trastuzumab: prescribing information – dosing, contraindications, interactions, side effects

Breast cancer
Metastatic breast cancer
Herceptin is indicated for the treatment of adult patients with HER2 positive metastatic breast cancer:
(MBC):
- as monotherapy for the treatment of those patients who have received at least two chemotherapy regimens for their metastatic disease. Prior chemotherapy must have included at least an anthracycline and a taxane unless patients are unsuitable for these treatments. Hormone receptor positive patients must also have failed hormonal therapy, unless patients are unsuitable for these treatments.
- in combination with paclitaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease and for whom an anthracycline is not suitable.
- in combination with docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease.
- in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive MBC, not previously treated with trastuzumab.

Early breast cancer
Herceptin is indicated for the treatment of adult patients with HER2 positive early breast cancer.
(EBC).
- following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (see section 5.1).
- following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel.
- in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.
- in combination with neoadjuvant chemotherapy followed by adjuvant Herceptin therapy, for locally advanced (including inflammatory) disease or tumours > 2 cm in diameter (see sections 4.4 and 5.1).
Herceptin should only be used in patients with metastatic or early breast cancer whose tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay (see sections 4.4 and 5.1).
Metastatic gastric cancer
Herceptin in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of adult patients with HER2 positive metastatic adenocarcinoma of the stomach or gastro- esophageal junction who have not received prior anti-cancer treatment for their metastatic disease.
Herceptin should only be used in patients with metastatic gastric cancer (MGC) whose tumours have HER2 overexpression as defined by IHC2+ and a confirmatory SISH or FISH result, or by an IHC 3+ result. Accurate and validated assay methods should be used (see sections 4.4 and 5.1).

Breast cancer
Metastatic breast cancer
Herceptin is indicated for the treatment of adult patients with HER2 positive metastatic breast cancer (MBC):
- as monotherapy for the treatment of those patients who have received at least two chemotherapy regimens for their metastatic disease. Prior chemotherapy must have included at least an anthracycline and a taxane unless patients are unsuitable for these treatments. Hormone receptor positive patients must also have failed hormonal therapy, unless patients are unsuitable for these treatments.
- in combination with paclitaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease and for whom an anthracycline is not suitable.
- in combination with docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease.
- in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive MBC, not previously treated with trastuzumab.
Early breast cancer
Herceptin is indicated for the treatment of adult patients with HER2 positive early breast cancer (EBC).
- following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (see section 5.1).

- following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel.
- in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.
- in combination with neoadjuvant chemotherapy followed by adjuvant Herceptin therapy, for locally advanced (including inflammatory) disease or tumours > 2 cm in diameter (see sections 4.4 and 5.1).
Herceptin should only be used in patients with metastatic or early breast cancer whose tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay (see sections 4.4 and 5.1).

HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Herceptin treatment should only be initiated by a physician experienced in the administration of cytotoxic chemotherapy (see section 4.4), and should be administered by a healthcare professional only.
It is important to check the product labels to ensure that the correct formulation (intravenous or subcutaneous fixed dose) is being administered to the patient, as prescribed. Herceptin intravenous formulation is not intended for subcutaneous administration and should be administered via an intravenous infusion only.
Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulations and vice versa, using the three-weekly (q3w) dosing regimen, was investigated in study MO22982 (see section 4.8).
In order to prevent medication errors it is important to check the vial labels to ensure that the drug being prepared and administered is Herceptin (trastuzumab) and not another trastuzumab-containing product (e.g. trastuzumab emtansine or trastuzumab deruxtecan).

Posology
Metastatic breast cancer
Three-weekly schedule
The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.
Weekly schedule
The recommended initial loading dose of Herceptin is 4 mg/kg body weight. The recommended weekly maintenance dose of Herceptin is 2 mg/kg body weight, beginning one week after the loading dose.
Administration in combination with paclitaxel or docetaxel
In the pivotal trials (H0648g, M77001), paclitaxel or docetaxel was administered the day following the first dose of Herceptin (for dose, see the Summary of Product Characteristics (SmPC) for paclitaxel or docetaxel) and immediately after the subsequent doses of Herceptin if the preceding dose of Herceptin was well tolerated.
Administration in combination with an aromatase inhibitor
In the pivotal trial (BO16216) Herceptin and anastrozole were administered from day 1. There were no restrictions on the relative timing of Herceptin and anastrozole at administration (for dose, see the SmPC for anastrozole or other aromatase inhibitors).
Early breast cancer
Three-weekly and weekly schedule
As a three-weekly regimen the recommended initial loading dose of Herceptin is 8 mg/kg body weight. The recommended maintenance dose of Herceptin at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.
As a weekly regimen (initial loading dose of 4 mg/kg followed by 2 mg/kg every week) concomitantly with paclitaxel following chemotherapy with doxorubicin and cyclophosphamide.
See section 5.1 for chemotherapy combination dosing.
Metastatic gastric cancer
Three-weekly schedule
The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.
Breast cancer and gastric cancer
Duration of treatment
Patients with MBC or MGC should be treated with Herceptin until progression of disease.
Patients with EBC should be treated with Herceptin for 1 year or until disease recurrence, whichever occurs first; extending treatment in EBC beyond one year is not recommended (see section 5.1).

Dose reduction
No reductions in the dose of Herceptin were made during clinical trials. Patients may continue therapy during periods of reversible, chemotherapy-induced myelosuppression but they should be monitored carefully for complications of neutropenia during this time. Refer to the SmPC for paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or delays.
If left ventricular ejection fraction (LVEF) percentage drops ≥ 10 points from baseline AND to below 50 %, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or has declined further, or if symptomatic congestive heart failure (CHF) has developed, discontinuation of Herceptin should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.
Missed doses
If the patient has missed a dose of Herceptin by one week or less, then the usual maintenance dose (weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg) should be administered as soon as possible. Do not wait until the next planned cycle. Subsequent maintenance doses should be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.
If the patient has missed a dose of Herceptin by more than one week, a re-loading dose of Herceptin should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weekly regimen: 8 mg/kg) as soon as possible. Subsequent Herceptin maintenance doses (weekly regimen:
2 mg/kg; three-weekly regimen 6 mg/kg respectively) should be administered 7 days or 21 days later according to the weekly or three-weekly schedules respectively.
Special populations
Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not been carried out. In a population pharmacokinetic analysis, age and renal impairment were not shown to affect trastuzumab disposition.
Paediatric population
There is no relevant use of Herceptin in the paediatric population.
Method of administration
Herceptin loading dose should be administered as a 90-minute intravenous infusion. Do not administer as an intravenous push or bolus. Herceptin intravenous infusion should be administered by a health- care provider prepared to manage anaphylaxis and an emergency kit should be available. Patients should be observed for at least six hours after the start of the first infusion and for two hours after the start of the subsequent infusions for symptoms like fever and chills or other infusion-related symptoms (see sections 4.4 and 4.8). Interruption or slowing the rate of the infusion may help control such symptoms. The infusion may be resumed when symptoms abate.
If the initial loading dose was well tolerated, the subsequent doses can be administered as a 30-minute infusion.
For instructions on reconstitution of Herceptin intravenous formulation before administration, see section 6.6.

HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Herceptin treatment should only be initiated by a physician experienced in the administration of cytotoxic chemotherapy (see section 4.4), and should be administered by a healthcare professional only.
It is important to check the product labels to ensure that the correct formulation (intravenous or subcutaneous fixed dose) is being administered to the patient, as prescribed. Herceptin subcutaneous formulation is not intended for intravenous administration and should be administered via a subcutaneous injection only.
Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulations and vice versa, using the three-weekly (q3w) dosing regimen, was investigated in study MO22982 (see section 4.8).
In order to prevent medication errors it is important to check the vial labels to ensure that the drug being prepared and administered is Herceptin (trastuzumab) and not another trastuzumab-containing product (e.g. trastuzumab emtansine or trastuzumab deruxtecan).
Posology
The recommended dose for Herceptin subcutaneous formulation is 600 mg irrespective of the patient’s body weight. No loading dose is required. This dose should be administered subcutaneously over 2-5 minutes every three weeks.
In the pivotal trial (BO22227) Herceptin subcutaneous formulation was administered in the neoadjuvant/adjuvant setting in patients with early breast cancer. The preoperative chemotherapy regimen consisted of docetaxel (75 mg/m²) followed by FEC (5FU, epirubicin and cyclophosphamide) at a standard dose.
See section 5.1 for chemotherapy combination dosing.
Duration of treatment
Patients with MBC should be treated with Herceptin until progression of disease. Patients with EBC should be treated with Herceptin for 1 year or until disease recurrence, whichever occurs first;
extending treatment in EBC beyond one year is not recommended (see section 5.1).
Dose reduction
No reductions in the dose of Herceptin were made during clinical trials. Patients may continue therapy during periods of reversible, chemotherapy-induced myelosuppression butthey should be monitored carefully for complications of neutropenia during this time. Refer to the Summary of Product

Characteristics (SmPC) for paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or delays.
If left ventricular ejection fraction (LVEF) percentage drops ≥ 10 points from baseline AND to below 50 %, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or has declined further, or if symptomatic congestive heart failure (CHF) has developed, discontinuation of Herceptin should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.
Missed doses
If the patient misses a dose of Herceptin subcutaneous formulation, it is recommended to administer the next 600 mg dose (i.e. the missed dose) as soon as possible. The interval between consecutive Herceptin subcutaneous formulation administrations should not be less than three weeks.
Special populations
Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not been carried out. In a population pharmacokinetic analysis, age and renal impairment were not shown to affect trastuzumab disposition.
Paediatric population
There is no relevant use of Herceptin in the paediatric population.
Method of administration
The 600 mg dose should be administered as a subcutaneous injection only over 2-5 minutes every three weeks. The injection site should be alternated between the left and right thigh. New injections should be given at least 2.5 cm from the old site and never into areas where the skin is red, bruised, tender, or hard. During the treatment course with Herceptin subcutaneous formulation other medicinal products for subcutaneous administration should preferably be injected at different sites. Patients should be observed for 30 minutes after the first injection and for 15 minutes after subsequent injections for signs or symptoms of administration-related reactions (see sections 4.4 and 4.8).
For instructions on use and handling of Herceptin subcutaneous formulation refer to section 6.6.


Hypersensitivity to trastuzumab, murine proteins, or to any of the excipients listed in section 6.1


Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.


Hypersensitivity to trastuzumab, murine proteins, hyaluronidase or to any of the other excipients listed in section 6.1.

Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.

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 and unspecified (incl. Cysts and polyps) Malignant neoplasm progression Not known Neoplasm progression Not known Blood and lymphatic system disorders Febrile neutropenia Very common Anaemia Very common Neutropenia Very common White blood cell count decreased/leukopenia Very common

System organ class
Adverse reaction
Frequency
Thrombocytopenia
Very common
Hypoprothrombinaemia
Not known
Immune thrombocytopenia
Not known
Immune system disorders
Hypersensitivity
Common
+Anaphylactic reaction
Rare
+Anaphylactic shock
Rare
Metabolism and nutrition disorders
Weight decreased/Weight loss
Very common
Anorexia
Very common
Tumour lysis syndrome
Not known
Hyperkalaemia
Not known
Psychiatric disorders
Insomnia
Very common
Anxiety
Common
Depression
Common
Nervous system disorders
1Tremor
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 Heart beat irregular
Very common
1Cardiac flutter
Very common
Ejection fraction decreased*
Very common
+Cardiac failure (congestive)
Common
+1Supraventricular tachyarrhythmia
Common
Cardiomyopathy
Common
1Palpitation
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 mediastinal disorders
+Dyspnoea
Very common
Cough
Very common
Epistaxis
Very common
Rhinorrhoea
Very common
+Pneumonia
Common
Asthma
Common
Lung disorder
Common
+Pleural effusion
Common
+1Wheezing
Uncommon
Pneumonitis
Uncommon

System organ class
Adverse reaction
Frequency
+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 tissue disorders
Erythema
Very common
Rash
Very common
1 Swelling face
Very common
Alopecia
Very common
Nail disorder
Very common
Palmar-plantar erythrodysaesthesia syndrome
Very common
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 tissue disorders
Arthralgia
Very common
1Muscle tightness
Very common
Myalgia
Very common
Arthritis
Common
Back pain
Common
Bone pain
Common
Muscle spasms
Common
Neck Pain
Common

System organ class
Adverse reaction
Frequency
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 perinatal conditions
Oligohydramnios
Not known
Renal hypoplasia
Not known
Pulmonary hypoplasia
Not known
Reproductive system and breast disorders
Breast inflammation/mastitis
Common
General disorders and administration site conditions
Asthenia
Very common
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 oedema
Very common
Malaise
Common
Oedema
Common
Injury, poisoning and procedural complications
Contusion
Common
+ 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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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 Rhinitis Common Upper respiratory tract infection Common Urinary tract infection Common Pharyngitis Common Neoplasms benign, malignant and unspecified (incl. Cysts and polyps) Malignant neoplasm progression Not known Neoplasm progression Not known Febrile neutropenia Very common

System organ class
Adverse reaction
Frequency
Blood and lymphatic system disorders
Anaemia
Very common
Neutropenia
Very common
White blood cell count decreased/leukopenia
Very common
Thrombocytopenia
Very common
Hypoprothrombinaemia
Not known
Immune thrombocytopenia
Not known
Immune system disorders
Hypersensitivity
Common
+Anaphylactic reaction
Rare
+Anaphylactic shock
Rare
Metabolism and nutrition disorders
Weight decreased/Weight loss
Very common
Anorexia
Very common
Tumour lysis syndrome
Not known
Hyperkalaemia
Not known
Psychiatric disorders
Insomnia
Very common
Anxiety
Common
Depression
Common
Nervous system disorders
1Tremor
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 Heart beat irregular
Very common
1Cardiac flutter
Very common
Ejection fraction decreased*
Very common
+Cardiac failure (congestive)
Common
+1Supraventricular tachyarrhythmia
Common
Cardiomyopathy
Common
1Palpitation
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 mediastinal disorders
+Dyspnoea
Very common
Cough
Very common
Epistaxis
Very common
Rhinorrhoea
Very common
+Pneumonia
Common
Asthma
Common
Lung disorder
Common

System organ class
Adverse reaction
Frequency
+Pleural effusion
Common
+1Wheezing
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 tissue disorders
Erythema
Very common
Rash
Very common
1 Swelling face
Very common
Alopecia
Very common
Nail disorder
Very common
Palmar-plantar erythrodysaesthesia syndrome
Very common
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 tissue disorders
Arthralgia
Very common
1Muscle tightness
Very common
Myalgia
Very common
Arthritis
Common
Back pain
Common

System organ class
Adverse reaction
Frequency
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 perinatal conditions
Oligohydramnios
Not known
Renal hypoplasia
Not known
Pulmonary hypoplasia
Not known
Reproductive system and breast disorders
Breast inflammation/mastitis
Common
General disorders and administration site conditions
Asthenia
Very common
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 oedema
Very common
Malaise
Common
Oedema
Common
Injury, poisoning and procedural complications
Contusion
Common
+ 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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Traceability
In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded.
HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of the testing procedures (see section 5.1).
Currently no data from clinical trials are available on re-treatment of patients with previous exposure to Herceptin in the adjuvant setting.
Cardiac dysfunction
General considerations
Patients treated with Herceptin are at increased risk for developing CHF (New York Heart Association [NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in patients receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularly following anthracycline (doxorubicin or epirubicin) containing chemotherapy. These may be moderate to severe and have been associated with death (see section 4.8). In addition, caution should be exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary artery disease, CHF, LVEF of <55%, older age.
All candidates for treatment with Herceptin, but especially those with prior anthracycline and cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and physical examination, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition (MUGA) scan or magnetic resonance imaging. Monitoring may help to identify patients who develop cardiac dysfunction. Cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Herceptin. A careful risk-benefit assessment should be made before deciding to treat with Herceptin.
Trastuzumab may persist in the circulation for up to 7 months after stopping Herceptin treatment based on population pharmacokinetic analysis of all available data (see section 5.2). Patients who receive anthracyclines after stopping Herceptin may possibly be at increased risk of cardiac dysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping Herceptin. If anthracyclines are used, the patient’s cardiac function should be monitored carefully.
Formal cardiological assessment should be considered in patients in whom there are cardiovascular concerns following baseline screening. In all patients cardiac function should be monitored during treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac dysfunction. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6 - 8 weeks). If patients have a continued decrease in left ventricular function, but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of Herceptin therapy has been seen.
The safety of continuation or resumption of Herceptin in patients who experience cardiac dysfunction has not been prospectively studied. If LVEF percentage drops ≥10 points from baseline AND to below 50%, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, or symptomatic CHF has developed, discontinuation of Herceptin should be strongly considered, unless the benefits for the individual

patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.
If symptomatic cardiac failure develops during Herceptin therapy, it should be treated with standard medicinal products for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunction in pivotal trials improved with standard CHF treatment consisting of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on therapy without additional clinical cardiac events.
Metastatic breast cancer
Herceptin and anthracyclines should not be given concurrently in combination in the MBC setting.
Patients with MBC who have previously received anthracyclines are also at risk of cardiac dysfunction with Herceptin treatment, although the risk is lower than with concurrent use of Herceptin and anthracyclines.
Early breast cancer
For patients with EBC, cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Herceptin. In patients who receive anthracycline-containing chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last administration of Herceptin, or longer if a continuous decrease of LVEF is observed.
Patients with history of myocardial infarction (MI), angina pectoris requiring medical treatment, history of or existing CHF (NYHA Class II –IV), LVEF of < 55%, other cardiomyopathy, cardiac arrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorly controlled hypertension (hypertension controlled by standard medical treatment eligible), and hemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBC pivotal trials with Herceptin and therefore treatment cannot be recommended in such patients.
Adjuvant treatment
Herceptin and anthracyclines should not be given concurrently in combination in the adjuvant treatment setting.
In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac events was observed when Herceptin was administered after anthracycline-containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel and carboplatin and was more marked when Herceptin was administered concurrently with taxanes than when administered sequentially to taxanes. Regardless of the regimen used, most symptomatic cardiac events occurred within the first 18 months. In one of the 3 pivotal studies conducted in which a median follow-up of 5.5 years was available (BCIRG006) a continuous increase in the cumulative rate of symptomatic cardiac or LVEF events was observed in patients who were administered Herceptin concurrently with a taxane following anthracycline therapy up to 2.37% compared to approximately 1% in the two comparator arms (anthracycline plus cyclophosphamide followed by taxane and taxane, carboplatin and Herceptin).
Risk factors for a cardiac event identified in four large adjuvant studies included advanced age (> 50 years), low LVEF (<55%) at baseline, prior to or following the initiation of paclitaxel treatment, decline in LVEF by 10-15 points, and prior or concurrent use of anti-hypertensive medicinal products.
In patients receiving Herceptin after completion of adjuvant chemotherapy, the risk of cardiac dysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of Herceptin and a body mass index (BMI) >25 kg/m2.

Neoadjuvant-adjuvant treatment
In patients with EBC eligible for neoadjuvant-adjuvant treatment, Herceptin should be used concurrently with anthracyclines only in chemotherapy-naive patients and only with low-dose anthracycline regimens i.e. maximum cumulative doses of doxorubicin 180 mg/m2 or epirubicin 360 mg/m2.
If patients have been treated concurrently with a full course of low-dose anthracyclines and Herceptin in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery. In other situations, the decision on the need for additional cytotoxic chemotherapy is determined based on individual factors.
Experience of concurrent administration of trastuzumab with low dose anthracycline regimens is currently limited to two trials (MO16432 and BO22227).
In the pivotal trial MO16432, Herceptin was administered concurrently with neoadjuvant chemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m2 ) .
The incidence of symptomatic cardiac dysfunction was 1.7% in the Herceptin arm .
The pivotal trial BO22227 was designed to demonstrate non-inferiority of treatment with Herceptin subcutaneous formulation versus treatment with Herceptin intravenous formulation based on co- primary PK and efficacy endpoints (trastuzumab Ctrough at pre-dose Cycle 8, and pCR rate at definitive surgery, respectively) (See Section 5.1. of Herceptin subcutaneous formulation SmPC). In the pivotal trial BO22227, Herceptin was administered concurrently with neoadjuvant chemotherapy that contained four cycles of epirubicin (cumulative dose 300 mg/m2); at a median follow-up exceeding 70 months, the incidence of cardiac failure/congestive cardiac failure was 0.3% in the Herceptin intravenous arm.
Clinical experience is limited in patients above 65 years of age.
Infusion-related reactions (IRRs) and hypersensitivity
Serious IRRs to Herceptin infusion including dyspnoea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, anaphylaxis, respiratory distress, urticaria and angioedema have been reported (see section 4.8). Pre-medication may be used to reduce risk of occurrence of these events. The majority of these events occur during or within 2.5 hours of the start of the first infusion. Should an infusion reaction occur the infusion should be discontinued or the rate of infusion slowed and the patient should be monitored until resolution of all observed symptoms (see section 4.2). These symptoms can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as diphenhydramine. The majority of patients experienced resolution of symptoms and subsequently received further infusions of Herceptin.
Serious reactions have been treated successfully with supportive therapy such as oxygen, beta- agonists, and corticosteroids. In rare cases, these reactions are associated with a clinical course culminating in a fatal outcome. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a fatal infusion reaction.
Therefore, these patients should not be treated with Herceptin (see section 4.3).
Initial improvement followed by clinical deterioration and delayed reactions with rapid clinical deterioration have also been reported. Fatalities have occurred within hours and up to one week following infusion. On very rare occasions, patients have experienced the onset of infusion symptoms and pulmonary symptoms more than six hours after the start of the Herceptin infusion. Patients should be warned of the possibility of such a late onset and should be instructed to contact their physician if these symptoms occur.

Pulmonary events
Severe pulmonary events have been reported with the use of Herceptin in the post-marketing setting (see section 4.8). These events have occasionally been fatal. In addition, cases of interstitial lung disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy. These events may occur as part of an infusion-related reaction or with a delayed onset. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated with Herceptin (see section 4.3). Caution should be exercised for pneumonitis, especially in patients being treated concomitantly with taxanes.
Excipient with known effect
Herceptin contains 0.6 mg of polysorbate 20 in each 150mg vial, which is equivalent to 0.083mg/mL (after reconstitution with 7.2mL sterile water for injection). Polysorbates may cause allergic reactions.

Traceability
In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded.
HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of the testing procedures (see section 5.1).
Currently no data from clinical trials are available on re-treatment of patients with previous exposure to Herceptin in the adjuvant setting.

Cardiac dysfunction
General considerations
Patients treated with Herceptin are at increased risk for developing CHF (New York Heart Association [NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in patients receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularly following anthracycline (doxorubicin or epirubicin)–containing chemotherapy. These may be moderate to severe and have been associated with death (see section 4.8). In addition, caution should be exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary artery disease, CHF, LVEF of <55%, older age.
All candidates for treatment with Herceptin, but especially those with prior anthracycline and cyclophosphamide exposure, should undergo baseline cardiac assessment including history and physical examination and electrocardiogram (ECG), echocardiogram, and/or multigated acquisition (MUGA) scan or magnetic resonance imaging. Monitoring may help to identify patients who develop cardiac dysfunction. Cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Herceptin. A careful risk-benefit assessment should be made before deciding to treat with Herceptin.
Trastuzumab may persist in the circulation for up to 7 months after stopping Herceptin treatment based on population pharmacokinetic analysis of all available data (see section 5.2). Patients who receive anthracyclines after stopping Herceptin may possibly be at increased risk of cardiac dysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping Herceptin. If anthracyclines are used, the patient’s cardiac function should be monitored carefully.
Formal cardiological assessment should be considered in patients in whom there are cardiovascular concerns following baseline screening. In all patients cardiac function should be monitored during treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac dysfunction. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6-8 weeks). If patients have a continued decrease in left ventricular function, but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of Herceptin therapy has been seen.
The safety of continuation or resumption of Herceptin in patients who experience cardiac dysfunction has not been prospectively studied. If LVEF percentage drops ≥ 10 points from baseline AND to below 50%, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, or symptomatic CHF has developed, discontinuation of Herceptin should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.
If symptomatic cardiac failure develops during Herceptin therapy, it should be treated with standard medicinal products for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunction in pivotal trials improved with standard CHF treatment consisting of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on therapy without additional clinical cardiac events.

