Section 4.8 (undesirable effects): Extensive changes have been made to this section in order to provide a consolidated table of all ADR's in line with the applicable EU guidelines. 

Name change Section 1 and  throught out the  SmPC:

Caelyx pegylated liposomal 2mg/ml concentrate for solution for infusion

no changes to SmPC , pdf format uploaded

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

One ml of Caelyx contains 2 mg doxorubicin hydrochloride in a pegylated liposomal formulation.

Caelyx, a liposome formulation, is doxorubicin hydrochloride encapsulated in liposomes with surface‑bound methoxypolyethylene glycol (MPEG). This process is known as pegylation and protects liposomes from detection by the mononuclear phagocyte system (MPS), which increases blood circulation time.

Excipients with known effect

Contains fully hydrogenated soy phosphatidylcholine (from soyabean) – see section 4.3

Contains less than 1  mmol sodium (23  mg) per dose, and is essentially ‘sodium-free’.

For the full list of excipients, see section 6.1.

4.3     Contraindications

Hypersensitivity to the active substance, peanut or soya, or to any of the excipients listed in section 6.1.

Caelyx must not be used to treat AIDS‑KS that may be treated effectively with local therapy or systemic alfa‑interferon.

6.1     List of excipients

a-(2-[1,2-distearoyl-sn-glycero(3)phosphooxy]ethylcarbamoyl)-w-methoxypoly(oxyethylen)-40 sodium salt (MPEG‑DSPE)

fully hydrogenated soy phosphatidylcholine (HSPC)

cholesterol

ammonium sulphate

sucrose

histidine

water for injections

hydrochloric acid (for pH-adjustment)

sodium hydroxide (for pH-adjustment)

SPC Section 4.8

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%‑46.1%. These effects were mostly mild, with severe (grade 3) cases reported in 17%‑19.5%. The reported incidence of life-threatening (grade 4) 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)…

SPC Section 4.8

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%‑46.1%. These effects were mostly mild, with severe (grade 3) cases reported in 17%‑19.5%. The reported incidence of life-threatening (grade 4) 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)…

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Cytotoxic agents (anthracyclines and related substances), ATC code: L01DB01.

Mechansim of action

The active ingredient of Caelyx is doxorubicin hydrochloride, a cytotoxic anthracycline antibiotic obtained from Streptomyces peucetius var. caesius. The exact mechanism of the antitumour activity of doxorubicin is not known. It is generally believed that inhibition of DNA, RNA and protein synthesis is responsible for the majority of the cytotoxic effects. This is probably the result of intercalation of the anthracycline between adjacent base pairs of the DNA double helix thus preventing their unwinding for replication.

Clinical efficacy and safety

A phase III randomised study of Caelyx versus doxorubicin in patients with metastatic breast cancer was completed in 509 patients. The protocol‑specified objective of demonstrating non‑inferiority between Caelyx and doxorubicin was met, the hazard ratio (HR) for progression‑free survival (PFS) was 1.00 (95% CI for HR=0.82‑1.22). The treatment HR for PFS when adjusted for prognostic variables was consistent with PFS for the ITT population.

The primary analysis of cardiac toxicity showed the risk of developing a cardiac event as a function of cumulative anthracycline dose was significantly lower with Caelyx than with doxorubicin (HR=3.16, p < 0.001). At cumulative doses greater than 450 mg/m² there were no cardiac events with Caelyx.

A phase III comparative study of Caelyx versus topotecan in patients with epithelial ovarian cancer following the failure of first‑line, platinum‑based chemotherapy was completed in 474 patients. There was a benefit in overall survival (OS) for Caelyx‑treated patients over topotecan‑treated patients as indicated by a hazard ratio (HR) of 1.216 (95% CI: 1.000; 1.478), p=0.050. The survival rates at 1, 2 and 3 years were 56.3%, 34.7% and 20.2% respectively on Caelyx, compared to 54.0%, 23.6% and 13.2% on topotecan.

For the sub‑group of patients with platinum‑sensitive disease the difference was greater: HR of 1.432 (95% CI: 1.066; 1.923), p=0.017. The survival rates at 1, 2 and 3 years were 74.1%, 51.2% and 28.4% respectively on Caelyx, compared to 66.2%, 31.0% and 17.5% on topotecan.

