Adverse reactions : תופעות לוואי

4.8 Undesirable effects

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 Caelyx 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 Caelyx liposomal System Organ Class   Frequency All Grades                     Adverse Drug Reaction 
Infections and           Common                              Sepsis infestations                                                 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
Nasopharyngitis
Uncommon                            Herpes simplex
Fungal infection
Rare                                Opportunistic infection (including Aspergillus, Histoplasma, Isospora, Legionella, Microsporidium, Salmonella,
Staphylococcus, Toxoplasma, Tuberculosis)a
Neoplasms benign,        Not known                           Acute myeloid leukaemiab malignant and                                                Myelodysplastic syndromeb unspecified (including                                       Oral neoplasmb cysts and polyps)
Blood and lymphatic      Very common                         Leukopaenia system disorders                                             Neutropaenia Lymphopaenia
Anaemia (including hypochromic)
Common                              Thrombocytopaenia
Febrile neutropaenia
Uncommon                            Pancytopaenia
Thrombocytosis
Rare                                Bone marrow failure
Immune system            Uncommon                            Hypersensitivity disorders                                                    Anaphylactic reaction Rare                                Anaphylactoid reaction
Metabolism and           Very common                         Decreased appetite nutrition disorders      Common                              Cachexia Dehydration
Hypokalaemia
Hyponatraemia
Hypocalcaemia
Uncommon                            Hyperkalaemia
Hypomagnesaemia
Psychiatric disorders    Common                              Confusional state Anxiety
Depression
Insomnia
Nervous system           Common                              Neuropathy peripheral disorders                                                    Peripheral sensory neuropathy Neuralgia
Paraesthesia
Hypoaesthesia
Dysgeusia
Headache
Lethargy
Dizziness
Uncommon      Polyneuropathy
Convulsion
Syncope
Dysaesthesia
Somnolence
Eye disorders           Common        Conjunctivitis
Uncommon      Vision blurred
Lacrimation increased
Rare          Retinitis
Cardiac disordersa      Common        Tachycardia
Uncommon      Palpitations
Cardiac arrest
Cardiac failure
Cardiac failure congestive
Cardiomyopathy
Cardiotoxicity
Rare          Ventricular arrhythmia
Bundle branch block right
Conduction disorder
Atrioventricular block
Cyanosis
Vascular disorders      Common        Hypertension
Hypotension
Flushing
Uncommon      Pulmonary embolism
Infusion site necrosis (including soft tissue necrosis and skin necrosis)
Phlebitis
Orthostatic hypotension
Rare          Thrombophlebitis
Venous thrombosis
Vasodilatation
Respiratory, thoracic   Common        Dyspnoea and mediastinal                       Dyspnoea exertional disorders                             Epistaxis
Cough
Uncommon      Asthma
Chest discomfort
Rare          Throat tightness
Not Known     Interstitial lung disease
Gastrointestinal        Very common   Stomatitis disorders                             Nausea
Vomiting
Diarrhoea
Constipation
Common        Gastritis
Aphthous stomatitis
Mouth ulceration
Dyspepsia
Dysphagia
Oesophagitis
Abdominal pain
Abdominal pain upper
Oral pain
Dry mouth
Uncommon      Flatulence
Gingivitis
Rare          Glossitis
Lip ulceration
Skin and subcutaneous    Very common   Palmar plantar erythrodysaesthesia syndromea tissue disorders                       Rash (including erythematous, maculo-papular, and papular) Alopecia
Common        Skin exfoliation
Blister
Dry skin
Erythema
Pruritus
Hyperhidrosis
Skin hyperpigmentation
Uncommon      Dermatitis
Dermatitis exfoliative
Acne
Skin ulcer
Dermatitis allergic
Urticaria
Skin discolouration
Petechiae
Pigmentation disorder
Nail disorder
Rare          Toxic epidermal necrolysis
Erythema multiforme
Dermatitis bullous
Lichenoid keratosis
Not known     Stevens-Johnson syndromeb
Musculoskeletal and      Very common   Musculoskeletal pain (including musculoskeletal chest pain, back connective tissue                      pain, pain in extremity) disorders                Common        Muscle spasms
Myalgia
Arthralgia
Bone pain
Uncommon      Muscular weakness
Renal and urinary        Common        Dysuria disorders
Reproductive disorders   Uncommon      Breast pain
Rare          Vaginal infection
Scrotal erythema
General disorders and    Very common   Pyrexia administration site                    Fatigue conditions
Common        Infusion-related reaction
Pain
Chest pain
Influenza-like illness
Chills
Mucosal inflammation
Asthenia
Malaise
Oedema
Oedema peripheral
Uncommon      Administration site extravasation
Injection site reaction
Face oedema
Hyperthermia
Rare          Mucous membrane disorder
Investigations            Common                                     Weight decreased Uncommon                                   Ejection fraction decreased Rare                                       Liver function test abnormal (including Blood bilirubin increased, Alanine aminotransferase increased, and Aspartate aminotransferase increased)
Blood creatinine increased
Injury, poisoning and     Uncommon                                   Radiation recall phenomenona procedural complications 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 Caelyx 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 Caelyx liposomal and may be related to opportunistic infections (OI’s) in the AIDS population. Opportunistic infections are observed in KS patients after administration with Caelyx 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 patients with cardiac risk factors. Endomyocardial biopsies on nine of ten AIDS-KS patients receiving cumulative doses of Caelyx liposomal greater than 460 mg/m2 indicate no evidence of anthracycline-induced cardiomyopathy. The recommended dose of Caelyx 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 Caelyx 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%) randomized subjects (10 treated with Caelyx 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 Caelyx 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 Caelyx 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 occurred uncommonly with Caelyx liposomal administration.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form www.sideeffects.health.gov.il