Metastatic breast cancer
Herceptin and anthracyclines should not be given concurrently in combination in the MBC setting.
Patients with MBC who have previously received anthracyclines are also at risk of cardiac dysfunction with Herceptin treatment, although the risk is lower than with concurrent use of Herceptin and anthracyclines.
Early breast cancer
For patients with EBC, cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Herceptin. In patients who receive anthracycline-containing chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last administration of Herceptin, or longer if a continuous decrease of LVEF is observed.
Patients with history of myocardial infarction (MI), angina pectoris requiring medical treatment, history of or existing CHF (NYHA Class II –IV), LVEF of < 55%, other cardiomyopathy, cardiac arrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorly controlled hypertension (hypertension controlled by standard medical treatment eligible), and hemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBC pivotal trials with Herceptin and therefore treatment cannot be recommended in such patients.
Adjuvant treatment
Herceptin and anthracyclines should not be given concurrently in the adjuvant treatment setting.
In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac events was observed when Herceptin (intravenous formulation) was administered after anthracycline- containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel and carboplatin and was more marked when Herceptin (intravenous formulation) was administered concurrently with taxanes than when administered sequentially to taxanes. Regardless of the regimen used, most symptomatic cardiac events occurred within the first 18 months. In one of the 3 pivotal studies conducted in which a median follow-up of 5.5 years was available (BCIRG006) a continuous increase in the cumulative rate of symptomatic cardiac or LVEF events was observed (up to 2.37 %) in patients who were administered Herceptin concurrently with a taxane following anthracycline therapy, compared to approximately 1 % in the two comparator arms (anthracycline plus cyclophosphamide followed by taxane and taxane, carboplatin and Herceptin).
Risk factors for a cardiac event identified in four large adjuvant studies included advanced age (> 50 years), low LVEF (<55%) at baseline, prior to or following the initiation of paclitaxel treatment, decline in LVEF by 10-15 points, and prior or concurrent use of anti-hypertensive medicinal products.
In patients receiving Herceptin after completion of adjuvant chemotherapy, the risk of cardiac dysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of Herceptin and a body mass index (BMI) >25 kg/m2.
Neoadjuvant-adjuvant treatment
In patients with EBC eligible for neoadjuvant-adjuvant treatment, Herceptin should be used concurrently with anthracyclines only in chemotherapy-naive patients and only with low-dose anthracycline regimens, i.e., with maximum cumulative doses of doxorubicin 180 mg/m2 or epirubicin 360 mg/m2.
If patients have been treated concurrently with a full course of low-dose anthracyclines and Herceptin in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery. In other situations, the decision on the need for additional cytotoxic chemotherapy is determined based on individual factors.

Experience of concurrent administration of trastuzumab with low dose anthracycline regimens is currently limited to two trials (MO16432 and BO22227).
In the pivotal trial MO16432, Herceptin was administered concurrently with neoadjuvant chemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m2) . The incidence of symptomatic cardiac dysfunction was 1.7% in the Herceptin arm .
In the pivotal trial BO22227, Herceptin was administered concurrently with neoadjuvant chemotherapy that contained four cycles of epirubicin (cumulative dose 300 mg/m2); at a median follow-up exceeding 70 months, the incidence of cardiac failure/congestive cardiac failure was 0.3% in the Herceptin intravenous arm and 0.7% in the Herceptin subcutaneous arm. In patients with lower body weights (<59 kg, the lowest body weight quartile) the fixed dose used in the Herceptin subcutaneous arm was not associated with an increased risk of cardiac events or significant drop in LVEF.
Clinical experience is limited in patients above 65 years of age.
Administration-related reactions
Administration-related reactions (ARRs) are known to occur with Herceptin subcutaneous formulation. Pre-medication may be used to reduce risk of occurrence of ARRs.
Although serious ARRs, including dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress, were not reported in the clinical trial with the Herceptin subcutaneous formulation, caution should be exercised as these have been associated with the intravenous formulation. Patients should be observed for ARRs for 30 minutes after the first injection and for 15 minutes after subsequent injections. ARRs considered mild in severity can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as diphenhydramine. Serious reactions to intravenous Herceptin have been treated successfully with supportive therapy such as oxygen, beta-agonists, and corticosteroids. In rare cases, these reactions were associated with a clinical course culminating in a fatal outcome. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a fatal ARR. Therefore, these patients should not be treated with Herceptin (see section 4.3).
Pulmonary events
Caution is recommended with Herceptin subcutaneous formulation as severe pulmonary events have been reported with the use of the intravenous formulation in the post-marketing setting (see section 4.8). These events have occasionally been fatal and may occur as part of an infusion-related reaction or with delayed onset. In addition, cases of interstitial lung disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy.
Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated with Herceptin (see section 4.3). Caution should be exercised for pneumonitis, especially in patients being treated concomitantly with taxanes.
Excipients with known effect
Sodium
Herceptin contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially sodium-free.

Polysorbate 20
Herceptin contains 2.0 mg of polysorbate 20 in each 600mg/5mL vial, which is equivalent to 0.4mg/mL. Polysorbates may cause allergic reactions.

No formal drug interaction studies have been performed. Clinically significant interactions between Herceptin and the concomitant medicinal products used in clinical trials have not been observed.
Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents
Pharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive MBC suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl- paclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (8 mg/kg or 4 mg/kg IV loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w IV, respectively).
However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this metabolite was unclear.
Data from study JP16003, a single-arm study of Herceptin (4 mg/kg IV loading dose and 2 mg/kg IV weekly) and docetaxel (60 mg/m2 IV) in Japanese women with HER2- positive MBC, suggested that concomitant administration of Herceptin had no effect on the single dose pharmacokinetics of docetaxel. Study JP19959 was a substudy of BO18255 (ToGA) performed in male and female Japanese patients with advanced gastric cancer to study the pharmacokinetics of capecitabine and cisplatin when used with or without Herceptin. The results of this substudy suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus Herceptin. However, capecitabine itself showed higher concentrations and a longer half-life when combined with Herceptin. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus Herceptin.
Pharmacokinetic data from Study H4613g/GO01305 in patients with metastatic or locally advanced inoperable HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin.
Effect of antineoplastic agents on trastuzumab pharmacokinetics
By comparison of simulated serum trastuzumab concentrations after Herceptin monotherapy (4 mg/kg loading/2 mg/kg q1w IV) and observed serum concentrations in Japanese women with HER2- positive

MBC (study JP16003) no evidence of a PK effect of concurrent administration of docetaxel on the pharmacokinetics of trastuzumab was found.
Comparison of PK results from two Phase II studies (BO15935 and M77004) and one Phase III study (H0648g) in which patients were treated concomitantly with Herceptin and paclitaxel and two Phase II studies in which Herceptin was administered as monotherapy (W016229 and MO16982), in women with HER2-positive MBC indicates that individual and mean trastuzumab trough serum concentrations varied within and across studies but there was no clear effect of the concomitant administration of paclitaxel on the pharmacokinetics of trastuzumab. Comparison of trastuzumab PK data from Study M77004 in which women with HER2-positive MBC were treated concomitantly with Herceptin, paclitaxel and doxorubicin to trastuzumab PK data in studies where Herceptin was administered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamide or paclitaxel (Study H0648g), suggested no effect of doxorubicin and paclitaxel on the pharmacokinetics of trastuzumab.
Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the PK of trastuzumab.
The administration of concomitant anastrozole did not appear to influence the pharmacokinetics of trastuzumab.

Women of childbearing potential
Women of childbearing potential should be advised to use effective contraception during treatment with Herceptin and for 7 months after treatment has concluded (see section 5.2).
Pregnancy
Reproduction studies have been conducted in Cynomolgus monkeys at doses up to 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin intravenous formulation and have revealed no evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumab during the early (days 20–50 of gestation) and late (days 120–150 of gestation) foetal development period was observed. It is not known whether Herceptin can affect reproductive capacity. As animal reproduction studies are not always predictive of human response, Herceptin should be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus.
In the post-marketing setting, cases of foetal renal growth and/or function impairment in association with oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus, have been reported in pregnant women receiving Herceptin. Women who become pregnant should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with Herceptin, or if a patient becomes pregnant while receiving Herceptin or within 7 months following the last dose of Herceptin, close monitoring by a multidisciplinary team is desirable.
Breast-feeding
A study conducted in Cynomolgus monkeys at doses 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin intravenous formulation from days 120 to 150 of pregnancy demonstrated that trastuzumab is secreted in the milk postpartum. The exposure to trastuzumab in utero and the presence of trastuzumab in the serum of infant monkeys was not associated with any adverse effects on their growth or development from birth to 1 month of age. It is not known whether trastuzumab is secreted in human milk. As human IgG1 is secreted into human milk, and the potential for harm to the infant is unknown, women should not breast-feed during Herceptin therapy and for 7 months after the last dose.