The treatments were similar in the sub‑group of patients with platinum‑refractory disease: HR of 1.069 (95% CI: 0.823; 1.387), p=0.618. The survival rates at 1, 2 and 3 years were 41.5%, 21.1% and 13.8% respectively on Caelyx, compared to 43.2%, 17.2% and 9.5% on topotecan.

A phase III randomised, parallel‑group, open‑label, multicentre study comparing the safety and efficacy of Caelyx plus bortezomib combination therapy with bortezomib monotherapy in patients with multiple myeloma who have received at least 1 prior therapy and who did not progress while receiving anthracycline‑based therapy, was conducted in 646 patients. There was a significant improvement in the primary endpoint of time to progression (TTP) for patients treated with combination therapy of Caelyx plus bortezomib compared to patients treated with bortezomib monotherapy as indicated by a risk reduction (RR) of 35% (95% CI: 21‑47%), p < 0.0001, based on 407 TTP events. The median TTP was 6.9 months for the bortezomib monotherapy patients compared with 8.9 months for the Caelyx plus bortezomib combination therapy patients. A protocol‑defined interim analysis (based on 249 TTP events) triggered early study termination for efficacy. This interim analysis showed a TTP risk reduction of 45% (95% CI: 29‑57%), p < 0.0001. The median TTP was 6.5 months for the bortezomib monotherapy patients compared with 9.3 months for the Caelyx plus bortezomib combination therapy patients. These results, though not mature, constituted the protocol defined final analysis. The final analysis for overall survival (OS) performed after a median follow‑up of 8.6 years showed no significant difference in OS between the two treatment arms. The median OS was 30.8 months (95% CI; 25.2‑36.5 months) for the bortezomib monotherapy patients and 33.0 months (95% CI; 28.9‑37.1 months) for the Caelyx plus bortezomib combination therapy patients.

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Cytotoxic agents (anthracyclines and related substances), ATC code: L01DB01.

Mechansim of action

The active ingredient of Caelyx is doxorubicin hydrochloride, a cytotoxic anthracycline antibiotic obtained from Streptomyces peucetius var. caesius. The exact mechanism of the antitumour activity of doxorubicin is not known. It is generally believed that inhibition of DNA, RNA and protein synthesis is responsible for the majority of the cytotoxic effects. This is probably the result of intercalation of the anthracycline between adjacent base pairs of the DNA double helix thus preventing their unwinding for replication.

Clinical efficacy and safety

A phase III randomised study of Caelyx versus doxorubicin in patients with metastatic breast cancer was completed in 509 patients. The protocol‑specified objective of demonstrating non‑inferiority between Caelyx and doxorubicin was met, the hazard ratio (HR) for progression‑free survival (PFS) was 1.00 (95% CI for HR=0.82‑1.22). The treatment HR for PFS when adjusted for prognostic variables was consistent with PFS for the ITT population.

The primary analysis of cardiac toxicity showed the risk of developing a cardiac event as a function of cumulative anthracycline dose was significantly lower with Caelyx than with doxorubicin (HR=3.16, p < 0.001). At cumulative doses greater than 450 mg/m² there were no cardiac events with Caelyx.

A phase III comparative study of Caelyx versus topotecan in patients with epithelial ovarian cancer following the failure of first‑line, platinum‑based chemotherapy was completed in 474 patients. There was a benefit in overall survival (OS) for Caelyx‑treated patients over topotecan‑treated patients as indicated by a hazard ratio (HR) of 1.216 (95% CI: 1.000; 1.478), p=0.050. The survival rates at 1, 2 and 3 years were 56.3%, 34.7% and 20.2% respectively on Caelyx, compared to 54.0%, 23.6% and 13.2% on topotecan.

For the sub‑group of patients with platinum‑sensitive disease the difference was greater: HR of 1.432 (95% CI: 1.066; 1.923), p=0.017. The survival rates at 1, 2 and 3 years were 74.1%, 51.2% and 28.4% respectively on Caelyx, compared to 66.2%, 31.0% and 17.5% on topotecan.

The treatments were similar in the sub‑group of patients with platinum‑refractory disease: HR of 1.069 (95% CI: 0.823; 1.387), p=0.618. The survival rates at 1, 2 and 3 years were 41.5%, 21.1% and 13.8% respectively on Caelyx, compared to 43.2%, 17.2% and 9.5% on topotecan.

