ZOLSKETIL Concentrate for dispersion for infusion Ref.[50039] Active ingredients: Doxorubicin

Given the difference in pharmacokinetic profiles and dosing schedules, doxorubicin pegylated liposomal should not be used interchangeably with other formulations of doxorubicin hydrochloride.

Cardiac toxicity

It is recommended that all patients receiving doxorubicin 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 pegylated liposomal 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 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 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 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 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 pegylated liposomal only when the benefit outweighs the risk to the patient.

Exercise caution in patients with impaired cardiac function who receive doxorubicin pegylated liposomal.

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 (see section 4.8).

Myelosuppression

Many patients treated with doxorubicin pegylated liposomal have baseline myelosuppression due to such factors as their pre-existing HIV disease or numerous concomitant or previousmedicines, 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 pegylated liposomal vs. topotecan, the incidence of treatment related sepsis was substantially less in the doxorubicin 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 pegylated liposomal 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 reaction 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 doxorubicin pegylated liposomal therapy, and at a minimum, prior to each dose of doxorubicin 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 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 pegylated liposomal. 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 pegylated liposomal or those receiving a cumulative doxorubicin pegylated liposomal dose greater than 720 mg/m². Cases of secondary oral cancer were diagnosed both, during treatment with doxorubicin 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 be indicative of secondary oral cancer.

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 doxorubicin pegylated liposomal. Very rarely, 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, medicines 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 (see section 4.2).

Palmar plantar erythrodysaesthesia syndrome (PPE)

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 1-2 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 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 (see section 4.2). However, this reaction can be severe and debilitating in some patients and may require discontinuation of treatment (see section 4.8).

Extravasation

Although local necrosis following extravasation has been reported very rarely, doxorubicin pegylated liposomal is considered to be an irritant. Animal studies indicate that administration of doxorubicin hydrochloride as a liposomal formulation reduces the potential for extravasation injury. If any signs or symptoms of extravasation occur (e.g., stinging, erythema) terminate the infusion immediately and restart in another vein. The application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction. Doxorubicin pegylated liposomalmust not be given by the intramuscular or subcutaneous route.

Diabetic patients

Doxorubicin pegylated liposomal contains sucrose and the dose is administered in glucose 50 mg/mL (5%) solution for infusion.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per dose and is essentially ‘sodium-free’.

For common adverse reaction which required dose modification or discontinuation see section 4.8.

No formal medicinal product interaction studies have been performed with doxorubicin pegylated liposomal, 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. Doxorubicin pegylated liposomal, 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.

Women of child-bearing potential

Women of child-bearing potential must be advised to avoid pregnancy while they or their male partner are receiving doxorubicin pegylated liposomal and in the six months following discontinuation of doxorubicin pegylated liposomal therapy (see section 5.3).

Pregnancy

Doxorubicin hydrochloride is suspected to cause serious birth defects when administered during pregnancy. Therefore, doxorubicin pegylated liposomal should not be used during pregnancy unless clearly necessary.

Breast-feeding

It is not known whether doxorubicin pegylated liposomal 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 breast-feeding infants, mothers must discontinue breast-feeding prior to beginning doxorubicin pegylated liposomal treatment. Health experts recommend that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

Fertility

The effect of doxorubicin hydrochloride on human fertility has not been evaluated (see section 5.3).

Doxorubicin pegylated liposomal has no or negligible influence on the ability to drive and use machines. However, in clinical studies to date, dizziness and somnolence were associated infrequently (<5%) with the administration of doxorubicin pegylated liposomal. Patients who suffer from these effects must avoid driving and operating machines.

Summary of the safety profile

The most frequent adverse reactions (≥ 20%) were neutropaenia, nausea, leukopaenia, anaemia, and fatigue.