Fertility
There is no fertility data available.

Women of childbearing potential / Contraception
Women of childbearing potential should be advised to use effective contraception during treatment with Herceptin and for 7 months after treatment has concluded (see section 5.2).
Pregnancy
Reproduction studies have been conducted in Cynomolgus monkeys at doses up to 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin intravenous formulation and have revealed no evidence of impaired fertility or harm to the fetus. Placental transfer of trastuzumab during the early (days 20-50 of gestation) and late (days 120-150 of gestation) fetal development period was observed.
It is not known whether Herceptin can affect reproductive capacity. As animal reproduction studies are not always predictive of human response, Herceptin should be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the fetus.
In the post-marketing setting, cases of fetal renal growth and/or function impairment in association with oligohydramnios, some associated with fatal pulmonary hypoplasia of the fetus, have been reported in pregnant women receiving Herceptin. Women who become pregnant should be advised of the possibility of harm to the fetus. If a pregnant woman is treated with Herceptin, or if a patient becomes pregnant while receiving Herceptin or within 7 months following last dose of Herceptin, close monitoring by a multidisciplinary team is desirable.
Breast-feeding
A study conducted in Cynomolgus monkeys at doses 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin intravenous formulation from days 120 to 150 of pregnancy demonstrated that trastuzumab is secreted in the milk postpartum. The exposure to trastuzumab in utero and the presence of trastuzumab in the serum of infant monkeys was not associated with any adverse effects on their growth or development from birth to 1 month of age. It is not known whether trastuzumab is secreted in human milk. As human IgG1 is secreted into human milk, and the potential for harm to the infant is unknown, women should not breast-feed during Herceptin therapy and for 7 months after the last dose.
Fertility
There is no fertility data available.

Herceptin has a minor influence on the ability to drive or use machines (see section 4.8). Dizziness and somnolence may occur during treatment with Herceptin (see section 4.8). Patients experiencing infusion-related symptoms (see section 4.4) should be advised not to drive and use machines until symptoms abate.

Herceptin has a minor influence on the ability to drive or use machines (see section 4.8). Dizziness and somnolence may occur during treatment with Herceptin (see section 4.8). Patients experiencing administration-related symptoms (see section 4.4) should be advised not to drive and use machines until symptoms abate.

There is no experience with overdose in human clinical trials. Single doses of Herceptin alone greater than 10 mg/kg have not been administered in the clinical trials; a maintenance dose of 10 mg/kg q3w following a loading dose of 8 mg/kg has been studied in a clinical trial with metastatic gastric cancer patients. Doses up to this level were well tolerated.
5.
PHARMACOLOGICAL PROPERTIES

Single doses of up to 960 mg of Herceptin subcutaneous formulation have been administered with no reported untoward effects.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FD01 Trastuzumab is a recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). Overexpression of HER2 is observed in 20 %-30 % of primary breast cancers. Studies of HER2-positivity rates in gastric cancer (GC) using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) have shown that there is a broad variation of HER2-positivity ranging from 6.8 % to 34.0 % for IHC and 7.1 % to 42.6 % for FISH. Studies indicate that breast cancer patients whose tumours overexpress HER2 have a shortened disease-free survival compared to patients whose tumours do not overexpress HER2. The extracellular domain of the receptor (ECD, p105) can be shed into the blood stream and measured in serum samples.

Mechanism of action
Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of HER2’s extracellular domain. Binding of trastuzumab to HER2 inhibits ligand-independent HER2 signalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism of HER2. As a result, trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. Additionally, trastuzumab is a potent mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
Detection of HER2 overexpression or HER2 gene amplification
Detection of HER2 overexpression or HER2 gene amplification in breast cancer
Herceptin should only be used in patients whose tumours have HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay. HER2 overexpression should be detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks (see section 4.4). HER2 gene amplification should be detected using fluorescence in situ hybridisation (FISH) or chromogenic in situ hybridisation (CISH) of fixed tumour blocks. Patients are eligible for Herceptin treatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a positive FISH or CISH result.
To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory, which can ensure validation of the testing procedures.
The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 2:

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FD01 Herceptin subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously.
Trastuzumab is a recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). Overexpression of HER2 is observed in 20% - 30% of primary breast cancers. Studies indicate that breast cancer patients whose tumours overexpress HER2 have a shortened disease-free survival compared to patients whose tumours do not overexpress HER2. The extracellular domain of the receptor (ECD, p105) can be shed into the blood stream and measured in serum samples.
Mechanism of action
Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of HER2’s extracellular domain. Binding of trastuzumab to HER2 inhibits ligand-independent HER2 signalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism of HER2. As a result, trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. Additionally, trastuzumab is a potent mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
Detection of HER2 overexpression or HER2 gene amplification
Detection of HER2 overexpression or HER2 gene amplification in breast cancer
Herceptin should only be used in patients whose tumours have HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay. HER2 overexpression should be detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks (see section 4.4). HER2 gene amplification should be detected using fluorescence in situ hybridisation (FISH) or chromogenic in situ hybridisation (CISH) of fixed tumour blocks. Patients are eligible for Herceptin treatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a positive FISH or CISH result.

To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory, which can ensure validation of the testing procedures.
The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 2:
Table 2: Recommended scoring system to evaluate the IHC staining patterns
Score
Staining pattern
HER2 overexpression assessment
No staining is observed or membrane staining is observed in < 10 % of the tumour cells Negative 1+ A faint/barely perceptible membrane staining is detected in > 10 % of the tumour cells. The cells are only stained in part of their membrane.
Negative
2+

The pharmacokinetics of trastuzumab were evaluated in a population pharmacokinetic model analysis using pooled data from 1,582 subjects, including patients with HER2 positive MBC, EBC, AGC or other tumor types, and healthy volunteers, in 18 Phase I, II and III trials receiving Herceptin IV. A two-compartment model with parallel linear and non-linear elimination from the central compartment described the trastuzumab concentration-time profile. Due to non-linear elimination, total clearance increased with decreasing concentration. Therefore, no constant value for half-life of trastuzumab can be deduced. The t1/2 decreases with decreasing concentrations within a dosing interval (see Table 16).
MBC and EBC patients had similar PK parameters (e.g. clearance (CL), the central compartment volume (Vc)) and population-predicted steady-state exposures (Cmin, Cmax and AUC). Linear clearance was 0.136 L/day for MBC, 0.112 L/day for EBC and 0.176 L/day for AGC. The non-linear elimination parameter values were 8.81 mg/day for the maximum elimination rate (Vmax) and 8.92

µg/mL for the Michaelis-Menten constant (Km) for the MBC, EBC, and AGC patients. The central compartment volume was 2.62 L for patients with MBC and EBC and 3.63 L for patients with AGC.
In the final population PK model, in addition to primary tumor type, body-weight, serum aspartate aminotransferase and albumin were identified as a statistically significant covariates affecting the exposure of trastuzumab. However, the magnitude of effect of these covariates on trastuzumab exposure suggests that these covariates are unlikely to have a clinically meaningful effect on trastuzumab concentrations.

The pharmacokinetics of trastuzumab at a dose of 600 mg administered three-weekly by the subcutaneous route was compared to the intravenous route (8 mg/kg loading dose, 6 mg/kg maintenance every three weeks) in the phase III study BO22227. The pharmacokinetic results for the co primary endpoint, Ctrough pre dose Cycle 8, showed non-inferiority of the Herceptin subcutaneous compared to the Herceptin intravenous dose adjusted by body weight.