A phase III randomised, parallel‑group, open‑label, multicentre study comparing the safety and efficacy of Caelyx plus bortezomib combination therapy with bortezomib monotherapy in patients with multiple myeloma who have received at least 1 prior therapy and who did not progress while receiving anthracycline‑based therapy, was conducted in 646 patients. There was a significant improvement in the primary endpoint of time to progression (TTP) for patients treated with combination therapy of Caelyx plus bortezomib compared to patients treated with bortezomib monotherapy as indicated by a risk reduction (RR) of 35% (95% CI: 21‑47%), p < 0.0001, based on 407 TTP events. The median TTP was 6.9 months for the bortezomib monotherapy patients compared with 8.9 months for the Caelyx plus bortezomib combination therapy patients. A protocol‑defined interim analysis (based on 249 TTP events) triggered early study termination for efficacy. This interim analysis showed a TTP risk reduction of 45% (95% CI: 29‑57%), p < 0.0001. The median TTP was 6.5 months for the bortezomib monotherapy patients compared with 9.3 months for the Caelyx plus bortezomib combination therapy patients. These results, though not mature, constituted the protocol defined final analysis. The final analysis for overall survival (OS) performed after a median follow‑up of 8.6 years showed no significant difference in OS between the two treatment arms. The median OS was 30.8 months (95% CI; 25.2‑36.5 months) for the bortezomib monotherapy patients and 33.0 months (95% CI; 28.9‑37.1 months) for the Caelyx plus bortezomib combination therapy patients.

 First sentence changed from:

     Caelyx contains 2 mg/ml doxorubicin hydrochloride in a pegylated liposomal formulation.

 To: 

One ml of Caelyx contains 2 mg doxorubicin hydrochloride in a pegylated liposomal formulation.

 Last sentence changed from:

     For excipients, see section 6.1.

 To:

     For a full list of excipients, see section 6.1.

 Section 4.2

 Section entitled Paediatric patients: changed from: 

Paediatric patients: Safety and effectiveness in patients less than 18 years of age have not been established.

 To: 

Paediatric patients: The experience in children is limited. Caelyx is not recommended in patients below 18 years of age.

 Section 4.3 

Changed from: 

Caelyx must not be used to treat AIDS-KS that may be treated effectively with local therapy or systemic alfa-interferon.

 To: 

·                Hypersensitivity to the active substance or to any of the excipients. 

Caelyx must not be used to treat AIDS-KS that may be treated effectively with local therapy or systemic alfa-interferon.

 Section 4.5 

First sentence has been changed from: 

No formal drug interaction studies have been conducted with Caelyx, although phase II combination trials with conventional chemotherapy agents have been conducted in patients with gynaecological malignancies

 To: 

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.

 Section 4.6 

Pregnancy: Second sentence has been changed from: 

Therefore, Caelyx should not be used unless clearly necessary. 

To: 

Therefore, Caelyx should not be used during pregnancy unless clearly necessary. 

Lactation:  First sentence changed from: 

It is not known whether Caelyx is 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.

 To: 

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.

 Section 4.8

 Section entitled Breast Cancer Program: (heading amended to Breast cancer program).

 Last sentence of second paragraph changed from: 

See Table 4 for complete listing of undesirable effects reported in ³ 5 % of Caelyx-treated patients.

 To: 

See Table 4 for complete listing of undesirable effects reported in Caelyx-treated patients.

 Paragraph 3 changed from: 

Anaemia, leukopaenia and thrombocytopaenia were infrequently reported among Caelyx patients at incidences of 5 %, 2 %, and 1 %, respectively. The incidence of life threatening (Grade IV) 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).

To: 

The incidence of life threatening (Grade IV) 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).

Table 4 completely updated in respect of Adverse Events.

First paragraph after Table 4 (Undesirable effects reported between ….) has been deleted.

Next paragraph changed from: 

Ovarian cancer program: 512 patients with ovarian cancer (a subset of 876 solid tumour patients) were treated with Caelyx at a dose of 50 mg/m² in clinical trials. See Table 4 for undesirable effects reported in ³ 5 % of Caelyx-treated patients.

 To: 

Ovarian cancer program: 512 patients with ovarian cancer (a subset of 876 solid tumour patients) were treated with Caelyx at a dose of 50 mg/m² in clinical trials. See Table 5 for undesirable effects reported in Caelyx-treated patients.

