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 (46.8%), thrombocytopenia (36.7%) and anaemia (28.4%). The most frequently reported adverse reaction was peripheral sensory neuropathy (47.8%). The most commonly reported Grade 3 or 4 adverse reactions were blood and lymphatic system disorders including neutropenia (41.7%), thrombocytopenia (27.3%) and anaemia (14.0%). The most commonly reported serious adverse reaction was pneumonia (11.5%).
Other serious adverse reactions reported included pyrexia (4.0%), lower respiratory tract infection (2.9%), pulmonary embolism (2.9%), influenza (2.9%), 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

• Pomalidomide in combination with bortezomib and dexamethasone
In randomised study CC-4047-MM-007, 278 patients received pomalidomide, bortezomib and dexamethasone (Pom+Btz+Dex arm). See section 4.2 for dosing information.

The adverse reactions observed in patients treated with pomalidomide in combination with bortezomib and dexamethasone 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 for Pom+Btz+Dex (any grade) 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).


Table 7. All Adverse Reactions (ADRs) reported in clinical trial MM-007 in patients treated with pomalidomide in combination with bortezomib and dexamethasone.
System Organ Class/       All Adverse Reactions                   Grade 3−4 Adverse Reactions Preferred Term            /Frequency                              /Frequency Infections and            Very Common                             Very Common infestations              Pneumonia                               Pneumonia Bronchitis
Upper respiratory tract infection       Common
Viral upper respiratory tract infection Sepsis
Septic shock
Common                                  Clostridium difficile colitis Sepsis                                  Bronchitis
Septic shock                            Upper respiratory tract infection Clostridium difficile colitis           Respiratory tract infection
Respiratory tract infection             Lower respiratory tract infection Lower respiratory tract infection       Lung infection
Lung infection                          Influenza
Influenza                               Bronchiolitis
Bronchiolitis                           Urinary tract infection
Urinary tract infection
Neoplasms benign,         Common
malignant and             Basal cell carcinoma
unspecified (incl cysts
and polyps)
Blood and lymphatic       Very Common                             Very Common system disorders          Neutropenia                             Neutropenia Thrombocytopenia                        Thrombocytopenia
Leucopenia                              Anaemia
Anaemia
Common
Common                                  Febrile neutropenia
Febrile neutropenia                     Leucopenia
Lymphopenia                             Lymphopenia


System Organ Class/     All Adverse Reactions                Grade 3−4 Adverse Reactions Preferred Term          /Frequency                           /Frequency Metabolism and          Very Common                          Common
nutrition disorders     Hypokalaemia                         Hypokalaemia Hyperglycaemia                       Hyperglycaemia
Hypomagnaesaemia
Common                               Hypocalcaemia
Hypomagnesaemia                      Hypophosphataemia
Hypocalcaemia                        Hyperkalaemia
Hypophosphataemia                    Hypercalcaemia
Hyperkalaemia
Hypercalcaemia
Psychiatric disorders   Very Common                          Common
Insomnia                             Depression
Insomnia
Common
Depression
Nervous system          Very Common                          Common
disorders               Peripheral sensory neuropathy        Syncope
Dizziness                            Peripheral sensory neuropathy
Tremor                               Peripheral sensorimotor neuropathy 
Common                               Uncommon
Syncope                              Dizziness
Peripheral sensorimotor neuropathy   Tremor
Paraesthesia
Dysgeusia
Eye disorders           Common                               Common
Cataract                             Cataract
Cardiac disorders       Common                               Common
Atrial fibrillation                  Atrial fibrillation
Vascular disorders      Common                               Common
Deep vein thrombosis                 Hypotension
Hypotension                          Hypertension
Hypertension
Uncommon
Deep vein thrombosis

System Organ Class/     All Adverse Reactions        Grade 3−4 Adverse Reactions Preferred Term          /Frequency                   /Frequency
Respiratory, thoracic   Very Common                  Common
and mediastinal         Dyspnoea                     Pulmonary embolism disorders
Cough                        Dyspnoea

Common
Pulmonary embolism
Gastrointestinal        Very Common                  Common
disorders               Diarrhoea                    Diarrhoea
Vomiting                     Vomiting
Nausea                       Abdominal pain
Constipation                 Constipation

Common                       Uncommon
Abdominal pain               Abdominal pain upper
Abdominal pain upper         Stomatitis
Stomatitis                   Nausea
Dry mouth                    Abdominal distension
Abdominal distension
Skin and subcutaneous   Common                       Common
tissue disorders        Rash                         Rash
Musculoskeletal and     Very Common                  Common
connective tissue       Muscular weakness            Muscular weakness disorders
Back pain                    Back pain

