Ontruzant - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Ontruzant 150 mg powder for concentrate for solution for infusion

Ontruzant 420 mg powder for concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Ontruzant 150 mg powder for concentrate for solution for infusion

One vial contains 150 mg of trastuzumab, a humanised IgG1 monoclonal antibody produced by mammalian (Chinese hamster ovary) cell suspension culture and purified by several chromatography steps including specific viral inactivation and removal procedures.

Ontruzant 420 mg powder for concentrate for solution for infusion

One vial contains 420 mg of trastuzumab, a humanised IgG1 monoclonal antibody produced by mammalian (Chinese hamster ovary) cell suspension culture and purified by several chromatography steps including specific viral inactivation and removal procedures.

The reconstituted Ontruzant solution contains 21 mg/mL of trastuzumab.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

White to pale yellow lyophilised powder.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Breast cancer

Metastatic breast cancer

Ontruzant 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

Ontruzant 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 Ontruzant therapy, for

locally advanced (including inflammatory) disease or tumours >2 cm in diameter (see sections 4.4 and 5.1).

Ontruzant 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

Ontruzant 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-oesophageal junction who have not received prior anti-cancer treatment for their metastatic disease.

Ontruzant 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 IHC3+ 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). Ontruzant 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.

Ontruzant 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 Ontruzant (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 Ontruzant is 4 mg/kg body weight. The recommended weekly maintenance dose of Ontruzant 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 Ontruzant is 8 mg/kg body weight. The recommended maintenance dose of Ontruzant 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 Ontruzant until progression of disease. Patients with EBC should be treated with Ontruzant 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 Ontruzant 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 Ontruzant 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 Ontruzant by more than one week, a re-loading dose of Ontruzant should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weekly regimen: 8 mg/kg) as soon as possible. Subsequent Ontruzant 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 Ontruzant in the paediatric population.

Method of administration

Ontruzant is for intravenous use. The loading dose should be administered as a 90-minute intravenous infusion. Administration as an intravenous push or bolus is prohibited. Ontruzant 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 Ontruzant intravenous formulation before administration, see section 6.6.

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 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 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%, 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 the circulation for up to 7 months after stopping trastuzumab 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 haemodynamic 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/m2.

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/m2 or epirubicin 360 mg/m2.

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 the trial MO16432.

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.

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

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

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-a hydroxyl-paclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (8 mg/kg or 4 mg/kg loading dose as an intravenous infusion followed by 6 mg/kg q3w or 2 mg/kg q1w infusion, 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 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 infusion) 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 (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 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 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 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 trastuzumab. Women who become pregnant should be advised of the possibility of harm to the fetus. 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

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

+ 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 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 intravenous trastuzumab 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.

4.9 Overdose

5.  PHARMACOLOGICAL PROPERTIES

5.1  Pharmacodynamic properties

5.2 Pharmacokinetic properties

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 via an intravenous infusion. 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 ^g/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 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 population predicted PK exposure values (median with 5th-95th Percentiles) and PK parameter values at clinically relevant concentrations (Cmax and Cmin) for MBC, EBC and AGC patients treated with the approved q1w and q3w dosing regimens are shown in Table 14 (Cycle 1), Table 15 (steady-state), and Table 16 (PK parameters).

Table 14 Population predicted cycle 1 PK exposure values (median with 5th – 95th percentiles) for trastuzumab intravenous infusion dosing regimens in MBC, EBC and AGC patients

Table 15 Population predicted steady state PK exposure values (median with 5th – 95th percentiles) for trastuzumab intravenous infusion dosing regimens in MBC, EBC and AGC patients

*Cmin,ss  Cmin at steady state

**Cmax,ss = Cmax at steady state *** time to 90% of steady-state

Table 16 Population predicted PK parameter values at steady state for trastuzumab intravenous infusion dosing regimens in MBC, EBC and AGC patients

Trastuzumab washout

Trastuzumab washout period was assessed following q1w or q3w intravenous administration using the population PK model. The results of these simulations indicate that at least 95% of patients will reach concentrations that are <1 gg/mL (approximately 3% of the population predicted Cmm.ss, or about 97% washout) by 7 months.

Circulating shed HER2 ECD

The exploratory analyses of covariates with information in only a subset of patients suggested that patients with greater shed HER2-ECD level had faster nonlinear clearance (lower Km) (P<0.001). There was a correlation between shed antigen and SGOT/AST levels; part of the impact of shed antigen on clearance may have been explained by SGOT/AST levels.