 New Table 5 added

 Following paragraph changed from: 

Myelosuppression was mostly mild or moderate and manageable. Leukopaenia was the most frequently reported haematological adverse effect, followed by anaemia, neutropaenia and thrombocytopaenia. Life threatening (Grade IV) haematological effects were reported at incidences of 1.6 %, 0.4 %, 2.9 %, 0.2 % respectively. Sepsis related to leukopaenia was observed infrequently (< 1 %). Growth factor support was required infrequently (< 5 %) and transfusion support was required in approximately 15 % of patients (see section 4.2).

 The following paragraph has been deleted: 

Undesirable effects reported between 1 % and 5 % in Caelyx-treated patients were headache, allergic reaction, chills, infection, chest pain, back pain, malaise, vasodilatation, cardiovascular disorder, oral moniliasis, mouth ulceration, esophagitis, nausea and vomiting, gastritis, dysphagia, dry mouth, flatulence, gingivitis, hypochromic anaemia, peripheral oedema, weight loss, dehydration, cachexia, myalgia, dizziness, insomnia, anxiety, neuropathy, depression, hypertonia, dyspnoea, increased cough, vesiculobullous rash, pruritus, exfoliative dermatitis, skin disorder, maculopapular rash, sweating, acne, herpes zoster, skin ulcer, conjunctivitis, taste perversion, urinary tract infection, dysuria and vaginitis.

 Under section entitled AIDS-KS program, paragraph changed from: 

Clinical studies on AIDS-KS patients treated at 20 mg/m² with Caelyx show that myelosuppression was the most frequent undesirable effect considered related to Caelyx occurring in approximately one-half of the patients.

 To: 

Clinical studies on AIDS-KS patients treated at 20 mg/m² with Caelyx show that myelosuppression was the most frequent undesirable effect considered related to Caelyx occurring very commonly (in approximately one-half of the patients).

 The following paragraph has been deleted: 

Other frequently (³ 5 %) observed undesirable effects were nausea, asthenia, alopecia, fever, diarrhoea, infusion-associated acute reactions, and stomatitis.

 The first sentence of next paragraph has been amended slightly from: 

Respiratory undesirable effects frequently (³ 5 %) occurred in clinical studies of Caelyx and may be related to opportunistic infections in the AIDS population.

 To:

 After this paragraph, the following has been added: 

Undesirable effects observed in patients with AIDS-KS according to CIOMS III frequency categories (Very common (> 1/10); Common (> 1/100, < 1/10); Uncommon (> 1/1,000, < 1/100)) were as follows:

 Infections and infestations:

Common: oral moniliasis 

Blood and lymphatic system disorders:

Very common: neutropaenia, anaemia, leukopaenia

Common: thrombocytopaenia 

Metabolism and nutrition disorders:

Common: anorexia 

Psychiatric disorders:

Uncommon: confusion 

Nervous system disorders:

Common: dizziness

Uncommon: paresthesia  

Eye disorders:

Common: retinitis 

Vascular disorders:

Common: vasodilatation 

Respiratory, thoracic and mediastinal disorders:

Common: dyspnoea 

Gastrointestinal disorders:

Very common: nausea

Common: diarrhoea, stomatitis, vomiting, mouth ulceration, abdominal pain, glossitis, constipation, nausea and vomiting 

Skin and subcutaneous tissue disorders:

Common: alopecia, rash

Uncommon: palmar-plantar erythrodysesthesia (PPE) 

General disorders and administration site conditions:

Common: asthenia, fever, infusion-associated acute reactions 

Investigations:

Common: weight loss. 

The next paragraph has been changed from: 

Other less frequently (< 5 %) observed undesirable effects included palmar-plantar erythrodysesthesia, oral moniliasis, nausea and vomiting, vomiting, weight loss, rash, mouth ulceration, dyspnoea, abdominal pain, hypersensitivity reactions including anaphylactic reactions, vasodilatation, dizziness, anorexia, glossitis, constipation, paresthesia, retinitis and confusion. Following marketing, bullous eruption has been reported rarely in this population.

 To: 

Other less frequently (< 5 %) observed undesirable effects included hypersensitivity reactions including anaphylactic reactions,   Following marketing, bullous eruption has been reported rarely in this population.

 In the paragraph starting All patients: the word “drug” has been changed to “medicinal product”.

 The following paragraph has been added to this section: 

Myelosuppression associated with anaemia, thrombocytopaenia, leukopaenia, and rarely febrile neutropaenia, has been reported in Caelyx -treated patients.