The mean Ctrough during the neoadjuvant treatment phase, at the pre dose Cycle 8 time point, was higher in the Herceptin subcutaneous arm (78.7 µg/mL) than the Herceptin intravenous arm (57.8 µg/mL) of the study. During the adjuvant phase of treatment, at the pre-dose Cycle 13 time point, the mean Ctrough values were 90.4 µg/mL and 62.1 µg/mL, respectively. Based on the observed data in study BO22227, steady state with the intravenous formulation was reached at cycle 8. With Herceptin subcutaneous formulation, concentrations were approximately at steady-state following Cycle 7 dose (pre-dose Cycle 8) with small increase in concentration (<15%) up to cycle 13. The mean Ctrough at the subcutaneous pre- dose cycle 18 was 90.7 µg/mL and is similar to that of cycle 13, suggesting no further increase after cycle 13.
The median Tmax following subcutaneous administration was approximately 3 days, with high interindividual variability (range 1-14 days). The mean Cmax was expectedly lower in the Herceptin subcutaneous formulation (149 μg/mL) than in the intravenous arm (end of infusion value: 221 μg/mL).

Breast cancer

Metastatic breast cancer

Tuznue is indicated for the treatment of adult patients with HER2 positive metastatic breast cancer (MBC):

• as monotherapy for the treatment of those patients who have received at least two chemotherapy regimens for their metastatic disease. Prior chemotherapy must have included at least an anthracycline and a taxane unless patients are unsuitable for these treatments. Hormone receptor positive patients must also have failed hormonal therapy, unless patients are unsuitable for these treatments.

• in combination with paclitaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease and for whom an anthracycline is not suitable.

• in combination with docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease.

• in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive MBC, not previously treated with trastuzumab.

Early breast cancer

Tuznue is indicated for the treatment of adult patients with HER2 positive early breast cancer (EBC):

• following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (see section 5.1).

• following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel.

• in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.

• in combination with neoadjuvant chemotherapy followed by adjuvant Tuznue therapy, for locally advanced (including inflammatory) disease or tumours > 2 cm in diameter (see sections 4.4. and 5.1).

Tuznue should only be used in patients with metastatic or early breast cancer whose tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay (see sections 4.4 and 5.1)

Metastatic gastric cancer

Tuznue in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of adult patients with HER2 positive metastatic adenocarcinoma of the stomach or gastro-esophageal junction who have not received prior anti-cancer treatment for their metastatic disease.

Tuznue should only be used in patients with metastatic gastric cancer (MGC) whose tumours have HER2 overexpression as defined by IHC 2+ and a confirmatory SISH or FISH result, or by an IHC 3+ result. Accurate and validated assay methods should be used (see sections 4.4 and 5.1).

HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Tuznue treatment should only be initiated by a physician experienced in the administration of cytotoxic chemotherapy (see section 4.4), and should be administered by a healthcare professional only.

Tuznue intravenous formulation is not intended for subcutaneous administration and should be administered via an intravenous infusion only.

In order to prevent medication errors, it is important to check the vial labels to ensure that the medicinal product being prepared and administered is Tuznue (trastuzumab) and not another trastuzumab-containing product (e.g. trastuzumab emtansine or trastuzumab deruxtecan).

Posology

Metastatic breast cancer

Three-weekly schedule

The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.

Weekly schedule

The recommended initial loading dose of Tuznue is 4 mg/kg body weight. The recommended weekly maintenance dose of Tuznue is 2 mg/kg body weight, beginning one week after the loading dose.

Administration in combination with paclitaxel or docetaxel

In the pivotal trials (H0648g, M77001), paclitaxel or docetaxel was administered the day following the first dose of trastuzumab (for dose, see the Summary of Product Characteristics (SmPC) for paclitaxel or docetaxel) and immediately after the subsequent doses of trastuzumab if the preceding dose of trastuzumab was well tolerated.

Administration in combination with an aromatase inhibitor

In the pivotal trial (BO16216) trastuzumab and anastrozole were administered from day 1. There were no restrictions on the relative timing of trastuzumab and anastrozole at administration (for dose, see the SmPC for anastrozole or other aromatase inhibitors).

Early breast cancer

Three-weekly and weekly schedule

As a three-weekly regimen the recommended initial loading dose of Tuznue is 8 mg/kg body weight.
The recommended maintenance dose of Tuznue at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.

As a weekly regimen (initial loading dose of 4 mg/kg followed by 2 mg/kg every week) concomitantly with paclitaxel following chemotherapy with doxorubicin and cyclophosphamide.

See section 5.1 for chemotherapy combination dosing.

Metastatic gastric cancer

Three-weekly schedule

The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.

Breast cancer and gastric cancer

Duration of treatment

Patients with MBC or MGC should be treated with Tuznue until progression of disease.

Patients with EBC should be treated with Tuznue for 1 year or until disease recurrence, whichever occurs first; extending treatment in EBC beyond one year is not recommended (see section 5.1).

Dose reduction

No reductions in the dose of trastuzumab were made during clinical trials. Patients may continue therapy during periods of reversible, chemotherapy-induced myelosuppression but they should be monitored carefully for complications of neutropenia during this time. Refer to the SmPC for paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or delays.

If left ventricular ejection fraction (LVEF) percentage drops ≥ 10 points from baseline AND to below 50%, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or has declined further, or if symptomatic congestive heart failure (CHF) has developed, discontinuation of Tuznue should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.

Missed doses

If the patient has missed a dose of Tuznue by one week or less, then the usual maintenance dose (weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg) should be administered as soon as possible. Do not wait until the next planned cycle. Subsequent maintenance doses should be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.

If the patient has missed a dose of Tuznue by more than one week, a re-loading dose should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weekly regimen:
8 mg/kg) as soon as possible. Subsequent Tuznue maintenance doses (weekly regimen: 2 mg/kg;
three-weekly regimen 6 mg/kg respectively) should be administered 7 days or 21 days later according to the weekly or three-weekly schedules respectively.

Special populations

Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not been carried out. In a population pharmacokinetic analysis, age and renal impairment were not shown to affect trastuzumab disposition.

Paediatric population

There is no relevant use of Tuznue in the paediatric population.

Method of administration

Tuznue is for intravenous use only. The loading dose should be administered as a 90-minute intravenous infusion. Do not administer as an intravenous push or bolus. Tuznue intravenous infusion should be administered by a healthcare provider prepared to manage anaphylaxis and an emergency kit should be available. Patients should be observed for at least six hours after the start of the first infusion and for two hours after the start of the subsequent infusions for symptoms like fever and chills or other infusion-related symptoms (see sections 4.4 and 4.8). Interruption or slowing the rate of the infusion may help control such symptoms. The infusion may be resumed when symptoms abate.

If the initial loading dose was well tolerated, the subsequent doses can be administered as a 30-minute infusion.

For instructions on reconstitution of Tuznue intravenous formulation before administration, see section 6.6.

• Hypersensitivity to trastuzumab, murine proteins, or to any of the excipients listed in section 6.1.
• Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary

oxygen therapy.

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, 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 and unspecified (incl. Cysts and polyps)
Malignant neoplasm progression
Not known
Neoplasm progression
Not known
Blood and lymphatic system disorders
Febrile neutropenia
Very common
Anaemia
Very common
Neutropenia
Very common
White blood cell count decreased/leukopenia
Very common
Thrombocytopenia
Very common
Hypoprothrombinaemia
Not known
Immune thrombocytopenia
Not known
Immune system disorders
Hypersensitivity
Common
+Anaphylactic reaction
Rare
+Anaphylactic shock
Rare

System organ class
Adverse reaction
Frequency
Metabolism and nutrition disorders
Weight decreased/Weight loss
Very common
Anorexia
Very common
Tumour lysis syndrome
Not known
Hyperkalaemia
Not known
Psychiatric disorders
Insomnia
Very common
Anxiety
Common
Depression
Common
Nervous system disorders
1Tremor
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
1Blood pressure decreased
Very common
1Blood pressure increased
Very common
1Heart beat irregular
Very common
1Cardiac flutter
Very common
Ejection fraction decreased*
Very common
+Cardiac failure (congestive)
Common
+1Supraventricular tachyarrhythmia
Common
Cardiomyopathy
Common
1Palpitation
Common
Pericardial effusion
Uncommon
Cardiogenic shock
Not known
Gallop rhythm present
Not known
Vascular disorders
Hot flush
Very common
+1Hypotension
Common
Vasodilation
Common
Respiratory, thoracic and mediastinal disorders
+Dyspnoea
Very common
Cough
Very common
Epistaxis
Very common
Rhinorrhoea
Very common
+Pneumonia
Common
Asthma
Common
Lung disorder
Common
+Pleural effusion
Common
+1Wheezing
Uncommon
Pneumonitis
Uncommon
+Pulmonary fibrosis
Not known
+Respiratory distress
Not known

