bortezomib regimen consists of 1,3 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 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 SOPILCIN should be administered over 90 minutes (see u201cMethod of Administrationu201d).

AIDS-KS patients: SOPILCIN should be administered intravenously at 20 mg/m2 every 2 to 3 weeks. Avoid intervals shorter than 10 days as medicine accumulation and increased toxicity cannot be ruled out. Patients should be treated for 2 to 3 months to achieve a therapeutic response. Treatment should be continued as needed to maintain a therapeutic response.

All patients: If the patient experiences early signs or symptoms of infusion reaction (see sections 4.4 and 4.8), immediately discontinue the infusion, give appropriate pre-medications (antihistamine and/or short acting corticosteroid) and restart at a slower rate. To manage adverse events such as palmar-plantar erythrodysaesthesia (PPE), stomatitis or haematological toxicity, the dose may be reduced or delayed. Guidelines for SOPILCIN dose modification secondary to these adverse events 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 and stomatitis 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 addressed in section 4.8.

SOPILCIN is contra-indicated in patients who have a history of hypersensitivity reactions to doxorubicin HCl, peanut or soya, or to any of the excipients listed in section 6.1. SOPILCIN should not be administered during pregnancy or while breast-feeding. SOPILCIN must not be used to treat AIDS-related KS that may be treated effectively with local therapy or systemic alpha-interferon. The safety and effectiveness in patients less than 18 years of age have not been established.

Given the difference in dosing schedules and pharmacokinetic profiles, SOPILCIN should not be used interchangeably with other formulations of doxorubicin hydrochloride (see section 4.2 and 5.2).

Cardiac risk: All patients receiving SOPILCIN should routinely undergo frequent electrocardiogram (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 SOPILCIN therapy. However, reduction of the QRS complex is considered more indicative of cardiac toxicity. If this change occurs, the most definitive test for SOPILCIN myocardial injury i.e., endomyocardial biopsy, should 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 Multiple Gated Arteriography (MUGA). These methods should be applied routinely before the initiation of SOPILCIN therapy and should be repeated periodically during treatment. The evaluation of left ventricular function is considered to be mandatory before each additional administration of SOPILCIN that exceeds a lifetime cumulative anthracycline dose of 450 mg/m2. 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 is lower than a prognostically relevant value (e.g., < 45 %), endomyocardial biopsies should be performed and the benefit of continued therapy with SOPILCIN must be carefully evaluated against the risk of producing 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. The evaluation tests and methods mentioned above concerning the monitoring of cardiac performance during SOPILCIN therapy should 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 SOPILCIN 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 SOPILCIN only when the benefit outweighs the risk to the patient. Exercise caution in patients with impaired cardiac function who receive SOPILCIN. Caution should be observed in patients who have received other anthracyclines. The total dose of doxorubicin HCl should also take into account any previous (or concomitant) therapy with cardiotoxic compounds such as other anthracyclines/anthraquinones or e.g., 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.

The cardiac safety profile for the dosing schedule recommended for both breast and ovarian cancer (50 mg/m2) is similar to the 20 mg/m2 profile in patients with AIDS-KS (see section 4.8).

Myelosuppression: Many patients treated with SOPILCIN have baseline myelosuppression due to such factors as their pre-existing HIV disease or numerous concomitants 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 neutropenic infection or sepsis. In contrast to the experience in patients with breast cancer or ovarian cancer, myelosuppression appears to be the dose-limiting adverse event in patients with AIDS-KS (see section 4.8). Because of the potential for bone marrow suppression, periodic blood counts must be performed frequently during the course of SOPILCIN therapy, and at a minimum, prior to each dose of SOPILCIN. Persistent severe myelosuppression, although not seen in patients with ovarian cancer, may result in haemorrhage or super-infection. In controlled clinical studies in patients with AIDS-KS against a bleomycin/vincristine regimen, opportunistic infections were apparently more frequent during treatment with doxorubicin. Patients and doctors must be aware of this higher incidence and take action as appropriate.

Secondary haematological malignancies: Secondary acute myeloid leukaemias 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: Cases of secondary oral cancer have been reported in patients with long-term (more than one year) exposure to SOPILCIN or those receiving a cumulative SOPILCIN dose greater than 720 mg/m2. Cases of secondary oral cancer were diagnosed both, during treatment with SOPILCIN, 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.

Infusion-associated reactions: Serious and sometimes life-threatening infusion reactions, which are characterised by allergic-like reactions or anaphylactoid-like reactions, with symptoms including asthma, flushing, urticarial rash, chest pain, fever, hypertension, tachycardia, pruritus, sweating, shortness of breath, facial oedema, chills, back pain, tightness in the chest and throat and/or hypotension may occur within minutes of starting the infusion of SOPILCIN (see section 4.8). Convulsions also have been observed in relation to infusion reactions (see section 4.8). Temporarily stopping the infusion usually resolves these symptoms without further therapy. However, medications to treat these symptoms (e.g., antihistamines, corticosteroids, adrenaline and anticonvulsants) as well as emergency equipment should be available for immediate use. In most patients treatment can be resumed after all symptoms have resolved, without recurrence. Infusion reactions rarely occur after the first treatment cycle. To minimise the risk of infusion reactions, the initial dose should be administered at a rate no greater than 1 mg/minute (see section 4.2).

Diabetic patients: Please note that each vial of SOPILCIN contains sucrose and is administered in Dextrose 5 % in Water for intravenous infusion. An adjustment to the treatment of diabetes may be required.

Other: Combination therapy with SOPILCIN has been extensively studied in solid tumour populations. However, the efficacy of SOPILCIN combination chemotherapy has not been established in the treatment of ovarian cancer. For common adverse events which required dose modification or discontinuation see section 4.8.