Baseline levels of the shed HER2-ECD observed in MGC patients were comparable to those in MBC and EBC patients and no apparent impact on trastuzumab clearance was observed.

5.3 Preclinical safety data

6.  PHARMACEUTICAL PARTICULARS

6.1 List of excipients

L-histidine hydrochloride monohydrate

L-histidine

a,a-trehalose dihydrate

polysorbate 20

6.2 Incompatibilities

This medicinal product must not be mixed or diluted with other medicinal products except those mentioned under section 6.6.

Do not dilute with glucose solutions since these cause aggregation of the protein.

6.3 Shelf life

Unopened vials: 4 years.

Aseptic reconstitution and dilution :

After aseptic reconstitution with sterile water for injection, chemical and physical stability of the reconstituted solution has been demonstrated for 7 days at 2°C-8°C.

After aseptic dilution in polyvinylchloride, polyethylene or polypropylene bags containing sodium chloride 9 mg/mL (0.9%) solution for injection, chemical and physical stability of Ontruzant has been demonstrated for up to 30 days at 2°C – 8°C, and 24 hours at temperatures not exceeding 30°C.

From a microbiological point of view, the reconstituted solution and Ontruzant infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user, and would not normally be longer than 24 hours at 2°C to 8°C, unless reconstitution and dilution have taken place under controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in a refrigerator (2°C-8°C).

Do not freeze the reconstituted solution.

For storage conditions of the opened medicinal product, see section 6.3 and 6.6.

6.5 Nature and contents of container

Ontruzant 150 mg powder for concentrate for solution for infusion

One 15 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film containing 150 mg of trastuzumab

Each carton contains one vial.

Ontruzant 420 mg powder for concentrate for solution for infusion

One 40 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film containing 420 mg of trastuzumab

Each carton contains one vial.

6.6 Special precautions for disposal and other handling

Ontruzant IV is provided in sterile, preservative-free, non-pyrogenic, single use vials.

Appropriate aseptic technique should be used for reconstitution and dilution procedures. Care must be taken to ensure the sterility of prepared solutions. Since the medicinal product does not contain any anti-microbial preservative or bacteriostatic agents, aseptic technique must be observed.

Aseptic preparation, handling and storage:

Aseptic handling must be ensured when preparing the infusion. Preparation should be:

• • performed under aseptic conditions by trained personnel in accordance with good practice rules

especially with respect to the aseptic preparation of parenteral products.

• • prepared in a laminar flow hood or biological safety cabinet using standard precautions for the

safe handling of intravenous agents.

• • followed by adequate storage of the prepared solution for intravenous infusion to ensure

maintenance of the aseptic conditions

Ontruzant should be carefully handled during reconstitution. Causing excessive foaming during reconstitution or shaking the reconstituted solution may result in problems with the amount of Ontruzant that can be withdrawn from the vial.

The reconstituted solution should not be frozen.

Ontruzant 150 mg powder for concentrate for solution for infusion

Each 150 mg vial of Ontruzant is reconstituted with 7.2 mL of sterile water for injection (not supplied). Use of other reconstitution solvents should be avoided.

This yields a 7.4 mL solution for single-dose use, containing approximately 21 mg/mL trastuzumab, at a pH of approximately 6.0. A volume overage of 4% ensures that the labelled dose of 150 mg can be withdrawn from each vial.

Ontruzant 420 mg powder for concentrate for solution for infusion

Each 420 mg vial of Ontruzant is reconstituted with 20 mL of sterile water for injection (not supplied). Use of other reconstitution solvents should be avoided.

This yields a 21 mL solution for single-dose use, containing approximately 21 mg/mL trastuzumab, at a pH of approximately 6.0. A volume overage of 5% ensures that the labelled dose of 420 mg can be withdrawn from each vial.

Instructions for aseptic reconstitution

• 1) Using a sterile syringe, slowly inject the appropriate volume (as noted above) of sterile water for injection in the vial containing the lyophilised Ontruzant, directing the stream into the lyophilised cake.

• 2) Swirl the vial gently to aid reconstitution. DO NOT SHAKE!

7. MARKETING AUTHORISATION HOLDER

Samsung Bioepis NL B.V.

Olof Palmestraat 10

2616 LR Delft

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1241/001

EU/1/17/1241/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 November 2017