Herzuma Product Monograph

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TABLE OF CONTENTS

PART I: HEALTH PROFESSIONAL INFORMATION .................................................................... 4

1 INDICATIONS ..................................................................................................................... 4

1.1 Pediatrics .................................................................................................................... 5

1.2 Geriatrics .................................................................................................................... 5

2 CONTRAINDICATIONS ..................................................................................................... 5

3 SERIOUS WARNINGS AND PRECAUTIONS BOX .......................................................... 5

4 DOSAGE AND ADMINISTRATION .................................................................................... 6

4.1 Dosing Considerations ............................................................................................... 6

4.2 Recommended Dose and Dosage Adjustment .......................................................... 6

4.3 Administration ............................................................................................................. 8

4.4 Reconstitution ............................................................................................................. 9

4.5 Missed Dose ............................................................................................................. 10

5 OVERDOSAGE ................................................................................................................ 11

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ......................... 11

7 DESCRIPTION .................................................................................................................. 12

8 WARNINGS AND PRECAUTIONS .................................................................................. 12

8.1 Special Populations .................................................................................................. 25

8.1.1 Pregnant Women ................................................................................................... 25

8.1.2 Breast-feeding ....................................................................................................... 26

8.1.3 Pediatrics ............................................................................................................... 26

8.1.4 Geriatrics (> 65 years of age) ................................................................................ 26

9 ADVERSE REACTIONS ................................................................................................... 27

9.1 Clinical Trial Adverse Drug Reactions ...................................................................... 27

9.2 Less Common Clinical Trial Adverse Reactions ...................................................... 61

9.3 Post-Market Adverse Drug Reactions ...................................................................... 65

10 DRUG INTERACTIONS .................................................................................................... 66

10.1 Overview .................................................................................................................. 66

10.2 Drug-Drug Interactions ............................................................................................. 67

11 ACTION AND CLINICAL PHARMACOLOGY .................................................................. 67

11.1 Mechanism of Action ................................................................................................ 67

11.2 Pharmacokinetics ..................................................................................................... 68

12 STORAGE, STABILITY AND DISPOSAL ........................................................................ 69

13 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 70

PART II: SCIENTIFIC INFORMATION ......................................................................................... 71

14 PHARMACEUTICAL INFORMATION .............................................................................. 71

15 COMPARATIVE CLINICAL TRIALS ................................................................................ 72

15.1 Comparative Trial Design and Study Demographics ............................................... 72

15.2 Comparative Study Results ...................................................................................... 73

15.2.1 Comparative Bioavailability Studies ....................................................................... 74

15.2.1.1 Pharmacokinetics .............................................................................................. 74

15.2.2 Comparative Safety and Efficacy ........................................................................... 74

15.2.2.1 Efficacy .............................................................................................................. 74

15.2.2.2 Safety ................................................................................................................ 75

15.2.2.3 Immunogenicity ................................................................................................. 75

16 COMPARATIVE NON-CLINICAL PHARMACOLOGY AND TOXICOLOGY ................... 75

16.1 Comparative Non-Clinical Pharmacodynamics ........................................................ 75

16.2 Comparative Toxicology ........................................................................................... 76

17 CLINICAL TRIALS – REFERENCE BIOLOGIC DRUG ................................................... 76

18 NON-CLINICAL TOXICOLOGY– REFERENCE BIOLOGIC DRUG ................................ 94

19 SUPPORTING PRODUCT MONOGRAPHS .................................................................. 103

PATIENT MEDICATION INFORMATION .................................................................................. 104

PATIENT MEDICATION INFORMATION .................................................................................. 111

HERZUMA^® (trastuzumab) is a biosimilar biologic drug (biosimilar) to HERCEPTIN^®.

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Indications have been granted on the basis of similarity between HERZUMA^® and the reference biologic drug HERCEPTIN^®.

• Early Breast Cancer (EBC)

  HERZUMA^® (trastuzumab) is indicated for the treatment of patients with early stage breast cancer with ECOG 0-1 status, whose tumours overexpress HER2,

  • following surgery and after chemotherapy
  • following adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel
  • in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.

