Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile
Pomalidomide in combination with bortezomib and dexamethasone
The most commonly reported blood and lymphatic system disorders were neutropenia (54.0%), thrombocytopenia (39.9%) and anaemia (32.0%). Other most frequently reported adverse reactions included peripheral sensory neuropathy (48.2%), fatigue (38.8%), diarrhoea (38.1%), constipation (38.1%), and oedema peripheral (36.3%). The most commonly reported Grade 3 or 4 adverse reactions were blood and lymphatic system disorders including neutropenia (47.1%), thrombocytopenia (28.1%) and anaemia (15.1%). The most commonly reported serious adverse reaction was pneumonia (12.2%).
Other serious adverse reactions reported included pyrexia (4.3%), lower respiratory tract infection (3.6%), influenza (3.6%), pulmonary embolism (3.2%), atrial fibrillation (3.2%) and acute kidney injury (2.9%).

Pomalidomide in combination with dexamethasone
The most commonly reported adverse reactions in clinical studies have been blood and lymphatic system disorders including anaemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%); in general disorders and administration site conditions including fatigue (28.3%), pyrexia (21%) and oedema peripheral (13%); and in infections and infestations including pneumonia (10.7%). Peripheral neuropathy adverse reactions were reported in 12.3% of patients and venous embolic or thrombotic (VTE) adverse reactions were reported in 3.3% of patients. The most commonly reported Grade 3 or 4 adverse reactions were in the blood and lymphatic system disorders including neutropenia (41.7%), anaemia (27%) and thrombocytopenia (20.7%); in infections and infestations including pneumonia (9%); and in general disorders and administration site conditions including fatigue (4.7%), pyrexia (3%) and oedema peripheral (1.3%). The most commonly reported serious adverse reaction was pneumonia (9.3%). Other serious adverse reactions reported included febrile neutropenia (4.0%), neutropenia (2.0%), thrombocytopenia (1.7%) and VTE adverse reactions (1.7 %).

Adverse reactions tended to occur more frequently within the first 2 cycles of treatment with pomalidomide.

Tabulated list of adverse reactions

The adverse reactions observed in patients treated with pomalidomide in combination with bortezomib and dexamethasone, pomalidomide in combination with dexamethasone and from post-marketing surveillance are listed in Table 7 by system organ class (SOC) and frequency for all adverse reactions and for Grade 3 or 4 adverse reactions.

Frequencies are defined in accordance with current guidance, as: very common (≥1/10), common (≥1/100 to <1/10); and uncommon (≥1/1,000 to <1/100) and not known (frequency cannot be determined).

Table 7. Adverse reactions (ADRs) reported in clinical trials and post-market settings Combination of treatment             Pomalidomide/                       Pomalidomide/ bortezomib/dexamethasone                  dexamethasone
System Organ Class            All               Grade             All              Grade /Preferred term               ADRs              3−4               ADRs             3−4 ADRs                               ADRs
Infections and infestations
Pneumonia                           Very           Very              -                  - common         common
Pneumonia (bacterial, viral         -              -                 Very common        Common and fungal infections,
including opportunistic infections)
Bronchitis                          Very           Common            Common             Uncommon common
Upper respiratory tract             Very           Common            Common             Common infection                           common
Viral upper respiratory tract       Very           -                 -                  - infection                           common
Sepsis                              Common         Common            -                  - Septic shock                        Common         Common            -                  - Neutropenic sepsis                  -              -                 Common             Common Clostridium difficile colitis       Common         Common            -                  - Bronchopneumonia                    -              -                 Common             Common Respiratory tract infection         Common         Common            Common             Common Lower respiratory tract             Common         Common            -                  - infection
Lung infection                      Common         Uncommon          -                  - 