 The following paragraphs have been added at the end of Section 4.8: 

Following the marketing of Caelyx, serious skin conditions including erythema multiforme, Stevens Johnson syndrome and toxic epidermal necrolysis have been reported very rarely. 

In patients treated with Caelyx, cases of venous thromboembolism, including thrombophlebitis, venous thrombosis and pulmonary embolism have been seen uncommonly. However, because patients with cancer are at increased risk for thromboembolic disease, a causal relationship cannot be determined.

 Section 5.2

 Table 5 and all references to Table 5 have been changed to Table 6

 Section 6.4

 The following sentence has been added: 

For storage conditions of the diluted medicinal product, see section 6.3.

 Section 10

 Date of revision of text updated

 First sentence changed from:

     Caelyx contains 2 mg/ml doxorubicin hydrochloride in a pegylated liposomal formulation.

 To: 

One ml of Caelyx contains 2 mg doxorubicin hydrochloride in a pegylated liposomal formulation.

 Last sentence changed from:

     For excipients, see section 6.1.

 To:

     For a full list of excipients, see section 6.1.

 Section 4.2

 Section entitled Paediatric patients: changed from: 

Paediatric patients: Safety and effectiveness in patients less than 18 years of age have not been established.

 To: 

Paediatric patients: The experience in children is limited. Caelyx is not recommended in patients below 18 years of age.

 Section 4.3 

Changed from: 

Caelyx must not be used to treat AIDS-KS that may be treated effectively with local therapy or systemic alfa-interferon.

 To: 

·                Hypersensitivity to the active substance or to any of the excipients. 

Caelyx must not be used to treat AIDS-KS that may be treated effectively with local therapy or systemic alfa-interferon.

 Section 4.5 

First sentence has been changed from: 

No formal drug interaction studies have been conducted with Caelyx, although phase II combination trials with conventional chemotherapy agents have been conducted in patients with gynaecological malignancies

 To: 

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.

 Section 4.6 

Pregnancy: Second sentence has been changed from: 

Therefore, Caelyx should not be used unless clearly necessary. 

To: 

Therefore, Caelyx should not be used during pregnancy unless clearly necessary. 

Lactation:  First sentence changed from: 

It is not known whether Caelyx is 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.

 To: 

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.

 Section 4.8

 Section entitled Breast Cancer Program: (heading amended to Breast cancer program).

 Last sentence of second paragraph changed from: 

See Table 4 for complete listing of undesirable effects reported in ³ 5 % of Caelyx-treated patients.

 To: 

See Table 4 for complete listing of undesirable effects reported in Caelyx-treated patients.

 Paragraph 3 changed from: 

Anaemia, leukopaenia and thrombocytopaenia were infrequently reported among Caelyx patients at incidences of 5 %, 2 %, and 1 %, respectively. The incidence of life threatening (Grade IV) 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).

To: 

The incidence of life threatening (Grade IV) 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).

Table 4 completely updated in respect of Adverse Events.

First paragraph after Table 4 (Undesirable effects reported between ….) has been deleted.

Next paragraph changed from: 

Ovarian cancer program: 512 patients with ovarian cancer (a subset of 876 solid tumour patients) were treated with Caelyx at a dose of 50 mg/m² in clinical trials. See Table 4 for undesirable effects reported in ³ 5 % of Caelyx-treated patients.

 To: 

Ovarian cancer program: 512 patients with ovarian cancer (a subset of 876 solid tumour patients) were treated with Caelyx at a dose of 50 mg/m² in clinical trials. See Table 5 for undesirable effects reported in Caelyx-treated patients.

 New Table 5 added

 Following paragraph changed from: 

Myelosuppression was mostly mild or moderate and manageable. Leukopaenia was the most frequently reported haematological adverse effect, followed by anaemia, neutropaenia and thrombocytopaenia. Life threatening (Grade IV) haematological effects were reported at incidences of 1.6 %, 0.4 %, 2.9 %, 0.2 % respectively. Sepsis related to leukopaenia was observed infrequently (< 1 %). Growth factor support was required infrequently (< 5 %) and transfusion support was required in approximately 15 % of patients (see section 4.2).