System organ class
Adverse reaction
Frequency
+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
1Lip 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 tissue disorders
Erythema
Very common
Rash
Very common
1Swelling face
Very common
Alopecia
Very common
Nail disorder
Very common
Palmar-plantar erythrodysaesthesia syndrome
Very common
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 tissue disorders
Arthralgia
Very common
1Muscle tightness
Very common
Myalgia
Very common
Arthritis
Common
Back pain
Common
Bone pain
Common

System organ class
Adverse reaction
Frequency
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 perinatal conditions
Oligohydramnios
Not known
Renal hypoplasia
Not known
Pulmonary hypoplasia
Not known
Reproductive system and breast disorders
Breast inflammation/mastitis
Common
General disorders and administration site conditions
Asthenia
Very common
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 oedema
Very common
Malaise
Common
Oedema
Common
Injury, poisoning and procedural complications
Contusion
Common
+
Denotes adverse reactions that have been reported in association with a fatal outcome.
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 hypoprothrombinaemia 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).

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 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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Traceability

In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded.

HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of the testing procedures (see section 5.1).

Currently no data from clinical trials are available on re-treatment of patients with previous exposure to trastuzumab in the adjuvant setting.

Cardiac dysfunction

General considerations

Patients treated with Tuznue are at increased risk for developing CHF (New York Heart Association [NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in patients receiving trastuzumab therapy alone or in combination with paclitaxel or docetaxel, particularly following anthracycline (doxorubicin or epirubicin) containing chemotherapy. These may be moderate to severe and have been associated with death (see section 4.8). In addition, caution should be exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary artery disease, CHF, LVEF of < 55%, older age.

All candidates for treatment with Tuznue, but especially those with prior anthracycline and cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and physical examination, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition (MUGA) scan or magnetic resonance imaging. Monitoring may help to identify patients who develop cardiac dysfunction. Cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Tuznue. A careful risk-benefit assessment should be made before deciding to treat with Tuznue.

Trastuzumab may persist in the circulation for up to 7 months after stopping Tuznue treatment based on population pharmacokinetic analysis of all available data (see section 5.2). Patients who receive anthracyclines after stopping Tuznue may possibly be at increased risk of cardiac dysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping Tuznue. If anthracyclines are used, the patient’s cardiac function should be monitored carefully.

Formal cardiological assessment should be considered in patients in whom there are cardiovascular concerns following baseline screening. In all patients cardiac function should be monitored during treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac dysfunction. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6 – 8 weeks). If patients have a continued decrease in left ventricular function, but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of Tuznue therapy has been seen.

The safety of continuation or resumption of trastuzumab in patients who experience cardiac dysfunction has not been prospectively studied. If LVEF percentage drops ≥ 10 points from baseline AND to below 50%, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, or symptomatic CHF has developed, discontinuation of Tuznue should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.

If symptomatic cardiac failure develops during Tuznue therapy, it should be treated with standard medicinal products for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunction in pivotal trials improved with standard CHF treatment consisting of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. The majority of patients with cardiac symptoms and evidence of a clinical benefit of trastuzumab treatment continued on therapy without additional clinical cardiac events.

Metastatic breast cancer

Tuznue and anthracyclines should not be given concurrently in combination in the MBC setting.

Patients with MBC who have previously received anthracyclines are also at risk of cardiac dysfunction with Tuznue treatment, although the risk is lower than with concurrent use of Tuznue and anthracyclines.

Early breast cancer

For patients with EBC, cardiac assessments, as performed at baseline, should be repeated every 3 months, during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Tuznue. In patients who receive anthracycline-containing chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last administration of Tuznue, or longer if a continuous decrease of LVEF is observed.

Patients with history of myocardial infarction (MI), angina pectoris requiring medical treatment, history of or existing CHF (NYHA Class II-IV), LVEF of < 55%, other cardiomyopathy, cardiac arrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorly controlled hypertension (hypertension controlled by standard medical treatment eligible), and hemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBC pivotal trials with trastuzumab and therefore treatment cannot be recommended in such patients.

Adjuvant treatment

Tuznue and anthracyclines should not be given concurrently in combination in the adjuvant treatment setting.

In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac events was observed when trastuzumab was administered after anthracycline-containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel and carboplatin and was more marked when trastuzumab was administered concurrently with taxanes than when administered sequentially to taxanes. Regardless of the regimen used, most symptomatic cardiac events occurred within the first 18 months. In one of the 3 pivotal studies conducted in which a median follow-up of 5.5 years was available (BCIRG006) a continuous increase in the cumulative rate of symptomatic cardiac or LVEF events was observed in patients who were administered trastuzumab concurrently with a taxane following anthracycline therapy up to 2.37% compared to approximately 1% in the two comparator arms (anthracycline plus cyclophosphamide followed by taxane and taxane, carboplatin and trastuzumab).

Risk factors for a cardiac event identified in four large adjuvant studies included advanced age (> 50 years), low LVEF (< 55%) at baseline, prior to or following the initiation of paclitaxel treatment, decline in LVEF by 10-15 points, and prior or concurrent use of anti-hypertensive medicinal products.
In patients receiving trastuzumab after completion of adjuvant chemotherapy, the risk of cardiac dysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of trastuzumab and a body mass index (BMI) > 25 kg/m2.

Neoadjuvant-adjuvant treatment

In patients with EBC eligible for neoadjuvant-adjuvant treatment, Tuznue should be used concurrently with anthracyclines only in chemotherapy-naive patients and only with low-dose anthracycline regimens i.e. maximum cumulative doses of doxorubicin 180 mg/m2 or epirubicin 360 mg/m2.

If patients have been treated concurrently with a full course of low-dose anthracyclines and Tuznue in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery. In other situations, the decision on the need for additional cytotoxic chemotherapy is determined based on individual factors.

Experience of concurrent administration of trastuzumab with low dose anthracycline regimens is currently limited to two trials (MO16432 and BO22227).

In the pivotal trial MO16432, trastuzumab was administered concurrently with neoadjuvant chemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m2).

The incidence of symptomatic cardiac dysfunction was 1.7% in the trastuzumab arm.

In the pivotal trial BO22227, trastuzumab was administered concurrently with neoadjuvant chemotherapy that contained four cycles of epirubicin (cumulative dose 300 mg/m2); at a median follow-up exceeding 70 months, the incidence of cardiac failure/congestive cardiac failure was 0.3% in the trastuzumab intravenous arm.

Clinical experience is limited in patients above 65 years of age.

Infusion-related reactions (IRRs) and hypersensitivity

Serious IRRs to trastuzumab infusion including dyspnoea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, anaphylaxis, respiratory distress, urticaria and angioedema have been reported (see section 4.8). Pre-medication may be used to reduce risk of occurrence of these events. The majority of these events occur during or within 2.5 hours of the start of the first infusion. Should an infusion reaction occur the infusion should be discontinued or the rate of infusion slowed and the patient should be monitored until resolution of all observed symptoms (see section 4.2). These symptoms can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as diphenhydramine. The majority of patients experienced resolution of symptoms and subsequently received further infusions of trastuzumab. Serious reactions have been treated successfully with supportive therapy such as oxygen, beta-agonists, and corticosteroids. In rare cases, these reactions are associated with a clinical course culminating in a fatal outcome. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a fatal infusion reaction.
Therefore, these patients should not be treated with Tuznue (see section 4.3).

Initial improvement followed by clinical deterioration and delayed reactions with rapid clinical deterioration have also been reported. Fatalities have occurred within hours and up to one week following infusion. On very rare occasions, patients have experienced the onset of infusion symptoms and pulmonary symptoms more than six hours after the start of the trastuzumab infusion. Patients should be warned of the possibility of such a late onset and should be instructed to contact their physician if these symptoms occur.

