Dazublys 150 mg Powder for concentrate for solution for infusion

4.1. Therapeutic indications

Breast cancer Metastatic breast cancer Dazublys 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 Dazublys 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 Dazublys therapy for locally advanced (including inflammatory) disease or tumors> 2 cm in diameter (see sections 4.4 and 5.1). Dazublys should only be used in patients with metastatic or early breast cancer whose tumors 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 Dazublys 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. Dazublys should only be used in patients with metastatic gastric cancer (MGC) whose tumors 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).

4.2. Posology and method of administration

HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Trastuzumab 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. Dazublys intravenous formulation is not intended for subcutaneous administration and should be administered via an intravenous infusion only. If an alternate route of administration is required, other trastuzumab products offering such an option should be used. In order to prevent treatment errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Dazublys (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 trastuzumab is 4 mg/kg body weight. The recommended weekly maintenance dose of trastuzumab 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 trastuzumab is 8 mg/kg body weight. The recommended maintenance dose of trastuzumab 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 trastuzumab until the progression of the disease. Patients with EBC should be treated with trastuzumab 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 inhibitors for information on dose reduction or delays. If the 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 trastuzumab 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 trastuzumab 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 trastuzumab by more than one week, a re-loading dose of trastuzumab should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weekly regimen: 8 mg/kg) as soon as possible. Subsequent trastuzumab 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 trastuzumab in the Paediatric population. Method of administration Trastuzumab loading dose should be administered as a 90-minute intravenous infusion. Do not administer as an intravenous push or bolus. Trastuzumab 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 is well tolerated, the subsequent doses can be administered as a 30-minute infusion. For instructions on reconstitution of trastuzumab intravenous formulation before administration, see section 6.6. Infusion Bags used for administering the trastuzumab finished product should be DEHP free.

4.3. Contraindications

• 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.

4.4. Special warnings and precautions for use

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 specialized 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 trastuzumab 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%, and older age. All candidates for treatment with trastuzumab, 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 trastuzumab. A careful risk-benefit assessment should be made before deciding to treat with trastuzumab. Trastuzumab may persist in circulation for up to 7 months after stopping Dazublys treatment based on population pharmacokinetic analysis of all available data (see section 5.2). Patients who receive anthracyclines after stopping trastuzumab may possibly be at increased risk of cardiac dysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab. 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 trastuzumab 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 trastuzumab 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 trastuzumab 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 Trastuzumab 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 trastuzumab treatment, although the risk is lower than with concurrent use of trastuzumab 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 trastuzumab. In patients who receive anthracycline-containing chemotherapy further monitoring is recommended and should occur yearly up to 5 years from the last administration of trastuzumab, 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 Trastuzumab 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/m 2 . Neoadjuvant-adjuvant treatment In patients with EBC eligible for neoadjuvant-adjuvant treatment, trastuzumab 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/m 2 or epirubicin 360 mg/m 2 . If patients have been treated concurrently with a full course of low-dose anthracyclines and trastuzumab 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 trial MO16432. In the pivotal trial MO16432, trastuzumab was administered concurrently with neoadjuvant chemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m 2 ). The incidence of symptomatic cardiac dysfunction was 1.7% in the trastuzumab 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 trastuzumab (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 trastuzumab (see section 4.3). Caution should be exercised for pneumonitis, especially in patients being treated concomitantly with taxanes. Sodium Dazublys contains less than 1 mmol of sodium (23 mg) per dose, that is to say essentially sodium-free. Polysorbate-20 This medicine contains 0.6 mg of polysorbate 20 in each 150 mg/vial (21 mg/mL) which is equivalent to 0.6 mg/60 kg/7.4 mL. Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

No 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 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 trastuzumab (4 mg/kg IV loading dose and 2 mg/kg IV weekly) and docetaxel (60 mg/m 2 IV) 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 sub study 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 sub study 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 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 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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential Women of childbearing potential should be advised to use effective contraception during treatment with trastuzumab 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 trastuzumab, or if a patient becomes pregnant while receiving trastuzumab or within 7 months following the last dose of trastuzumab, 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 trastuzumab therapy and for 7 months after the last dose. Fertility There is no fertility data available.

4.7. Effects on ability to drive and use machines

Dazublys has a minor influence on the ability to drive or use machines (see section 4.8). Dizziness and somnolence may occur during treatment with trastuzumab (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.

