Adverse reactions : תופעות לוואי

4.8. Undesirable effects

Summary of the safety profile
Amongst the most serious and/or common adverse reactions reported in trastuzumab usage (intravenous and subcutaneous formulations) to date are cardiac dysfunction, infusion-related reactions, haematotoxicity (in particular neutropenia), infections and pulmonary adverse reactions.

Tabulated list of adverse reactions

In this section, the following categories of frequency have been used: 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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Presented in Table 1 are adverse reactions that have been reported in association with the use of intravenous trastuzumab alone or in combination with chemotherapy in pivotal clinical trials and in the post-marketing setting.

All the terms included are based on the highest percentage seen in pivotal clinical trials. In addition, terms reported in the post-marketing setting are included in Table 1.

Table 1 Undesirable Effects Reported with Intravenous Trastuzumab Monotherapy or in Combination with Chemotherapy in Pivotal Clinical Trials (N = 8386) and Post-Marketing System organ class           Adverse reaction                             Frequency Infections and infestations  Infection                                    Very common Nasopharyngitis                              Very common
Neutropenic sepsis                           Common
Cystitis                                     Common
Influenza                                    Common

Sinusitis                             Common
Skin infection                        Common
Rhinitis                              Common
Upper respiratory tract infection     Common
Urinary tract infection               Common
Pharyngitis                           Common
Neoplasms benign,             Malignant neoplasm progression        Not known malignant and unspecified     Neoplasm progression                  Not known (incl. cysts and polyps)
Blood and lymphatic           Febrile neutropenia                   Very common system disorders              Anaemia                               Very common Neutropenia                           Very common
White blood cell count                Very common decreased/leukopenia
Thrombocytopenia                      Very common
Hypoprothrombinaemia                  Not known
Immune thrombocytopenia               Not known
Immune system disorders       Hypersensitivity                      Common +
Anaphylactic reaction               Rare
+
Anaphylactic shock                  Rare
Metabolism and nutrition      Weight decreased/Weight loss          Very common disorders                     Anorexia                              Very common Tumour lysis syndrome                 Not known
Hyperkalaemia                         Not known
Psychiatric disorders         Insomnia                              Very common Anxiety                               Common
Depression                            Common
Nervous system disorders      1
Tremor                               Very common
Dizziness                             Very common
Headache                              Very common
Paraesthesia                          Very common
Dysgeusia                             Very common
Peripheral neuropathy                 Common
Hypertonia                            Common
Somnolence                            Common
Eye disorders                 Conjunctivitis                        Very common Lacrimation increased                 Very common
Dry eye                               Common
Papilloedema                          Not known
Retinal haemorrhage                   Not known
Ear and labyrinth disorders   Deafness                              Uncommon Cardiac disorders             1
Blood pressure decreased            Very common
1
Blood pressure increased            Very common
1
Heartbeat irregular                 Very common
1
Cardiac flutter                      Very common
Ejection fraction decreased*          Very common
+
Cardiac failure (congestive)        Common
+1
Supraventricular tachyarrhythmia   Common
Cardiomyopathy                        Common
1
Palpitation                          Common
Pericardial effusion                  Uncommon
Cardiogenic shock                     Not known
Gallop rhythm present                   Not known
Vascular disorders           Hot flush                               Very common +1
Hypotension                          Common
Vasodilatation                          Common
Respiratory, thoracic and    +
Dyspnoea                              Very common mediastinal disorders        Cough                                   Very common Epistaxis                               Very common
Rhinorrhoea                             Very common
+
Pneumonia                             Common
Asthma                                  Common
Lung disorder                           Common
+
Pleural effusion                      Common
+1
Wheezing                             Uncommon
Pneumonitis                             Uncommon
+
Pulmonary fibrosis                    Not known
+
Respiratory distress                  Not known
+
Respiratory failure                   Not known
+
Lung infiltration                     Not known
+
Acute pulmonary oedema                Not known
+
Acute respiratory distress syndrome   Not known
+
Bronchospasm                          Not known
+
Hypoxia                               Not known
+
Oxygen saturation decreased           Not known
Laryngeal oedema                        Not known
Orthopnoea                              Not known
Pulmonary oedema                        Not known
Interstitial lung disease               Not known
Gastrointestinal disorders   Diarrhoea                               Very common Vomiting                                Very common
Nausea                                  Very common
1
Lip swelling                          Very common
Abdominal pain                          Very common
Dyspepsia                               Very common
Constipation                            Very common
Stomatitis                              Very common
Haemorrhoids                            Common
Dry mouth                               Common
Hepatobiliary disorders      Hepatocellular injury                   Common Hepatitis                               Common
Liver tenderness                        Common
Jaundice                                Rare
Skin and subcutaneous        Erythema                                Very common tissue disorders             Rash                                    Very common 1
Swelling face                         Very common
Alopecia                                Very common
Nail disorder                           Very common
Palmar-plantar erythrodysaesthesia      Very common syndrome
Acne                                    Common
Dry skin                                Common