Pulmonary events

Severe pulmonary events have been reported with the use of trastuzumab in the post-marketing setting (see section 4.8). These events have occasionally been fatal. In addition, cases of interstitial lung disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy. These events may occur as part of an infusion-related reaction or

with a delayed onset. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated with Tuznue (see section 4.3). Caution should be exercised for pneumonitis, especially in patients being treated concomitantly with taxanes.

Excipient with known effect

Tuznue contains 0.6 mg of polysorbate 20 in each 150 mg vial, which is equivalent to 0.083 mg/mL (after reconstitution with 7.2 mL sterile water for injection). Polysorbates may cause allergic reactions.

Tuznue contains 1.7 mg of polysorbate 20 in each 420 mg vial, which is equivalent to 0.085 mg/mL (after reconstitution with 20 mL sterile water for injection). Polysorbates may cause allergic reactions.

No formal drug interaction studies have been performed. Clinically significant interactions between trastuzumab and the concomitant medicinal products used in clinical trials have not been observed.

Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents

Pharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive MBC suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl- paclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (8 mg/kg or 4 mg/kg intravenous loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w intravenous dose, respectively).

However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this metabolite was unclear.

Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg loading dose as an intravenous infusion and 2 mg/kg intravenous infusion weekly) and docetaxel (60 mg/m2 intravenous infusion) in Japanese women with HER2-positive MBC, suggested that concomitant administration of trastuzumab had no effect on the single dose pharmacokinetics of docetaxel. Study JP19959 was a substudy of BO18255 (ToGA) performed in male and female Japanese patients with advanced gastric cancer to study the pharmacokinetics of capecitabine and cisplatin when used with or without trastuzumab. The results of this substudy suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus trastuzumab. However, capecitabine itself showed higher concentrations and a longer half-life when combined with trastuzumab. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus trastuzumab.

Pharmacokinetic data from Study H4613g/GO01305 in patients with metastatic or locally advanced inoperable HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin.

Effect of antineoplastic agents on trastuzumab pharmacokinetics

By comparison of simulated serum trastuzumab concentrations after trastuzumab monotherapy (4 mg/kg loading/2 mg/kg q1w intravenous) and observed serum concentrations in Japanese women with HER2-positive MBC (study JP16003) no evidence of a PK effect of concurrent administration of docetaxel on the pharmacokinetics of trastuzumab was found.

Comparison of PK results from two Phase II studies (BO15935 and M77004) and one Phase III study (H0648g) in which patients were treated concomitantly with trastuzumab and paclitaxel and two Phase II studies in which trastuzumab was administered as monotherapy (W016229 and MO16982), in women with HER2-positive MBC indicates that individual and mean trastuzumab trough serum concentrations varied within and across studies but there was no clear effect of the concomitant

administration of paclitaxel on the pharmacokinetics of trastuzumab. Comparison of trastuzumab PK data from Study M77004 in which women with HER2-positive MBC were treated concomitantly with trastuzumab, paclitaxel and doxorubicin to trastuzumab PK data in studies where trastuzumab was administered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamide or paclitaxel (Study H0648g), suggested no effect of doxorubicin and paclitaxel on the pharmacokinetics of trastuzumab.

Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the PK of trastuzumab.

The administration of concomitant anastrozole did not appear to influence the pharmacokinetics of trastuzumab.

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception during treatment with Tuznue and for 7 months after treatment has concluded (see section 5.2).

Pregnancy

Reproduction studies have been conducted in Cynomolgus monkeys at doses up to 25 times that of the weekly human maintenance dose of 2 mg/kg trastuzumab intravenous formulation and have revealed no evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumab during the early (days 20-50 of gestation) and late (days 120-150 of gestation) foetal development period was observed. It is not known whether trastuzumab can affect reproductive capacity. As animal reproduction studies are not always predictive of human response, trastuzumab should be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus.

In the post-marketing setting, cases of foetal renal growth and/or function impairment in association with oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus, have been reported in pregnant women receiving trastuzumab. Women who become pregnant should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with Tuznue, or if a patient becomes pregnant while receiving Tuznue or within 7 months following the last dose of Tuznue, close monitoring by a multidisciplinary team is desirable.

Breast-feeding

A study conducted in Cynomolgus monkeys at doses 25 times that of the weekly human maintenance dose of 2 mg/kg trastuzumab intravenous formulation from days 120 to 150 of pregnancy demonstrated that trastuzumab is secreted in the milk postpartum. The exposure to trastuzumab in utero and the presence of trastuzumab in the serum of infant monkeys was not associated with any adverse effects on their growth or development from birth to 1 month of age. It is not known whether trastuzumab is secreted in human milk. As human IgG1 is secreted into human milk, and the potential for harm to the infant is unknown, women should not breast-feed during Tuznue therapy and for 7 months after the last dose.

Fertility

There is no fertility data available.

Tuznue has a minor influence on the ability to drive or use machines (see section 4.8). Dizziness and somnolence may occur during treatment with Tuznue (see section 4.8). Patients experiencing infusion- related symptoms (see section 4.4) should be advised not to drive and use machines until symptoms

abate.

There is no experience with overdose in human clinical trials. Single doses of trastuzumab alone greater than 10 mg/kg have not been administered in the clinical trials; a maintenance dose of 10 mg/kg q3w following a loading dose of 8 mg/kg has been studied in a clinical trial with metastatic gastric cancer patients. Doses up to this level were well tolerated.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FD01

Tuznue is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency https://www.ema.europa.eu.

Trastuzumab is a recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). Overexpression of HER2 is observed in 20%-30% of primary breast cancers. Studies of HER2-positivity rates in gastric cancer (GC) using immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) or chromogenic in situ hybridisation (CISH) have shown that there is a broad variation of HER2-positivity ranging from 6.8% to 34.0% for IHC and 7.1% to 42.6% for FISH. Studies indicate that breast cancer patients whose tumours overexpress HER2 have a shortened disease-free survival compared to patients whose tumours do not overexpress HER2. The extracellular domain of the receptor (ECD, p105) can be shed into the blood stream and measured in serum samples.

Mechanism of action

Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of HER2’s extracellular domain. Binding of trastuzumab to HER2 inhibits ligand-independent HER2 signalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism of HER2. As a result, trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. Additionally, trastuzumab is a potent mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.

Detection of HER2 overexpression or HER2 gene amplification

Detection of HER2 overexpression or HER2 gene amplification in breast cancer

Trastuzumab should only be used in patients whose tumours have HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay. HER2 overexpression should be detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks (see section 4.4). HER2 gene amplification should be detected using fluorescence in situ hybridisation (FISH) or chromogenic in situ hybridisation (CISH) of fixed tumour blocks. Patients are eligible for Tuznue treatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a positive FISH or CISH result.

To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory, which can ensure validation of the testing procedures.

The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 2:

Table 2 Recommended scoring system to evaluate the IHC staining patterns in breast cancer

Score
Staining pattern
HER2 overexpression assessment

The pharmacokinetics of trastuzumab were evaluated in a population pharmacokinetic model analysis using pooled data from 1,582 subjects, including patients with HER2 positive MBC, EBC, AGC or other tumour types, and healthy volunteers, in 18 Phase I, II and III trials receiving trastuzumab intravenous. A two-compartment model with parallel linear and non-linear elimination from the central compartment described the trastuzumab concentration-time profile. Due to non-linear elimination, total clearance increased with decreasing concentration. Therefore, no constant value for half-life of trastuzumab can be deduced. The t1/2 decreases with decreasing concentrations within a dosing interval (see Table 16). MBC and EBC patients had similar PK parameters [e.g. clearance (CL), the central compartment volume (Vc)] and population-predicted steady state exposures (Cmin, Cmax and AUC). Linear clearance was 0.136 L/day for MBC, 0.112 L/day for EBC and 0.176 L/day for AGC. The non-linear elimination parameter values were 8.81 mg/day for the maximum elimination rate (Vmax) and 8.92 µg/mL for the Michaelis-Menten constant (Km) for the MBC, EBC, and AGC patients. The central compartment volume was 2.62 L for patients with MBC and EBC and 3.63 L for patients with AGC. In the final population PK model, in addition to primary tumour type, body- weight, serum aspartate aminotransferase and albumin were identified as a statistically significant covariates affecting the exposure of trastuzumab. However, the magnitude of effect of these covariates on trastuzumab exposure suggests that these covariates are unlikely to have a clinically meaningful effect on trastuzumab concentrations.