4.8. Undesirable effects

Summary of the safety profile Amongst the most serious and/or common adverse reactions reported in trastuzumab usage intravenous formulations to date are cardiac dysfunction, infusion-related reactions, haematotoxicity (in particular neutropenia), infections and pulmonary adverse reactions. Tabulated list of adverse reactions In this section, the following categories of frequency have been used: very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Presented in Table 1 are adverse reactions that have been reported in association with the use of intravenous trastuzumab alone or in combination with chemotherapy in pivotal clinical trials and in the post-marketing setting. All the terms included are based on the highest percentage seen in pivotal clinical trials. In addition, terms reported in the post marketing setting are included in Table 1. Table 1: Undesirable Effects Reported with Intravenous Trastuzumab Monotherapy or in Combination with Chemotherapy in Pivotal Clinical Trials (N = 8386) and in Post-Marketing System organ class Adverse reaction Frequency Infections and infestations Infection Very common Nasopharyngitis Very common Neutropenic sepsis Common Cystitis Common Influenza Common Sinusitis Common Skin infection Common Rhinitis Common Upper respiratory tract infection Common Urinary tract infection Common Pharyngitis Common Neoplasms benign, malignant 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 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 1 Tremor Very common Dizziness Very common Headache Very common Paraesthesia Very common Dysgeusia Very common System organ class Adverse reaction Frequency Peripheral neuropathy Common Hypertonia Common Somnolence Common Eye disorders Conjunctivitis Very common Lacrimation increased Very common Dry eye Common Papilloedema Not known Retinal haemorrhage Not known Ear and labyrinth disorders Deafness Uncommon Cardiac disorders 1 Blood pressure decreased Very common 1 Blood pressure increased Very common 1 Heart beat irregular Very common 1 Cardiac flutter Very common Ejection fraction decreased* Very common + Cardiac failure (congestive) Common +1 Supraventricular tachyarrhythmia Common Cardiomyopathy Common 1 Palpitation Common Pericardial effusion Uncommon Cardiogenic shock Not known Gallop rhythm present Not known Vascular disorders Hot flush Very common +1 Hypotension Common Vasodilatation Common Respiratory, thoracic and mediastinal disorders + Dyspnoea Very common Cough Very common Epistaxis Very common Rhinorrhoea Very common + Pneumonia Common Asthma Common Lung disorder Common + Pleural effusion Common +1 Wheezing Uncommon Pneumonitis Uncommon + Pulmonary fibrosis Not known + Respiratory distress Not known + Respiratory failure Not known + Lung infiltration Not known + Acute pulmonary oedema Not known + Acute respiratory distress syndrome Not known + Bronchospasm Not known + Hypoxia Not known + Oxygen saturation decreased Not known Laryngeal oedema Not known Orthopnoea Not known Pulmonary oedema Not known Interstitial lung disease Not known Gastrointestinal disorders Diarrhoea Very common Vomiting Very common Nausea Very common 1 Lip swelling Very common Abdominal pain Very common System organ class Adverse reaction Frequency 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 1 Muscle tightness Very common Myalgia Very common Arthritis Common Back pain Common Bone pain Common Muscle spasms Common Neck Pain Common Pain in extremity Common Renal and urinary disorders Renal disorder Common Glomerulonephritis membranous Not known Glomerulonephropathy Not known Renal failure Not known Pregnancy, puerperium and 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 System organ class Adverse reaction Frequency 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 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 edema, S3 gallop, or reduced ventricular ejection fraction, have been observed in patients treated with trastuzumab (see section 4.4). In 3 pivotal clinical trials of adjuvant trastuzumab given in combination with chemotherapy, the incidence of grade 3/4 cardiac dysfunction (specifically symptomatic Congestive Heart Failure) was similar in patients who were administered chemotherapy alone (ie did not receive trastuzumab) and in patients who were administered trastuzumab sequentially after a taxane (0.3 - 0.4%). The rate was highest in patients who were administered trastuzumab concurrently with a taxane (2.0%). In the neoadjuvant setting, the experience of concurrent administration of trastuzumab and low dose anthracycline regimen is limited (see section 4.4). When trastuzumab was administered after completion of adjuvant chemotherapy NYHA Class III-IV heart failure was observed in 0.6% of patients in the one-year arm after a median follow-up of 12 months. In study BO16348, after a median follow-up of 8 years the incidence of severe CHF (NYHA Class III & IV) in the trastuzumab 1 year treatment arm was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%. Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥ 50% after the event) was evident for 71.4% of trastuzumab-treated patients. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5% of patients. Approximately 17% of cardiac dysfunction related events occurred after completion of trastuzumab. In the pivotal metastatic trials of intravenous trastuzumab, the incidence of cardiac dysfunction varied between 9% and 12% when it was combined with paclitaxel compared with 1% – 4% for paclitaxel alone. For monotherapy, the rate was 6% – 9%. The highest rate of cardiac dysfunction was seen in patients receiving trastuzumab concurrently with anthracycline/cyclophosphamide (27%), and was significantly higher than for anthracycline/cyclophosphamide alone (7% – 10%). In a subsequent trial with prospective monitoring of cardiac function, the incidence of symptomatic CHF was 2.2% in patients receiving trastuzumab and docetaxel, compared with 0% in patients receiving docetaxel alone. Most of the patients (79%) who developed cardiac dysfunction in these trials experienced an improvement after receiving standard treatment for CHF. Infusion reactions, allergic-like reactions and hypersensitivity It is estimated that approximately 40% of patients who are treated with trastuzumab will experience some form of infusion-related reaction. However, the majority of infusion-related reactions are mild to moderate in intensity (NCI-CTC grading system) and tend to occur earlier in treatment, i.e. during infusions one, two and three and lessen in frequency in subsequent infusions. Reactions include chills, fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, respiratory distress, rash, nausea, vomiting and headache (see section 4.4). The rate of infusion-related reactions of all grades varied between studies depending on the indication, the data collection methodology, and whether trastuzumab was given concurrently with chemotherapy or as monotherapy. Severe anaphylactic reactions requiring immediate additional intervention can occur usually during either the first or second infusion of trastuzumab (see section 4.4) and have been associated with a fatal outcome. Anaphylactoid reactions have been observed in isolated cases. Haematotoxicity Febrile neutropenia, leukopenia, anaemia, thrombocytopenia and neutropenia occurred very commonly. The frequency of occurrence of hypoprothrombinemia is not known. The risk of neutropenia may be slightly increased when trastuzumab is administered with docetaxel following anthracycline therapy. Pulmonary events Severe pulmonary adverse reactions occur in association with the use of trastuzumab and have been associated with a fatal outcome. These include, but are not limited to, pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency (see section 4.4). 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 (see details below). United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

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.