Common                       Uncommon
Bone pain                    Bone pain
Muscle spasms
Renal and urinary       Common                       Common
disorders               Acute kidney injury          Acute kidney injury Chronic kidney injury        Chronic kidney injury
Urinary retention            Urinary retention
General disorders and   Very Common                  Common
administration site     Fatigue                      Fatigue
conditions
Pyrexia                      Pyrexia
Oedema peripheral            Non-cardiac chest pain
Oedema peripheral
Common                       Oedema
Non-cardiac chest pain
Oedema

System Organ Class/         All Adverse Reactions                Grade 3−4 Adverse Reactions Preferred Term              /Frequency                           /Frequency Investigations              Common                               Common Alanine aminotransferase increased   Weight decreased
Weight decreased
Uncommon
Alanine aminotransferase increased
Injury, poisoning and       Common                               Uncommon procedural                  Fall                                 Fall complications

Tabulated list of adverse reactions
• Pomalidomide in combination with dexamethasone
In randomised study CC-4047-MM-003, 302 patients with relapsed and refractory multiple myeloma were exposed to 4 mg pomalidomide administered once daily for 21 days of each 28–day cycle in combination with a weekly low dose of dexamethasone.

The adverse reactions observed in patients treated with pomalidomide plus dexamethasone are listed below in Table 8 by system organ class (SOC) and frequency for all adverse reactions (ADRs) and for Grade 3 or 4 adverse reactions.

The frequencies of adverse reactions are those reported in the pomalidomide plus dexamethasone arm of study CC-4047-MM-003 (n = 302). Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness. 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).

Table 8. ADRs reported in clinical study MM-003 in patients treated with pomalidomide in combination with dexamethasone.


System Organ Class/         All ADRs                             Grade 3−4 ADRs Preferred Term              /Frequency                           /Frequency Infections and              Very Common                          Common infestations                Pneumonia (bacterial, viral and      Neutropenic sepsis, Pneumonia fungal infections, including         (bacterial, viral and fungal infections, opportunistic infections)            including opportunistic infections), Bronchopneumonia, Respiratory tract
Common                               infection, Upper respiratory tract infection
Neutropenic sepsis,
Bronchopneumonia, Bronchitis
Respiratory tract infection, Upper   Uncommon
respiratory tract infection,         Bronchitis
Nasopharyngitis, Herpes zoster       Herpes zoster


System Organ Class/       All ADRs                            Grade 3−4 ADRs Preferred Term            /Frequency                          /Frequency Neoplasms benign,         Uncommon                            Uncommon malignant and             Basal cell carcinoma of the skin,   Basal cell carcinoma of the skin, unspecified (incl cysts
Squamous cell carcinoma of the skin Squamous cell carcinoma of the skin and polyps)

Blood and lymphatic       Very Common                         Very Common system disorders          Neutropenia,                        Neutropenia, Thrombocytopenia,                   Thrombocytopenia,
Leucopenia,                         Anaemia
Anaemia
Common
Common                              Febrile neutropenia,
Febrile neutropenia,                Leucopenia,


Metabolism and            Very Common                         Common
nutrition disorders       Decreased appetite                  Hyperkalaemia, Hyponatraemia,
Common
Hyperkalaemia,                      Uncommon
Hyponatraemia,                      Decreased appetite,


Psychiatric disorders     Common                              Common
Confusional state                   Confusional state
Nervous system            Common                              Common
disorders                 Depressed level of consciousness,   Depressed level of consciousness Peripheral sensory neuropathy,
Dizziness,                          Uncommon
Tremor,                             Peripheral sensory neuropathy,
Dizziness,
Tremor,

Ear and labyrinth         Common                              Common
disorders                 Vertigo                             Vertigo 

Vascular disorders        Common                              Uncommon Deep vein thrombosis                Deep vein thrombosis


System Organ Class/       All ADRs                       Grade 3−4 ADRs Preferred Term            /Frequency                     /Frequency
Respiratory, thoracic     Very Common                    Common
and mediastinal           Dyspnoea,                      Dyspnoea
disorders                 Cough
Uncommon
Common                         Pulmonary embolism,
Pulmonary embolism,            Cough,


Gastrointestinal          Very Common                    Common
disorders                 Diarrhoea,                     Diarrhoea,
Nausea,                        Vomiting,
Constipation                   Constipation
Common                         Uncommon
Vomiting,                      Nausea,
Gastrointestinal haemorrhage   Gastrointestinal haemorrhage


Hepatobiliary disorders   Uncommon                       Uncommon
Hyperbilirubinaemia,           Hyperbilirubinaemia


Skin and subcutaneous     Common                         Common
tissue disorders          Rash,                          Rash
Pruritus
Musculoskeletal and       Very Common                    Common
connective tissue         Bone pain,                     Bone pain
disorders                 Muscle spasms
Uncommon
Muscle spasms
Renal and urinary         Common                         Common
disorders                 Renal failure,                 Renal failure Urinary retention
Uncommon
Urinary retention
Reproductive system       Common                         Common
and breast disorders      Pelvic pain                    Pelvic pain


