Caelyx

/ Janssen

Caelyx should only be administered under the supervision of a qualified oncologist specialized in the administration of cytotoxic agents. Caelyx exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin hydrochloride.
Breast cancer/Ovarian cancer: Caelyx 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: Caelyx 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 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: Caelyx 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.
For all patients: If the patient experiences early symptoms or signs of infusion reaction, immediately discontinue the infusion, give appropriate premedications (antihistamine and/or short acting corticosteroid) and restart at a slower rate.
For Guidelines for Caelyx dose modification: Please refer to prescribing information.
Hepatic Impairment: Caelyx pharmacokinetics determined in a small number of patients with elevated total bilirubin levels do not differ from patients with normal total bilirubin; however, until further experience is gained, the Caelyx dosage in patients with impaired hepatic function should be reduced based on the experience from the breast and ovarian clinical trial programs as follows:
at initiation of therapy, if the bilirubin is between 1.2 – 3.0 mg/dl, the first dose is reduced by 25 %. If the bilirubin is > 3.0 mg/dl, the first dose is reduced by 50 %. If the patient tolerates the first dose without an increase in serum bilirubin or liver enzymes, the dose for cycle 2 can be increased to the next dose level, i.e., if reduced by 25 % for the first dose, increase to full dose for cycle 2; if reduced by 50 % for the first dose, increase to 75 % of full dose for cycle 2. The dosage can be increased to full dose for subsequent cycles if tolerated. Caelyx can be administered to patients with liver metastases with concurrent elevation of bilirubin and liver enzymes up to 4 x the upper limit of the normal range. Prior to Caelyx administration, evaluate hepatic function using conventional clinical laboratory tests such as ALT/AST, alkaline phosphatase, and bilirubin.
Renal Impairment: As doxorubicin is metabolised by the liver and excreted in the bile, dose modification should not be required.
AIDS- related KS patients with splenectomy: As there is no experience with Caelyx in patients who have had splenectomy, treatment with Caelyx is not recommended.
Paediatric population: The experience in children is limited. Caelyx is not recommended in patients below 18 years of age.
Elderly: Population based analysis demonstrates that age across the range tested (21 – 75 years) does not significantly alter the pharmacokinetics of Caelyx.
Method of administration: Caelyx is administered as an intravenous infusion.
Do not administer Caelyx as a bolus injection or undiluted solution. It is recommended that the Caelyx infusion line be connected through the side port of an intravenous infusion of 5 % (50 mg/ml) glucose to achieve further dilution and minimise the risk of thrombosis and extravasation. The infusion may be given through a peripheral vein. Do not use with inline filters. Caelyx must not be given by the intramuscular or subcutaneous route.
For doses < 90 mg: dilute Caelyx in 250 ml 5 % (50 mg/ml) glucose solution for infusion.
For doses ≥ 90 mg: dilute Caelyx in 500 ml 5 % (50 mg/ml) glucose solution for infusion.
Breast cancer/Ovarian cancer/Multiple Myeloma: To minimize the risk of infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction is observed, subsequent Caelyx infusions may be administered over a 60-minute period.
In those patients who experience an infusion reaction, 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 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.
AIDS-related KS: The dose of Caelyx is diluted in 250 ml 5 % (50 mg/ml) glucose solution for infusion and administered by intravenous infusion over 30 minutes.
For full details see prescribing information.

As monotherapy for patients with metastatic breast cancer, where there is an increased cardiac risk.
The treatment of patients with metastatic carcinoma of the ovary who are refractory to both paclitaxel and platiniumbased chemotherapy regimens and who may also be refractory to topotecan. Refractory is defined as a patient having progressive disease while on treatment, or within 6 months of completing treatment.
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 and extensive mucocutaneous or visceral disease.

Hypersensitivity to the active substance , peanut or soya, or to any of the excipients.
Caelyx must not be used to treat AIDS-KS that may be effectively treated with local therapy or systemic alfa-interferon.

Cardiac toxicity: It is recommended that all patients receiving Caelyx 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 Caelyx therapy. However, reduction of the QRS complex is considered more indicative of cardiac toxicity. If this change occurs, the most definitive test for anthracycline myocardial injury, i.e., endomyocardial biopsy, must be considered. More specific methods for the evaluation and monitoring of cardiac functions as compared to ECGare 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 Caelyx therapy and repeated periodically during treatment. The evaluation of left ventricular function is considered to be mandatory before each additional administration of Caelyx 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 Caelyx therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury. In patients with cardiac disease requiring treatment, administer Caelyx only when the benefit outweighs the risk to the patient. Exercise caution in patients with impaired cardiac function who receive this drug. Whenever cardiomyopathy is suspected, i.e., the left ventricular ejection fraction has substantially decreased relative to pre-treatment values and/or left ventricular ejection fraction is lower than a prognostically relevant value (e.g. < 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. The total dose of doxorubicin hydrochloride must 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.
Myelosuppression: Many patients treated with this drug 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 it vs. topotecan, the incidence of treatment related sepsis was substantially less in the Caelyx-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 Caelyx in a first-line clinical trial. 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. Because of the potential for bone marrow suppression, periodic blood counts must be performed frequently during the course of Caelyx therapy, and at a minimum, prior to each dose of it.
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 Caelyx. Patients and doctors must be aware of this higher incidence and take action as appropriate 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.
Infusion-associated reactions: Serious and sometimes life-threatening infusion reactions, which are characterised by allergic-like 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 Caelyx. Very rarely, convulsions also have been observed in relation to infusion reactions. 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 recur 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.
Diabetic patients: Please note that each vial of Caelyx contains sucrose and the dose is administered in 5 % (50 mg/ml) glucose solution for infusion. For common adverse events which required dose modification or discontinuation.
Secondary oral neoplasms: Very rare cases of secondary oral cancer have been reported in patients with long term (more than one year) exposure to CAELYX  or those receiving a cumulative CAELYX dose greater than 720 mg/m². Cases of secondary oral cancer were diagnosed both, during treatment with CAELYX, 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.

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 % – 46.1 %. These effects were mostly mild, with severe (Grade III) cases reported in 17% -19.5 %. The reported incidence of life-threatening (Grade IV) cases was < 1 %. PPE infrequently resulted in permanent treatment discontinuation (3.7 % – 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 – 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, which may be initiated for 4 to 7 days after treatment with Caelyx 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 – 2 weeks.
For full details please see prescribing information

No formal medicinal product interaction studies have been performed with Caelyx, although phase II combination trials with conventional chemotherapy agents have been conducted in patients with gynaecological malignancies. Exercise caution in the concomitant use of medicinal products known to interact with standard doxorubicin hydrochloride. Caelyx, 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 agents, especially myelotoxic agents, at the same time.

Pregnancy: Doxorubicin hydrochloride is suspected to cause serious birth defects when  administered during pregnancy. Therefore, Caelyx should not be used during pregnancy unless clearly necessary. Women of child-bearing potential must be advised to avoid pregnancy while they or their male partner are receiving Caelyx and in the six months following discontinuation of Caelyx therapy.
Lactation: It is not known whether Caelyx is excreted in human milk. Because many medicinal products, including anthracyclines, are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants, therefore mothers must discontinue nursing prior to beginning Caelyx treatment. Health experts recommend that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

Acute overdosing with doxorubicin hydrochloride worsens the toxic effects of mucositis, leukopaenia and thrombocytopaenia. Treatment of acute overdose of the severely myelosuppressed patient consists of hospitalisation, antibiotics, platelet and granulocyte transfusions and symptomatic treatment of mucositis.