Combination of treatment              Pomalidomide/                 Pomalidomide/ bortezomib/dexamethasone            dexamethasone
System Organ Class             All            Grade            All          Grade /Preferred term                ADRs           3−4              ADRs         3−4 ADRs                          ADRs
Influenza                     Very           Common           -             - common
Bronchiolitis                 Common         Common           -             - Urinary tract infection       Very           Common           -             - common
Nasopharyngitis               -              -                Common        - Herpes zoster                 -              -                Common        Uncommon Hepatitis B reactivation      -              -                Not known*    Not known* Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma          Common         Uncommon         -             - Basal cell carcinoma of the   -              -                Uncommon      Uncommon skin
Squamous cell carcinoma       -              -                Uncommon      Uncommon of the skin
Blood and lymphatic system disorders
Neutropenia                   Very           Very             Very common   Very common         common                         common
Thrombocytopenia              Very           Very             Very common   Very common         common                         common
Leucopenia                    Very           Common           Very common   Common common
Anaemia                       Very           Very             Very common   Very common         common                         common
Febrile neutropenia           Common         Common           Common        Common Lymphopenia                   Common         Common           -             - Pancytopenia                  -              -                Common*       Common* Immune system disorders
Angioedema                    -              -                Common*       Uncommon* Urticaria                     -              -                Common*       Uncommon* Anaphylactic reaction         Not known*     Not known*       -             - Solid organ transplant        Not known*     -                -             - rejection


Combination of treatment            Pomalidomide/             Pomalidomide/ bortezomib/dexamethasone        dexamethasone
System Organ Class           All            Grade        All          Grade /Preferred term              ADRs           3−4          ADRs         3−4 ADRs                      ADRs
Endocrine disorders
Hypothyroidism              Uncommon*     -             -             -- Metabolism and nutrition disorders
Hypokalaemia                Very          Common        -             - common
Hyperglycaemia              Very          Common        -             - common
Hypomagnesaemia             Common        Common        -             - Hypocalcaemia               Common        Common        -             - Hypophosphataemia           Common        Common        -             - Hyperkalaemia               Common        Common        Common        Common Hypercalcaemia              Common        Common        -             - Hyponatraemia               -             -             Common        Common Decreased appetite          -             -             Very common   Uncommon Hyperuricaemia              -             -             Common*       Common* Tumour lysis syndrome       -             -             Uncommon*     Uncommon* Psychiatric disorders
Insomnia                    Very          Common        -             - common
Depression                  Common        Common        -             - Confusional state           -             -             Common        Common Nervous system disorders
Peripheral sensory          Very          Common        Common        Uncommon neuropathy                  common
Dizziness                   Very          Uncommon      Common        Uncommon common
Tremor                      Very          Uncommon      Common        Uncommon common
Syncope                     Common        Common        -             - Peripheral sensorimotor     Common        Common        -             - neuropathy


Combination of treatment             Pomalidomide/                Pomalidomide/ bortezomib/dexamethasone           dexamethasone
System Organ Class            All            Grade           All          Grade /Preferred term               ADRs           3−4             ADRs         3−4 ADRs                         ADRs
Paraesthesia                 Common              -          -             - Dysgeusia                    Common              -          -             - Depressed level of           -                   -          Common        Common consciousness
Intracranial haemorrhage     -                   -          Common*       Uncommon* Cerebrovascular accident     -                   -          Uncommon*     Uncommon* Eye disorders
Cataract                     Common              Common     -             - Ear and labyrinth disorders
Vertigo                      -                   -          Common        Common Cardiac disorders
Atrial fibrillation          Very                Common     Common*       Common* common
Cardiac failure              -                   -          Common*       Common* Myocardial infarction        -                   -          Common*       Uncommon* Vascular disorders
Deep vein thrombosis         Common              Uncommon   Common        Uncommon Hypotension                  Common              Common     -             - Hypertension                 Common              Common     -             - Respiratory, thoracic and mediastinal disorders
Dyspnoea                     Very                Common     Very common   Common common
Cough                        Very                -          Very common   Uncommon common
Pulmonary embolism           Common              Common     Common        Uncommon Epistaxis                    -                   -          Common*       Uncommon* Interstitial lung disease    -                   -          Common*       Uncommon* Gastrointestinal disorders
Diarrhoea                    Very                Common     Very common   Common common
Vomiting                     Very                Common     Common        Common common