For detailed information on the inclusion criteria for the clinical trials of trastuzumab in EBC according to the TNM (Tumour, Node, Metastasis) classification system, see Part II: Clinical Trial – Reference Biologic Drug section.

Based on the analysis of the HERA trial, the benefit of the adjuvant treatment with trastuzumab for low risk patients not given adjuvant chemotherapy are unknown.

The comparative efficacy and safety between different chemotherapy regimens (i.e. concurrent versus sequential, anthracycline containing versus non-anthracycline containing) was not studied.

• Metastatic Breast Cancer (MBC)

  HERZUMA^® is indicated for the treatment of patients with MBC whose tumours overexpress HER2.

  The benefits of treatment with trastuzumab in patients who do not overexpress HER2 (HER2 expression 0 as defined by a validated immunohistochemical [IHC] assay) or who exhibit lower-level expression (HER2 expression 1+ as defined by a validated IHC assay, and the subgroup of patients with HER2 overexpression 2+ as defined by a validated IHC assay that corresponds to 1+ scoring by the investigative clinical trial assay), are unclear (see WARNINGS AND PRECAUTIONS: Selection of Patients / Diagnostic Tests).

  HERZUMA^® can be used in combination with pertuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. For information on the use of HERZUMA^® in combination with pertuzumab and docetaxel, consult the Product Monograph for pertuzumab.

• Metastatic Gastric Cancer (MGC)

  HERZUMA^® in combination with capecitabine or intravenous 5-fluorouracil and cisplatin is indicated for the treatment of 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.

  HERZUMA^® should only be administered to patients with MGC whose tumours have HER2 overexpression as defined by IHC 2+ confirmed by FISH+, or IHC 3+ as determined by an accurate and validated assay.

1.1 Pediatrics

The safety and effectiveness of HERZUMA^® in pediatric patients (< 18 years of age) have not been established.

1.2 Geriatrics

The reported clinical experience is not adequate to determine whether older patients respond differently to trastuzumab treatment than younger patients (see WARNINGS AND PRECAUTIONS, Geriatrics).

2 CONTRAINDICATIONS

• HERZUMA^® (trastuzumab) is contraindicated in patients with known hypersensitivity to trastuzumab, Chinese Hamster Ovary (CHO) cell proteins, or any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging.
• When using in combination with pertuzumab and docetaxel, consult Product Monographs for pertuzumab and docetaxel for further information on these drugs.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

There is a risk of medication errors between HERZUMA^® (trastuzumab) and KADCYLA^® (trastuzumab emtansine). In order to prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is HERZUMA^® (trastuzumab) and not KADCYLA^® (trastuzumab emtansine). Ensure that the recommended HERZUMA^® (trastuzumab) dose is administered (see Recommended Dose and Dosage Adjustment section).

HERZUMA^® should be prescribed using both the trade name and non-proprietary name. Do not substitute HERZUMA^® for or with KADCYLA^® (trastuzumab emtansine).

When using in combination with pertuzumab and docetaxel for treatment of patients with HER-2-positive metastatic breast cancer, consult Product Monographs for pertuzumab and docetaxel for further information, such as dose adjustment, sequence of administration of each medication and duration of treatment.

4.2 Recommended Dose and Dosage Adjustment

Early Breast Cancer (EBC)

3-Weekly Schedule: The recommended initial loading dose is 8 mg/kg HERZUMA^® (trastuzumab) administered as a 90-minute infusion. The recommended maintenance dose is 6 mg/kg HERZUMA^® 3 weeks later and then 6 mg/kg repeated at 3-weekly intervals administered as infusions over approximately 90 minutes. If the prior dose was well tolerated, the dose can be administered as a 30-minute infusion. Do not administer as an IV push or bolus (see Preparation for Administration).

Weekly schedule: As a weekly regimen, the recommended initial loading dose of HERZUMA^® is 4 mg/kg followed by 2 mg/kg every week.

See clinical trial – reference biological drug section for chemotherapy combination dosing.