No formal medicine interaction studies have been performed with doxorubicin, although phase II combination trials with conventional chemotherapy medicines have been conducted in patients with gynaecological malignancies. Exercise caution in the concomitant use of medicines known to interact with standard doxorubicin hydrochloride. SOPILCIN, like other doxorubicin hydrochloride preparations, may potentiate the toxicity of other anti-cancer therapies. During clinical trials in patients with solid tumours (including breast and ovarian cancer) who have received concomitant cyclophosphamide or taxanes, no new additive toxicities were noted. In patients with AIDS, exacerbation of cyclophosphamide-induced haemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with standard doxorubicin hydrochloride. Caution must be exercised when giving any other cytotoxic medicines, especially myelotoxic medicines, at the same time.

Pregnancy: Doxorubicin HCl is teratogenic in animals. There is no experience in pregnant women with SOPILCIN. Teratogenicity cannot be ruled out. Doxorubicin hydrochloride is suspected to cause serious birth defects when administered during pregnancy. Therefore, SOPILCIN should not be administered during pregnancy (see section 4.3).

Women of child bearing potential / Contraception in males and females: Women of child bearing potential must be advised to avoid pregnancy and must use highly effective contraception while they or their male partner are receiving SOPILCIN and in the 6 months following discontinuation of SOPILCIN therapy. Men should be advised not to father a child during this period.

Breastfeeding: It is not known whether doxorubicin is excreted in human milk. Because many medicines, including anthracyclines, are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants, mothers must discontinue nursing prior to beginning SOPILCIN treatment (see section 4.3).

Fertility: The effect of doxorubicin hydrochloride on human fertility has not been evaluated.

Doxorubicin HCl has no or negligible influence on the ability to drive and use machines. However, dizziness and somnolence have been associated infrequently with the administration of Doxorubicin HCl (see section 4.8). Patients who suffer from these effects must avoid driving and operating machinery.

Summary of the safety profile: The most common undesirable effect reported in breast/ovarian clinical trials (50 mg/m2 every 4 weeks) was palmar-plantar erythrodysesthesia (PPE). The overall incidence of PPE reported was 44,0 % to 46,1 %. These effects were mostly mild, with severe (grade 3) cases reported in 17 % to19,5 %. The reported incidence of life-threatening (grade 4) cases was < 1%. PPE infrequently resulted in permanent treatment discontinuation (3,7 % to 7,0 %). PPE is characterised by painful, macular reddening skin eruptions. In patients experiencing this event, it is generally seen after two or three cycles of treatment. Improvement usually occurs in one - two weeks, and in some cases, may take up to 4 weeks or longer for complete resolution. Pyridoxine at a dose of 50 to 150 mg per day and corticosteroids have been used for the prophylaxis and treatment of PPE, however, these therapies have not been evaluated in phase III trials. Other strategies to prevent and treat PPE include keeping hands and feet cool, by exposing them to cool 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 primarily related to the dose schedule and can be reduced by extending the dose interval 1 to 2 weeks (see section 4.2). However, this reaction can be severe and debilitating in some patients and may require discontinuation of treatment. Stomatitis/mucositis and nausea were also commonly reported in breast/ovarian cancer patient populations, whereas in the AIDS-KS Program (20 mg/m2 every 2 weeks), myelosuppression (mostly leukopaenia) was the most common side effect (see AIDS-KS). PPE was reported in 16 % of multiple myeloma patients treated with doxorubicin plus bortezomib combination therapy. Grade 3 PPE was reported in 5 % of patients. No grade 4 PPE was reported. The most frequently reported (medicine-related treatment-emergent) adverse events in combination therapy (doxorubicin HCl+ bortezomib) were nausea (40 %), diarrhoea (35 %), neutropaenia (33 %), thrombocytopaenia (29 %), vomiting (28 %), fatigue (27 %), and constipation (22 %).

Breast cancer program: 509 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with doxorubicin HCl at a dose of 50 mg/m2 every 4 weeks, or doxorubicin at a dose of 60 mg/m2 every 3 weeks, in a phase III clinical trial. The following common adverse events were reported more often with doxorubicin at a dose of 60 mg/m2 every 3 weeks than with doxorubicin HCl at a dose of 50 mg/m2 every 4 weeks: nausea, vomiting, alopecia and neutropaenia. Mucositis, and stomatitis were reported more commonly with doxorubicin HCl at a dose of 50 mg/m2 every 4 weeks than with doxorubicin at a dose of 60 mg/m2 every 3 weeks. The average duration of the most common severe (grade 3/4) events for both groups was 30 days or less. See TABLE 5 for complete listing of undesirable effects reported in doxorubicin patients - treated with a dose of 50 mg/m2 every 4 weeks. The incidence of life threatening (grade 4) haematologic effects was < 1,0 % and sepsis was reported in 1 % of patients. Growth factor support or transfusion support was necessary in 5,1 % and 5,5 % of patients, respectively (see section 4.2). Clinically significant laboratory abnormalities (grades 3 and 4) was low with elevated total bilirubin, AST and ALT reported in 2,4 %, 1,6 % and < 1 % of patients respectively. No clinically significant increases in serum creatinine were reported.

See sections 4.4 and 4.8. Acute overdosage with doxorubicin HCI worsens the toxic effects of mucositis, leukopaenia and thrombocytopaenia. Treatment of acute overdosage of the severely myelosuppressed patient consists of hospitalisation, antibiotics, platelet and granulocyte transfusions and symptomatic treatment of mucositis.