System Organ Class/           All ADRs                                Grade 3−4 ADRs Preferred Term                /Frequency                              /Frequency General disorders and         Very Common                             Common administration site           Fatigue,                                Fatigue, conditions
Pyrexia,                                Pyrexia,
Oedema peripheral                       Oedema peripheral


Investigations                Common                                  Common Neutrophil count decreased,             Neutrophil count decreased,
White blood cell count decreased,       White blood cell count decreased, Platelet count decreased,               Platelet count decreased,
Alanine aminotransferase increased,     Alanine aminotransferase increased 

Tabulated list of post-marketing adverse reactions

In addition to the above adverse reactions identified from the pivotal clinical trials, the following Table 9 is derived from data gathered from post-marketing surveillance.

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

Table 9. ADRs reported in post-marketing use in patients treated with pomalidomide.
System Organ Class/       All Adverse Reactions                Grade 3−4 Adverse Reactions Preferred Term            /Frequency                           /Frequency Infections and            Not Known                            Not Known infestations              Hepatitis B reactivation             Hepatitis B reactivation Blood and lymphatic           Common                                  Common system disorders              Pancytopenia                            Pancytopenia Immune system                 Common                                  Uncommon disorders
Angioedema                              Angioedema
Urticaria                               Urticaria
Not Known                               Not Known
Anaphylactic reaction                   Anaphylactic reaction
Solid organ transplant rejection
Endocrine disorders           Uncommon
Hypothyroidism
Metabolism and                Common                                  Common nutrition disorders           Hyperuricaemia                          Hyperuricaemia 
Uncommon                                Uncommon
Tumour lysis syndrome                   Tumour lysis syndrome

System Organ Class/          All Adverse Reactions                 Grade 3−4 Adverse Reactions Preferred Term               /Frequency                            /Frequency Nervous system               Common
disorders                    Intracranial haemorrhage

Uncommon                              Uncommon
Cerebrovascular accident              Cerebrovascular accident
Intracranial haemorrhage
Cardiac disorders            Common                                Common Cardiac failure                       Cardiac failure
Atrial fibrillation                   Atrial fibrillation
Myocardial infarction
Uncommon
Myocardial infarction
Respiratory, thoracic        Common                                Uncommon and mediastinal              Epistaxis                             Epistaxis disorders
Interstitial lung disease             Interstitial lung disease
Hepatobiliary disorders      Uncommon
Hepatitis
Skin and subcutaneous        Not Known                             Not Known tissue disorders             Drug Reaction with Eosinophilia and   Drug Reaction with Eosinophilia and Systemic Symptoms                     Systemic Symptoms
Toxic Epidermal Necrolysis            Toxic Epidermal Necrolysis
Stevens-Johnson Syndrome              Stevens-Johnson Syndrome
Investigations               Common                                Uncommon Blood uric acid increased             Blood uric acid increased

Description of selected adverse reactions

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
In patients receiving combination therapy with pomalidomide in clinical studies, neutropenia occurred in up to 46.8% of patients (41.7% Grade 3 or 4). Neutropenia did not lead to pomalidomide discontinuation in any patient and was infrequently serious.

Febrile neutropenia (FN) was reported in 3.2-6.7% of patients and was serious in 1.8-4.0% of patients (see section 4.2 and 4.4).

In patients receiving combination therapy with pomalidomide in clinical studies, thrombocytopenia occurred in 27.0-36.7% of patients. Thrombocytopenia was Grade 3 or 4 in 20.7-27.3% of patients, led to pomalidomide discontinuation in 0.7% of patients and was serious in 0.4-1.7% of 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.

Infection
Infection was the most common non haematological toxicity.

In patients receiving combination therapy with pomalidomide in clinical studies, infection occurred in 55.0-80.2% of patients (24.0-30.9% Grade 3 or 4).
Upper respiratory tract infection and pneumonia were the most frequently occurring infections. Fatal infections (Grade 5) occurred in 2.7-4.0% of patients. Infections led to pomalidomide discontinuation in 2.0-2.9% of 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).

In patients receiving combination therapy with pomalidomide in clinical studies, venous thromboembolic events (VTE) occurred in 3.3-11.5% of patients (1.3-5.4% Grade 3 or 4). VTE was reported as serious in 1.7-4.3% of patients, no fatal reactions were reported and VTE was associated with pomalidomide discontinuation in up to 1.8% 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 12.9% of patients, pomalidomide in 1.8% and dexamethasone in 2.2 - 8.9% of patients, respectively. Refer also to the bortezomib SmPC.

• 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