Metastatic Breast Cancer (MBC)

Weekly schedule: The recommended initial loading dose is 4 mg/kg HERZUMA^® administered as a 90-minute infusion. The recommended weekly maintenance dose is 2 mg/kg HERZUMA^® and can be administered as a 30-minute infusion if the initial loading dose was well tolerated. HERZUMA^® may be administered in an outpatient setting. Do not administer as an IV push or bolus (see Preparation for Administration).

Metastatic Gastric Cancer (MGC)

3-Weekly Schedule: The recommended initial loading dose is 8 mg/kg HERZUMA^® administered as a 90-minute infusion. The recommended maintenance dose is 6 mg/kg HERZUMA^® 3 weeks later and then 6 mg/kg repeated at 3-weekly intervals administered as infusions over approximately 90 minutes. If the prior dose was well tolerated, the dose can be administered as a 30-minute infusion. Do not administer as an IV push or bolus (see Preparation for Administration)

Duration of Treatment

In clinical studies, patients with MBC or MGC were treated with trastuzumab until progression of disease. Patients with EBC should be treated for 1 year or until disease recurrence or unacceptable cardiac toxicity, whichever occurs first (see WARNINGS AND PRECAUTIONS, Cardiovascular). Extending treatment in EBC beyond one year is not recommended (see Clinical Trials – Reference Biological Drug, Early Breast Cancer (EBC), HERA).

Dose Reduction

No reductions in the dose of trastuzumab were made during clinical trials. Patients may continue therapy with HERZUMA^® during periods of reversible, chemotherapy-induced myelosuppression, but they should be monitored carefully for complications of neutropenia during this time. The specific instructions to reduce or hold the dose of chemotherapy should be followed.

Table 1 depicts the criteria for permanent discontinuation of trastuzumab for cardiac dysfunction in pivotal studies in adjuvant breast cancer.

Table 1 Criteria for Permanent Discontinuation for Cardiac Dysfunction in Pivotal Studies in Adjuvant Breast Cancer

Dose Holding

Monitoring of Cardiac Function (also see WARNINGS AND PRECAUTIONS, Cardiovascular, Cardiotoxicity)

Table 2 Recommendations for Continuation or Withdrawal of HERZUMA^® Therapy in Asymptomatic Patients Based on Serial Measurements of Left Ventricular Ejection Fraction (LVEF)^a

(Adapted from the Canadian Consensus Guidelines*)

For the frequency of cardiac monitoring see WARNINGS AND PRECAUTIONS, Cardiovascular, Cardiotoxicity.

Health Canada has not authorized an indication for pediatric use (see Indications section).

4.3 Administration

Weekly Schedule: Treatment may be administered in an outpatient setting by administration of a 4 mg/kg loading dose of HERZUMA^® by intravenous (IV) infusion over 90 minutes. Do not administer as an IV push or bolus. Patients should be observed for fever and chills or other infusion associated symptoms. Serious adverse reactions to infusions of trastuzumab including dyspnea, hypotension, hypertension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress have been reported infrequently (also see ADVERSE REACTIONS). Interruption of the infusion may help control such symptoms. The infusion may be resumed when symptoms abate.

If prior infusion was well tolerated, subsequent weekly doses of 2 mg/kg HERZUMA^® may be administered over 30 minutes (see Recommended Dose and Dosage Adjustment). Patients should still be observed for fever and chills or other infusion-associated symptoms (see ADVERSE REACTIONS).

3-Weekly Schedule: Treatment may be administered in an outpatient setting by administration of an 8 mg/kg loading dose of HERZUMA^® by intravenous (IV) infusion over 90 minutes. Do not administer as an IV push or bolus. Patients should be observed for fever and chills or other infusion associated symptoms (see ADVERSE REACTIONS). Interruption of the infusion may help control such symptoms. The infusion may be resumed when symptoms abate.

If prior infusion was well tolerated, subsequent 3-weekly doses of 6 mg/kg HERZUMA^® may be administered over 30 minutes (see Recommended Dose and Dosage Adjustment). Patients should still be observed for fever and chills or other infusion-associated symptoms (see ADVERSE REACTIONS).

