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 to date are cardiac dysfunction, infusion-related reactions, hematotoxicity (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 = 8,386) 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 and    Malignant neoplasm progression      Not known unspecified (incl. Cysts and       Neoplasm progression                Not known polyps)
Blood and lymphatic system         Febrile neutropenia                 Very common disorders                          Anemia                              Very common Neutropenia                         Very common
White blood cell count              Very common decreased/leukopenia
Thrombocytopenia                    Very common
Hypoprothrombinemia                 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 Tumor lysis syndrome                Not known
Hyperkalemia                        Not known
Psychiatric disorders              Insomnia                            Very common Anxiety                             Common
Depression                          Common
1
Nervous system disorders             Tremor                            Very common Dizziness                           Very common
Headache                            Very common
Paresthesia                         Very common
Dysgeusia                           Very common
Peripheral neuropathy               Common
Hypertonia                          Common
Somnolence                          Common
Eye disorders                      Conjunctivitis                      Very common Lacrimation increased               Very common
Dry eye                             Common
Papilledema                         Not known
Retinal hemorrhage                  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
System organ class             Adverse reaction                      Frequency +
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        Dyspnea                             Very common mediastinal disorders          Cough                                 Very common Epistaxis                             Very common
Rhinorrhea                            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 edema               Not known
+
Acute respiratory distress          Not known syndrome
+
Bronchospasm                        Not known
+
Hypoxia                             Not known
+
Oxygen saturation decreased         Not known
Laryngeal edema                       Not known
Orthopnea                             Not known
Pulmonary edema                       Not known
Interstitial lung disease             Not known
Gastrointestinal disorders     Diarrhea                              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
Hemorrhoids                           Common
Dry mouth                             Common
Hepatobiliary disorders        Hepatocellular injury                 Common Hepatitis                             Common
Liver tenderness                      Common
Jaundice                              Rare
Skin and subcutaneous tissue   Erythema                              Very common disorders                      Rash                                  Very common 1
Swelling face                       Very common
Alopecia                              Very common
Nail disorder                         Very common

System organ class                        Adverse reaction                           Frequency Palmar-plantar erythrodysesthesia          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 connective            Arthralgia                                 Very common 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 disorders               Renal disorder                             Common Glomerulonephritis membranous              Not known
Glomerulonephropathy                       Not known
Renal failure                              Not known
Pregnancy, puerperium and                 Oligohydramnios                            Not known perinatal conditions                      Renal hypoplasia                           Not known Pulmonary hypoplasia                       Not known
Reproductive system and breast            Breast inflammation/mastitis               Common disorders
General disorders and                     Asthenia                                   Very common administration site conditions            Chest pain                                 Very common 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 edema                           Very common
Malaise                                    Common
Edema                                      Common
Injury, poisoning and procedural          Contusion                                  Common 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 dyspnea, orthopnea, increased cough, pulmonary edema, 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, dyspnea, 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.

Hematotoxicity
Febrile neutropenia, leukopenia, anemia, 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 edema 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 authorization 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/.