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 Lipodox 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 Lipodox Liposomal System Organ
Frequency All Grades             Adverse Drug Reaction
Class
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                                         Oral neoplasmb
(including cysts and polyps)
Blood and          Very common                      Leukopaenia lymphatic system                                    Neutropaenia disorders                                           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             Common                Confusional state disorders                                     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 a
Cardiac disorders       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,         Common                Dyspnoea thoracic                                   Dyspnoea exertional and mediastinal                            Epistaxis disorders                                  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             Very common           Palmar plantar erythrodysaesthesia syndromea subcutaneous                               Rash (including erythematous, maculo-papular, tissue disorders                           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      Very common           Musculoskeletal pain (including musculoskeletal and connective                             chest pain, back pain, pain in extremity) tissue disorders     Common                Muscle spasms
Myalgia
Arthralgia
Bone pain
Uncommon              Muscular weakness
Renal and urinary    Common                Dysuria disorders
Reproductive         Uncommon              Breast pain disorders            Rare                  Vaginal infection
Scrotal erythema
General disorders    Very common           Pyrexia and administration                         Fatigue site 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          Uncommon                          Radiation recall phenomenona and 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 Lipodox 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 Lipodox Liposomal and may be related to opportunistic infections (OI’s) in the AIDS population. Opportunistic infections are observed in KS patients after administration with Lipodox 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/m 2 or at lower doses for patients with cardiac risk factors. Endomyocardial biopsies on nine of ten AIDS-KS patients receiving cumulative doses of Lipodox Liposomal greater than 460 mg/m 2 indicate no evidence of anthracycline- induced cardiomyopathy. The recommended dose of Lipodox Liposomal for AIDS-KS patients is 20 mg/m 2 every two-to-three weeks. The cumulative dose at which cardiotoxicity would become a concern for these AIDS-KS patients (> 400 mg/m 2) would require more than 20 courses of Lipodox 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 Lipodox 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 Lipodox 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/m 2, the incidence of clinically significant cardiac dysfunction was low. Of the 418 patients treated with Lipodox 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/m 2, 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/m 2), 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 Lipodox 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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il