Combination of treatment             Pomalidomide/                Pomalidomide/ bortezomib/dexamethasone           dexamethasone
System Organ Class            All            Grade           All          Grade /Preferred term               ADRs           3−4             ADRs         3−4 ADRs                         ADRs
Nausea                       Very                Uncommon   Very common   Uncommon common
Constipation                 Very                Common     Very common   Common common
Abdominal pain               Very                Common     -             - common
Abdominal pain upper         Common              Uncommon   -             - Stomatitis                   Common              Uncommon   -             - Dry mouth                    Common              -          -             - Abdominal distension         Common              Uncommon   -             - Gastrointestinal             -                   -          Common        Uncommon haemorrhage
Hepatobiliary disorders
Hyperbilirubinaemia          -                   -          Uncommon      Uncommon Hepatitis                    -                   -          Uncommon*     - Skin and subcutaneous tissue disorders
Rash                         Very                Common     Common        Common common
Pruritus                     -                   -          Common        - Drug Reaction with           -                   -          Not known*    Not known* Eosinophilia and Systemic
Symptoms
Toxic Epidermal              -                   -          Not known*    Not known* Necrolysis
Stevens-Johnson Syndrome     -                   -          Not known*    Not known* Musculoskeletal and connective tissue disorders
Muscular weakness            Very                Common     -             - common
Back pain                    Very                Common     -             - common
Bone pain                    Common              Uncommon   Very common   Common Muscle spasms                Very                -          Very common   Uncommon common
Renal and urinary disorders
Combination of treatment             Pomalidomide/             Pomalidomide/ bortezomib/dexamethasone        dexamethasone
System Organ Class            All            Grade        All          Grade /Preferred term               ADRs           3−4          ADRs         3−4 ADRs                      ADRs
Acute kidney injury          Common             Common   -             - Chronic kidney injury        Common             Common   -             - Urinary retention            Common             Common   Common        Uncommon Renal failure                -                  -        Common        Common Reproductive system and breast disorders
Pelvic pain                                              Common        Common General disorders and administration site conditions
Fatigue                      Very             Common     Very common   Common common
Pyrexia                      Very               Common   Very common   Common common
Oedema peripheral            Very               Common   Very common   Common common
Non-cardiac chest pain       Common             Common   -             - Oedema                       Common             Common   -             - Investigations
Alanine aminotransferase     Common             Common   Common        Common increased
Weight decreased             Common             Common   -             - Neutrophil count decreased   -                  -        Common        Common White blood cell count       -                  -        Common        Common decreased
Platelet count decreased     -                  -        Common        Common Blood uric acid increased    -                  -        Common*       Uncommon* Injury, poisoning and procedural complications
Fall                          Common           Common   -             - * Reported during post-marketing use.


Description of selected adverse reactions
The frequencies in this section are from clinical studies in patients receiving pomalidomide treatment in combination either with bortezomib and dexamethasone (Pom+Btz+Dex) or with dexamethasone (Pom+Dex).

Teratogenicity
Pomalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Pomalidomide was found to be teratogenic in both rats and rabbits when administered during the period of major organogenesis (see sections 4.6 and 5.3). If pomalidomide is taken during pregnancy, a teratogenic effect of pomalidomide in humans is expected (see section 4.4).

Neutropenia and thrombocytopenia
Neutropenia occurred in up to 54.0% (Pom+Btz+Dex) patients (47.1% (Pom+Btz+Dex) Grade 3 or 4).
Neutropenia led to pomalidomide discontinuation in 0.7% of any patients and was infrequently serious.

Febrile neutropenia (FN) was reported in 3.2% (Pom+Btz+Dex) patients and 6.7% (Pom+Dex) patients and was serious in 1.8% (Pom+Btz+Dex) patients and 4.0% (Pom+Dex) patients (see sections 4.2 and 4.4).