HERZUMA^® should not be mixed or diluted with other drugs. Infusions of HERZUMA^® should not be administered or mixed with dextrose solutions.

Flush the intravenous line with 0.9% Sodium Chloride Injection, USP after each dose.

4.4 Reconstitution

Table 3 Reconstitution

Preparation for Administration

Use appropriate aseptic technique.

440 mg/vial

Each vial of HERZUMA^® should be reconstituted with 20 mL of BWFI, containing 1.1% benzyl alcohol, as supplied, to yield a multi-dose solution containing 21 mg/mL trastuzumab. Immediately upon reconstitution with BWFI, the vial of HERZUMA^® must be labelled with “Do not use after:” followed by the future date that is 28 days from the date of reconstitution.

If the patient has a known hypersensitivity to benzyl alcohol, HERZUMA^® must be reconstituted with Sterile Water for Injection (see WARNINGS AND PRECAUTIONS). HERZUMA^® which has been reconstituted with SWFI must be used immediately and any unused portion discarded. Use of other reconstitution diluents should be avoided.

150 mg/vial

Each vial of HERZUMA^® should be reconstituted with 7.2 mL of Sterile Water for Injection (SWFI) (not supplied), to yield a single-dose solution containing 21 mg/mL trastuzumab. The reconstituted solution should be used immediately and any remaining reconstituted solution should be discarded.

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

Reconstitution:

440 mg/vial

1. 1. Using a sterile syringe, slowly inject 20 mL of Bacteriostatic Water for Injection in the vial containing the lyophilized HERZUMA^® directing the stream into the lyophilized cake.
2. 2. Swirl vial gently to aid reconstitution. Do not shake.

150 mg/vial

1. 1. Using a sterile syringe, slowly inject 7.2 mL of Sterile Water for Injection (not supplied) in the vial containing the lyophilized HERZUMA^® directing the stream into the lyophilized cake.
2. 2. Swirl vial gently to aid reconstitution. Do not shake.

Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed for approximately 5 minutes. The reconstituted HERZUMA^® results in a colorless to pale yellow transparent solution and should be essentially free of visible particles.

Determine the volume in mL of HERZUMA^® solution needed:

Weekly Schedule: based on a loading dose of 4 mg trastuzumab/kg body weight or a maintenance dose of 2 mg trastuzumab/kg body weight. Volume (mL)= [Body Weight (kg) x Dose (4 mg/kg for loading OR 2 mg/kg for maintenance)] 21 mg/mL (concentration of reconstituted solution)

3-Weekly Schedule: based on a loading dose of 8 mg trastuzumab/kg body weight, or a subsequent 3 weekly dose of 6 mg trastuzumab/kg body weight:

Volume (mL)= [Body Weight (kg) x Dose (8 mg/kg for loading OR 6 mg/kg for maintenance)] 21 mg/mL (concentration of reconstituted solution)

Withdraw the appropriate volume of solution calculated from the vial and add it to an infusion bag containing 250 mL of 0.9% sodium chloride, USP. Dextrose (5%) solution should not be used since it causes aggregation of the protein. To mix the solution and avoid foaming, invert the bag gently. The reconstituted preparation results in a colourless to pale yellow transparent solution. Parenteral drug products should be inspected visually for particulates and discolouration prior to administration. No incompatibilities between HERZUMA^® and polyvinylchloride, polyethylene or polypropylene bags have been observed.

4.5 Missed Dose

Weekly schedule: If the patient has missed a dose of HERZUMA^® by one week or less, then the usual maintenance dose (2 mg/kg) should be given as soon as possible (do not wait until the next planned cycle). Subsequent maintenance HERZUMA^® doses of 2 mg/kg should be administered 7 days later according to the weekly schedule.

If the patient has missed a dose of HERZUMA^® by more than one week, a re-loading dose of HERZUMA^® should be administered (4 mg/kg over approximately 90 minutes) as soon as possible. Subsequent maintenance HERZUMA^® doses of 2 mg/kg should be administered 7 days later according to the weekly schedule.

