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, administration-related reactions, haematotoxicity (in particular neutropenia), infections and pulmonary adverse reactions.

The safety profile of Herceptin subcutaneous formulation (evaluated in 298 and 297 patients treated with the intravenous and subcutaneous formulations respectively) from the pivotal trial in EBC was overall similar to the known safety profile of the intravenous formulation.

Severe adverse events (defined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE grade ≥3) version 3.0) were equally distributed between both Herceptin formulations (52.3 % versus 53.5 % in the intravenous formulation versus subcutaneous formulation respectively).

Some adverse events / reactions were reported with a higher frequency for the subcutaneous formulation:
• Serious adverse events (most of which were identified because of in-patient hospitalisation or prolongation of existing hospitalisation): 14.1 % for the intravenous formulation versus 21.5 % for the subcutaneous formulation. The difference in serious adverse event rates between formulations was mainly due to infections with or without neutropenia (4.4 % versus 8.1 %) and cardiac disorders (0.7 % versus 1.7 %);
• Post-operative wound infections (severe and/or serious): 1.7 % versus 3.0 % for the intravenous formulation versus subcutaneous formulation, respectively; • Administration-related reactions: 37.2 % versus 47.8 % for the intravenous formulation versus subcutaneous formulation, respectively during the treatment phase;
• Hypertension: 4.7 % versus 9.8 % for the intravenous formulation versus subcutaneous formulation respectively.

Tabulated list of adverse reactions with the intravenous formulation

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


System organ class            Adverse reaction                      Frequency 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
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

System organ class           Adverse reaction                        Frequency 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

System organ class          Adverse reaction                                    Frequency Dermatitis                                          Common
Urticaria                                           Uncommon
Angioedema                                          Not known
Musculoskeletal and         Arthralgia                                          Very common connective tissue disorders 1Muscle 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 and Oligohydramnios                                       Not known 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 administration-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 to Herceptin. It has been associated with a fatal outcome. 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 EBC clinical trials of adjuvant intravenous 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.

Administration-related reactions/hypersensitivity

Administration-related reactions (ARRs)/hypersensitivity reactions such as chills and/or fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, respiratory distress, rash, nausea, vomiting and headache were seen in Herceptin clinical trials (see section 4.4).
The rate of ARRs 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.

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).

Description of selected adverse reactions with the subcutaneous formulation 
Administration-related reactions

In the pivotal trial, the rate of all grade ARRs was 37.2 % with the Herceptin intravenous formulation and 47.8 % with the Herceptin subcutaneous formulation; severe grade 3 reactions were reported in 2.0 % and 1.7 % of the patients, respectively during the treatment phase; no severe grade 4 or 5 reactions were observed. All of the severe ARRs with the Herceptin subcutaneous formulation 

occurred during concurrent administration with chemotherapy. The most frequent severe reaction was drug hypersensitivity.

The systemic reactions included hypersensitivity, hypotension, tachycardia, cough, and dyspnoea. The local reactions included erythema, pruritus, oedema, rash and pain at the site of the injection.

Infections

The rate of severe infections (NCI CTCAE grade ≥3) was 5.0 % versus 7.1 %, in the Herceptin intravenous formulation arm and the Herceptin subcutaneous formulation arm respectively.

The rate of serious infections (most of which were identified because of in-patient hospitalisation or prolongation of existing hospitalisation) was 4.4 % in the Herceptin intravenous formulation arm and 8.1 % in the Herceptin subcutaneous formulation arm. The difference between formulations was mainly observed during the adjuvant treatment phase (monotherapy) and was mainly due to postoperative wound infections, but also to various other infections such as respiratory tract infections, acute pyelonephritis and sepsis. They resolved within a mean of 13 days in the Herceptin intravenous treatment arm and a mean of 17 days in the Herceptin subcutaneous treatment arm.

Hypertensive events

In the pivotal trial BO22227, there were more than twice as many patients reporting all grade hypertension with the Herceptin subcutaneous formulation (4.7 % versus 9.8 % in the intravenous and subcutaneous formulations respectively), with a greater proportion of patients with severe events (NCI CTCAE grade ≥3) <1 % versus 2.0 % the intravenous and subcutaneous formulations respectively. All but one patient who reported severe hypertension had a history of hypertension before they entered the study. Some of the severe events occurred on the day of the injection.

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 and 15.9 % (47/295) of patients receiving Herceptin subcutaneous vial developed antibodies against trastuzumab. Neutralizing anti- trastuzumab antibodies were detected in post-baseline samples in 2 of 30 patients in the Herceptin intravenous arm and 3 of 47 in the Herceptin subcutaneous arm. 21.0 % of patients treated with Herceptin subcutaneous formulation developed antibodies against the excipient hyaluronidase (rHuPH20).

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 and Herceptin subcutaneous.

Details of risk minimisation measures that are consistent with the EU Risk Management Plan are presented in Section 4.4.

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 the 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 sideeffects.health.gov.il/