Ecchymosis                                        Common
Hyperhydrosis                                     Common
Maculopapular rash                                Common
Pruritus                                          Common
Onychoclasis                                      Common
Dermatitis                                        Common
Urticaria                                         Uncommon
Angioedema                                        Not known
Musculoskeletal and               Arthralgia                                        Very common connective tissue disorders       1
Muscle tightness                                 Very common
Myalgia                                           Very common
Arthritis                                         Common
Back pain                                         Common
Bone pain                                         Common
Muscle spasms                                     Common
Neck pain                                         Common
Pain in extremity                                 Common
Renal and urinary                 Renal disorder                                    Common disorders                         Glomerulonephritis membranous                     Not known Glomerulonephropathy                              Not known
Renal failure                                     Not known
Pregnancy, puerperium             Oligohydramnios                                   Not known and perinatal conditions          Renal hypoplasia                                  Not known Pulmonary hypoplasia                              Not known
Reproductive system and           Breast inflammation/mastitis                      Common breast disorders
General disorders and             Asthenia                                          Very common administration site               Chest pain                                        Very common conditions                        Chills                                            Very common Fatigue                                           Very common
Influenza-like symptoms                           Very common
Infusion-related reaction                         Very common
Pain                                              Very common
Pyrexia                                           Very common
Mucosal inflammation                              Very common
Peripheral oedema                                 Very common
Malaise                                           Common
Oedema                                            Common
Injury, poisoning and             Contusion                                         Common procedural complications


+ Denotes adverse reactions that have been reported in association with a fatal outcome.
1 Denotes adverse reactions that are reported largely in association with infusion-related reactions. Specific percentages for these are not available.
* Observed with combination therapy following anthracyclines and combined with taxanes.

Description of selected adverse reactions

Cardiac dysfunction
Congestive heart failure (NYHA Class II – IV) is a common adverse reaction associated with the use of trastuzumab and has been associated with a fatal outcome (see section 4.4). Signs and symptoms of cardiac dysfunction, such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, S3 gallop, or reduced ventricular ejection fraction, have been observed in patients treated with trastuzumab (see section 4.4).

In 3 pivotal clinical trials of adjuvant trastuzumab given in combination with chemotherapy, the incidence of grade 3/4 cardiac dysfunction (specifically symptomatic congestive heart failure) was similar in patients who were administered chemotherapy alone (i.e., did not receive trastuzumab) and in patients who were administered trastuzumab sequentially after a taxane (0.3-0.4 %). The rate was highest in patients who were administered trastuzumab concurrently with a taxane (2.0 %). In the neoadjuvant setting, the experience of concurrent administration of trastuzumab and low-dose anthracycline regimen is limited (see section 4.4).

When trastuzumab was administered after completion of adjuvant chemotherapy, NYHA Class III-IV heart failure was observed in 0.6 % of patients in the one-year arm after a median follow-up of 12 months. In study BO16348, after a median follow-up of 8 years, the incidence of severe CHF (NYHA Class III & IV) in the trastuzumab 1-year treatment arm was 0.8 %, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6 %.

Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥50 % after the event) was evident for 71.4 % of trastuzumab-treated patients. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5 % of patients.
Approximately 17 % of cardiac dysfunction-related events occurred after completion of trastuzumab.

In the pivotal metastatic trials of intravenous trastuzumab, the incidence of cardiac dysfunction varied between 9 % and 12 % when it was combined with paclitaxel compared with 1 % – 4 % for paclitaxel alone. For monotherapy, the rate was 6 % – 9 %. The highest rate of cardiac dysfunction was seen in patients receiving trastuzumab concurrently with anthracycline/cyclophosphamide (27 %), and was significantly higher than for anthracycline/cyclophosphamide alone (7 % – 10 %). In a subsequent trial with prospective monitoring of cardiac function, the incidence of symptomatic CHF was 2.2 % in patients receiving trastuzumab and docetaxel, compared with 0 % in patients receiving docetaxel alone. Most of the patients (79 %) who developed cardiac dysfunction in these trials experienced an improvement after receiving standard treatment for CHF.

Infusion reactions, allergic-like reactions and hypersensitivity
It is estimated that approximately 40 % of patients who are treated with trastuzumab will experience some form of infusion-related reaction. However, the majority of infusion-related reactions are mild to moderate in intensity (NCI-CTC grading system) and tend to occur earlier in treatment, i.e., during infusions one, two and three and lessen in frequency in subsequent infusions. Reactions include chills, fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, respiratory distress, rash, nausea, vomiting and headache (see section 4.4). The rate of infusion- related reactions of all grades varied between studies depending on the indication, the data collection methodology, and whether trastuzumab was given concurrently with chemotherapy or as monotherapy.

Severe anaphylactic reactions requiring immediate additional intervention can occur usually during either the first or second infusion of trastuzumab (see section 4.4) and have been associated with a fatal outcome.

Anaphylactoid reactions have been observed in isolated cases.

Haematotoxicity
Febrile neutropenia, leukopenia, anaemia, thrombocytopenia and neutropenia occurred very commonly. The frequency of occurrence of hypoprothrombinemia is not known. The risk of neutropenia may be slightly increased when trastuzumab is administered with docetaxel following anthracycline therapy.



Pulmonary events
Severe pulmonary adverse reactions occur in association with the use of trastuzumab and have been associated with a fatal outcome. These include, but are not limited to, pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency (see section 4.4).

Immunogenicity

In the neoadjuvant-adjuvant EBC study (BO22227), at a median follow-up exceeding 70 months, 10.1% (30/296) of patients treated with intravenous trastuzumab developed antibodies against trastuzumab. Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of 30 patients in the trastuzumab intravenous arm.

The clinical relevance of these antibodies is not known; The presence of anti-trastuzumab antibodies had no impact on pharmacokinetics, efficacy (determined by pathological Complete Response [pCR] and event-free survival [EFS]) and safety determined by occurrence of administration related reactions (ARRs) of intravenous trastuzumab.

There are no immunogenicity data available for trastuzumab in gastric cancer.


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/

Additionally, you can report to Unipharm Ltd. via the following address: https://unipharm.co.il/