Thrombocytopenia occurred in 39.9% (Pom+Btz+Dex) patients and 27.0% (Pom+Dex) patients.
Thrombocytopenia was Grade 3 or 4 in 28.1% (Pom+Btz+Dex) patients and 20.7% (Pom+Dex) patients, led to pomalidomide discontinuation in 0.7% (Pom+Btz+Dex) patients and 0.7% (Pom+Dex) patients, and was serious in 0. 7% (Pom+ Btz+Dex) and 1.7% (Pom+Dex) patients (see sections 4.2 and 4.4).

Neutropenia and thrombocytopenia tended to occur more frequently within the first 2 cycles of treatment with pomalidomide in combination either with bortezomib and dexamethasone or with dexamethasone.

Infection
Infection was the most common non haematological toxicity.

Infection occurred in 83.1% (Pom+Btz+Dex) patients and 55.0% (Pom+Dex) patients (34.9% (Pom+Btz+Dex) and 24.0% (Pom +Dex) Grade 3 or 4). Upper respiratory tract infection and pneumonia were the most frequently occurring infections. Fatal infections (Grade 5) occurred in 4.0% (Pom+Btz+Dex) patients and 2.7% (Pom+Dex) patients. Infections led to pomalidomide discontinuation in 3.6% (Pom+Btz+Dex) patients and 2.0% (Pom+Dex) patients.

Thromboembolic events
Prophylaxis with acetylsalicylic acid (and other anticoagulants in high risk patients) was mandatory for all patients in clinical studies. Anticoagulation therapy (unless contraindicated) is recommended (see section 4.4).

Venous thromboembolic events (VTE) occurred in 12.2% (Pom+Btz+Dex) and 3.3% (Pom+Dex) patients (5.8% (Pom+Btz+Dex) and 1.3% (Pom+Dex) Grade 3 or 4). VTE was reported as serious in 4.7% (Pom+Btz+Dex) and 1.7% (Pom+Dex) patients, no fatal reactions were reported and VTE was associated with pomalidomide discontinuation in up to 2.2% (Pom+Btz+Dex) of patients.


Peripheral neuropathy
Pomalidomide in combination with bortezomib and dexamethasone
Patients with ongoing peripheral neuropathy ≥ Grade 2 with pain within 14 days prior to randomisation were excluded from clinical trials. Peripheral neuropathy occurred in 55.4 % of patients (10.8% Grade 3; 0.7% Grade 4). Exposure-adjusted rates were comparable across treatment arms. Approximately 30% of the patients experiencing peripheral neuropathy had a history of neuropathy at baseline. Peripheral neuropathy led to discontinuation of bortezomib in approximately 14.4% of patients, pomalidomide in 1.8% and dexamethasone in 1.8% of patients in the Pom+Btz+Dex arm and 8.9% of patients in the Btz+Dex arm.

Peripheral neuropathy - Pomalidomide in combination with dexamethasone Patients with ongoing peripheral neuropathy ≥Grade 2 were excluded from clinical studies. Peripheral neuropathy occurred in 12.3% of patients (1.0% Grade 3 or 4). No peripheral neuropathy reactions were reported as serious and peripheral neuropathy led to dose discontinuation in 0.3% of patients (see section 4.4).

Haemorrhage
Haemorrhagic disorders have been reported with pomalidomide, especially in patients with risk factors such as concomitant medicinal products that increase susceptibility to bleeding. Haemorrhagic events have included epistaxis, intracranial haemorrhage and gastrointestinal haemorrhage.

Allergic reactions and severe skin reactions
Angioedema, anaphylactic reaction and severe cutaneous reactions including SJS, TEN and DRESS have been reported with the use of pomalidomide. Patients with a history of severe rash associated with lenalidomide or thalidomide should not receive pomalidomide (see section 4.4).

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 and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com