3-Weekly Schedule: If the patient has missed a dose of HERZUMA^® by one week or less, then the usual maintenance dose (6 mg/kg) should be administered as soon as possible (do not wait until the next planned cycle). Subsequent maintenance HERZUMA^® doses of 6 mg/kg should be administered 21 days later according to the 3-weekly schedule.

If the patient has missed a dose of HERZUMA^® by more than one week, a re-loading dose of HERZUMA^® should be administered (8 mg/kg over approximately 90 minutes) as soon as possible. Subsequent maintenance HERZUMA^® doses of 6 mg/kg should be administered 21 days later according to the 3-weekly schedule.

5 OVERDOSAGE

There is no experience with overdosage in human clinical trials. Single doses higher than 500 mg (10 mg/kg) have not been tested.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

To help ensure the traceability of biologic products, including biosimilars, health professionals should recognise the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table 4 Dosage Forms, Strengths, Composition and Packaging

Composition:

HERZUMA^® (trastuzumab) is a sterile, white to pale yellow, preservative-free lyophilized powder for intravenous (IV) administration.

440 mg/vial

Each vial of HERZUMA^® contains 440 mg trastuzumab, 6.4 mg L-histidine, 9.9 mg L-histidine HCl, 1.8 mg polysorbate 20, and 879 mg α,α-trehalose dihydrate. Reconstitution with 20 mL of the supplied BWFI, containing 1.1% benzyl alcohol as a preservative, yields a multi-dose solution containing 21 mg/mL trastuzumab, at a pH of approximately 6.

150 mg/vial

Each vial of HERZUMA^® contains 150 mg trastuzumab, 2.2 mg L-histidine, 3.4 mg L-histidine HCl, 0.6 mg polysorbate 20, and 299.6 α,α-trehalose dihydrate. Reconstitution with 7.2 mL of the SWFI (not supplied), yields a single-dose solution containing 21 mg/mL trastuzumab, at a pH of approximately 6.

Availability:

440 mg/vial

HERZUMA^® is supplied as a lyophilized, sterile powder containing 440 mg trastuzumab per vial under vacuum.

BWFI is supplied as a 20 mL vial of sterile solution containing 1.1% benzyl alcohol as an antimicrobial preservative.

Each carton contains one vial of 440 mg HERZUMA^® and one 20 mL vial of BWFI containing 1.1% benzyl alcohol.

150 mg/vial

HERZUMA^® is supplied as a lyophilized, sterile powder containing 150 mg trastuzumab per vial under vacuum.

Each carton contains one vial of 150 mg HERZUMA^®.

7 DESCRIPTION

• HERZUMA^® (trastuzumab) is a biosimilar to HERCEPTIN^®. It consists of humanized immunoglobulin G1 (IgG₁) monoclonal antibody that selectively binds with high affinity to extra cellular domain (ECD) of the human epidermal growth factor receptor 2 (HER2).

8 WARNINGS AND PRECAUTIONS

Please see the Serious Warnings and Precautions Box at the beginning of Part I: Health Professional Information.

General

Therapy with HERZUMA^® should only be initiated under supervision of a physician experienced in the treatment of cancer patients.

When using in combination with pertuzumab and docetaxel, consult Product Monographs for pertuzumab and docetaxel for further information on these drugs.

In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

Early Breast Cancer (EBC)

The safety of the various combination chemotherapy regimens prior to trastuzumab therapy was not separately analyzed in the HERA trial. The data provided in the Product Monograph reflects the safety and efficacy of trastuzumab for the recommended 1 year treatment duration.

Benzyl Alcohol: Benzyl alcohol, used as a preservative in BWFI, has been associated with toxicity in neonates and children up to 3 years old. For patients with a known hypersensitivity to benzyl alcohol (the preservative in BWFI), reconstitute HERZUMA^® with Sterile Water for Injection (SWFI). Use SWFI-reconstituted HERZUMA^® immediately and discard the vial (see DOSAGE AND ADMINISTRATION).

