Adverse reactions : תופעות לוואי

4.8. Undesirable effects
Summary of the safety profile

Amongst the most serious and/or common adverse reactions reported in Herceptin 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 Herceptin 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 Herceptin 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 System organ class            Adverse reaction                        Frequency Anxiety                                 Common
Depression                              Common
1
Nervous system disorders       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 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
+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
System organ class            Adverse reaction                     Frequency 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 1 connective tissue disorders     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
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 Herceptin 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 Herceptin (see section 4.4).

In 3 pivotal clinical trials of adjuvant Herceptin 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 Herceptin) and in patients who were administered Herceptin sequentially after a taxane (0.3-0.4 %). The rate was highest in patients who were administered Herceptin concurrently with a taxane (2.0 %). In the neoadjuvant setting, the experience of concurrent administration of Herceptin and low dose anthracycline regimen is limited (see section 4.4).

When Herceptin 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 Herceptin 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 Herceptin-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 Herceptin.

In the pivotal metastatic trials of intravenous Herceptin, 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 Herceptin 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 Herceptin 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 Herceptin 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 Herceptin (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 Herceptin 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).

Details of risk minimisation measures that are consistent with the EU Risk Management Plan are presented in (section 4.4) Warnings and Precautions.

Immunogenicity

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

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

Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulation and vice versa

Study MO22982 investigated switching between the Herceptin intravenous and Herceptin subcutaneous formulation with a primary objective to evaluate patient preference for either intravenous or the subcutaneous route of trastuzumab administration. In this trial, 2 cohorts (one using subcutaneous formulation in vial and one using subcutaneous formulation in administration system) were investigated using a 2-arm , cross-over design with 488 patients being randomized to one of two different three-weekly Herceptin treatment sequences (IV [Cycles 1-4]→ SC [Cycles 5-8], or SC [Cycles 1-4]→ IV [Cycles 5-8]). Patients were either naïve to Herceptin IV treatment (20.3%) or pre- exposed to Herceptin IV (79.7%). For the sequence IV→SC (SC vial and SC formulation in administration system cohorts combined), adverse event rates (all grades) were described pre- switching (Cycles 1-4) and post-switching (Cycles 5-8) as 53.8% vs. 56.4%, respectively; for the sequence SC→IV (SC vial and SC formulation in administration system cohorts combined), adverse event rates (all grades) were described pre- and post-switching as 65.4% vs. 48.7%, respectively.
Pre-switching rates (Cycles 1-4) for serious adverse events, grade 3 adverse events and treatment discontinuations due to adverse events were low (<5%) and similar to post-switching rates (Cycles 5- 8). No grade 4 or grade 5 adverse events were reported.

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