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 in 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
1Tremor
Nervous system disorders                                                     Very common Dizziness                                     Very common
Headache                                      Very common
Paraesthesia                                  Very common
Dysgeusia                                     Very common
System organ class            Adverse reaction                       Frequency 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 1
Cardiac disorders               Blood pressure decreased             Very common 1
Blood pressure increased             Very common
1
Heart beat irregular                 Very common
1
Cardiac flutter                       Very common
Ejection fraction decreased*           Very common
+
Cardiac failure (congestive)         Common
+1Supraventricular 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
+Dyspnoea
Very common
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
System organ class            Adverse reaction                     Frequency 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 1Muscle tightness connective tissue disorders                                        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
System organ class               Adverse reaction                                   Frequency 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 (ie 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 trastuzumab intravenous 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 trastuzumab intravenous.

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