 The following paragraph has been deleted: 

Undesirable effects reported between 1 % and 5 % in Caelyx-treated patients were headache, allergic reaction, chills, infection, chest pain, back pain, malaise, vasodilatation, cardiovascular disorder, oral moniliasis, mouth ulceration, esophagitis, nausea and vomiting, gastritis, dysphagia, dry mouth, flatulence, gingivitis, hypochromic anaemia, peripheral oedema, weight loss, dehydration, cachexia, myalgia, dizziness, insomnia, anxiety, neuropathy, depression, hypertonia, dyspnoea, increased cough, vesiculobullous rash, pruritus, exfoliative dermatitis, skin disorder, maculopapular rash, sweating, acne, herpes zoster, skin ulcer, conjunctivitis, taste perversion, urinary tract infection, dysuria and vaginitis.

 Under section entitled AIDS-KS program, paragraph changed from: 

Clinical studies on AIDS-KS patients treated at 20 mg/m² with Caelyx show that myelosuppression was the most frequent undesirable effect considered related to Caelyx occurring in approximately one-half of the patients.

 To: 

Clinical studies on AIDS-KS patients treated at 20 mg/m² with Caelyx show that myelosuppression was the most frequent undesirable effect considered related to Caelyx occurring very commonly (in approximately one-half of the patients).

 The following paragraph has been deleted: 

Other frequently (³ 5 %) observed undesirable effects were nausea, asthenia, alopecia, fever, diarrhoea, infusion-associated acute reactions, and stomatitis.

 The first sentence of next paragraph has been amended slightly from: 

Respiratory undesirable effects frequently (³ 5 %) occurred in clinical studies of Caelyx and may be related to opportunistic infections in the AIDS population.

 To:

 After this paragraph, the following has been added: 

Undesirable effects observed in patients with AIDS-KS according to CIOMS III frequency categories (Very common (> 1/10); Common (> 1/100, < 1/10); Uncommon (> 1/1,000, < 1/100)) were as follows:

 Infections and infestations:

Common: oral moniliasis 

Blood and lymphatic system disorders:

Very common: neutropaenia, anaemia, leukopaenia

Common: thrombocytopaenia 

Metabolism and nutrition disorders:

Common: anorexia 

Psychiatric disorders:

Uncommon: confusion 

Nervous system disorders:

Common: dizziness

Uncommon: paresthesia  

Eye disorders:

Common: retinitis 

Vascular disorders:

Common: vasodilatation 

Respiratory, thoracic and mediastinal disorders:

Common: dyspnoea 

Gastrointestinal disorders:

Very common: nausea

Common: diarrhoea, stomatitis, vomiting, mouth ulceration, abdominal pain, glossitis, constipation, nausea and vomiting 

Skin and subcutaneous tissue disorders:

Common: alopecia, rash

Uncommon: palmar-plantar erythrodysesthesia (PPE) 

General disorders and administration site conditions:

Common: asthenia, fever, infusion-associated acute reactions 

Investigations:

Common: weight loss. 

The next paragraph has been changed from: 

Other less frequently (< 5 %) observed undesirable effects included palmar-plantar erythrodysesthesia, oral moniliasis, nausea and vomiting, vomiting, weight loss, rash, mouth ulceration, dyspnoea, abdominal pain, hypersensitivity reactions including anaphylactic reactions, vasodilatation, dizziness, anorexia, glossitis, constipation, paresthesia, retinitis and confusion. Following marketing, bullous eruption has been reported rarely in this population.

 To: 

Other less frequently (< 5 %) observed undesirable effects included hypersensitivity reactions including anaphylactic reactions,   Following marketing, bullous eruption has been reported rarely in this population.

 In the paragraph starting All patients: the word “drug” has been changed to “medicinal product”.

 The following paragraph has been added to this section: 

Myelosuppression associated with anaemia, thrombocytopaenia, leukopaenia, and rarely febrile neutropaenia, has been reported in Caelyx -treated patients.

 The following paragraphs have been added at the end of Section 4.8: 

Following the marketing of Caelyx, serious skin conditions including erythema multiforme, Stevens Johnson syndrome and toxic epidermal necrolysis have been reported very rarely. 

In patients treated with Caelyx, cases of venous thromboembolism, including thrombophlebitis, venous thrombosis and pulmonary embolism have been seen uncommonly. However, because patients with cancer are at increased risk for thromboembolic disease, a causal relationship cannot be determined.

 Section 5.2

 Table 5 and all references to Table 5 have been changed to Table 6

 Section 6.4

 The following sentence has been added: 

For storage conditions of the diluted medicinal product, see section 6.3.

 Section 10

 Date of revision of text updated