Severe adverse reactions (Grade ¾ 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 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 pegylated liposomal:

^a See Description of selected adverse reactions
^b Post-marketing adverse reaction

Description of selected adverse reactions

Palmar plantar erythrodysaesthesia

The most common undesirable effect reported in breast/ovarian clinical trials was palmar-plantar erythrodysesthesia (PPE). The overall incidence of PPE reported was 41.3% and 51.1% in the ovarian and breast clinical trials, respectively. These effects were mostly mild, with severe (grade 3) cases reported in 16.3% and 19.6% of patients. The reported incidence of life-threatening (grade 4) cases was <1%. PPE infrequently resulted in permanent treatment discontinuation (1.9% and 10.8%). PPE was reported in 16% of multiple myeloma patients treated with doxorubicin pegylated liposomal plus bortezomib combination therapy. Grade 3 PPE was reported in 5% of patients. No grade 4 PPE was reported. The rate of PPE was substantially lower in the AIDS-KS population (1.3% all grade, 0.4% grade 3 PPE, no grade 4 PPE). See section 4.4.

Opportunistic infections

Respiratory undesirable effects commonly occurred in clinical studies of doxorubicin pegylated liposomal and may be related to opportunistic infections (OI’s) in the AIDS population. Opportunistic infections are observed in KS patients after administration with doxorubicin pegylated liposomal, and are frequently observed in patients with HIV induced immunodeficiency. The most frequently observed OI’s in clinical studies were candidiasis, cytomegalovirus, herpes simplex, Pneumocystis jirovecii pneumonia, and mycobacterium avium complex.

Cardiac toxicity

An increased incidence of congestive heart failure is associated with doxorubicin therapy at cumulative lifetime doses >450 mg/m² or at lower doses for patientswith cardiac risk factors. Endomyocardial biopsies on nine of ten AIDS-KS patients receiving cumulative doses of doxorubicin pegylated liposomal greater than 460 mg/m² indicate no evidence of anthracycline-induced cardiomyopathy. The recommended dose of doxorubicin pegylated liposomal for AIDS-KS patients is 20 mg/m² every two-to-three weeks. The cumulative dose at which cardiotoxicity would become a concern for these AIDS-KS patients (>400 mg/m²) would require more than 20 courses of doxorubicin pegylated liposomal therapy over 40 to 60 weeks.

In addition, endomyocardial biopsies were performed in 8 solid tumour patients with cumulative anthracycline doses of 509 mg/m² - 1,680 mg/m². The range of Billingham cardiotoxicity scores was grades 0-1.5. These grading scores are consistent with no or mild cardiac toxicity.

In the pivotal phase III trial versus doxorubicin, 58/509 (11.4%) randomised subjects (10 treated with doxorubicin pegylated liposomal at a dose of 50 mg/m²/every 4 weeks versus 48 treated with doxorubicin at a dose of 60 mg/m²/every 3 weeks) met the protocol-defined criteria for cardiac toxicity during treatment and/or follow-up. Cardiac toxicity was defined as a decrease of 20 points or greater from baseline if the resting LVEF remained in the normal range or a decrease of 10 points or greater if the LVEF became abnormal (less than the lower limit for normal). None of the 10 doxorubicin pegylated liposomal subjects who had cardiac toxicity by LVEF criteria developed signs and symptoms of CHF. In contrast, 10 of 48 doxorubicin subjects who had cardiac toxicity by LVEF criteria also developed signs and symptoms of CHF.

In patients with solid tumours, including a subset of patients with breast and ovarian cancers, treated at a dose of 50 mg/m²/cycle with lifetime cumulative anthracycline doses up to 1,532 mg/m², the incidence of clinically significant cardiac dysfunction was low. Of the 418 patients treated with doxorubicin pegylated liposomal 50 mg/m²/cycle, and having a baseline measurement of left ventricular ejection fraction (LVEF) and at least one follow-up measurement assessed by MUGA scan, 88 patients had a cumulative anthracycline dose of >400 mg/m², an exposure level associated with an increased risk of cardiovascular toxicity with conventional doxorubicin. Only 13 of these 88 patients (15%) had at least one clinically significant change in their LVEF, defined as an LVEF value less than 45% or a decrease of at least 20 points from baseline. Furthermore, only 1 patient (cumulative anthracycline dose of 944 mg/m²), discontinued study treatment because of clinical symptoms of congestive heart failure.

Radiation recall phenomenon

Recall of skin reaction due to prior radiotherapy has rarely occurred with doxorubicin pegylated liposomal administration.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.