Cardiovascular

Cardiotoxicity: Administration of HERZUMA^® can result in the development of ventricular dysfunction and congestive heart failure. In the adjuvant treatment setting, the incidence of cardiac dysfunction was higher in patients who received trastuzumab plus chemotherapy versus chemotherapy alone. 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. The incidence was more marked when trastuzumab was administered concurrently with a taxane than when administered sequentially to a taxane. In the metastatic setting, the incidence and severity of cardiac dysfunction were particularly high in patients who received trastuzumab concurrently with anthracyclines and cyclophosphamide. The incidence of cardiac adverse events was also higher in patients with previous exposure to anthracyclines based on post-market data.

Because the half-life of trastuzumab, using a population pharmacokinetic method, is approximately 28.5 days (95% CI, 25.5 - 32.8 days), trastuzumab may persist in the circulation for approximately 24 weeks (range: 22-28 weeks) after stopping treatment with HERZUMA^®. Since the use of an anthracycline during this period could possibly be associated with an increased risk of cardiac dysfunction, a thorough assessment of the risks versus the potential benefits is recommended in addition to careful cardiac monitoring. If possible, physicians should avoid anthracycline based therapy while trastuzumab persists in the circulation.

Patients who receive HERZUMA^® either as a component of adjuvant treatment or as a treatment for metastatic HER2 positive breast cancer may experience signs and symptoms of cardiac dysfunction such as dyspnea, increased cough, paroxysmal nocturnal dyspnea, peripheral edema, S₃ gallop, or reduced ejection fraction. Cardiac dysfunction associated with therapy with HERZUMA^® may be severe and has been associated with disabling cardiac failure, death, and mural thrombosis leading to stroke.

Left ventricular function should be evaluated in all patients prior to and during treatment with HERZUMA^®. If LVEF drops 10 ejection points from baseline and/or to below 50%, HERZUMA^® should be withheld and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, discontinuation of HERZUMA^® should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. The scientific basis of cardiac dysfunction has been incompletely investigated in pre-clinical studies.

Extreme caution should be exercised in treating patients with pre-existing cardiac dysfunction, and in EBC, in those patients with an LVEF of 55% or less. Candidates for treatment with HERZUMA^® as part of adjuvant treatment for operable breast cancer or for MBC, especially those with prior anthracycline and cyclophosphamide (AC) exposure, should undergo thorough baseline cardiac assessment including history and physical exam, electrocardiogram (ECG) and either 2D echocardiogram or multiple gated acquisition (MUGA) scan. A careful risk-benefit assessment should be made before deciding to treat with HERZUMA^®. 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 HERZUMA^®. In patients with EBC who receive anthracycline containing chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last administration of HERZUMA^®, or longer if a continued decrease of LVEF is observed. 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 unless the benefits for the individual patient are deemed to outweigh the risks.

If symptomatic cardiac failure develops during therapy with HERZUMA^®, it should be treated with the standard medications for this purpose. Discontinuation of HERZUMA^® should be strongly considered in patients who develop clinically significant congestive heart failure. In the MBC clinical trials, approximately two-thirds of patients with cardiac dysfunction were treated for cardiac symptoms, most patients responded to appropriate medical therapy (which may include one or more of the following: diuretics, angiotensin-converting enzyme inhibitors, β-blockers, angiotensin II receptor blockers, or cardiac glycosides) often including discontinuation of trastuzumab. The safety of continuation or resumption of trastuzumab in patients who have previously experienced cardiac toxicity has not been prospectively studied.

Early Breast Cancer (EBC)

HERZUMA^® and anthracyclines should not be given concurrently in the adjuvant treatment setting.

Risk factors for a cardiac event identified in four large adjuvant studies included advanced age (> 50 years), low level of baseline and declining LVEF (< 55%), low LVEF prior to or following the initiation of paclitaxel treatment, trastuzumab treatment, and prior or concurrent use of anti-hypertensive medications. 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 high body mass index (BMI > 25 kg/m²).

In EBC, the following patients were excluded from the HERA, JA (NSABP B-31 and NCCTG N9831) and BCIRG-006 trials there are no data about the benefit risk balance, and therefore treatment cannot be recommended in such patients:

• history of myocardial infarction (MI),
• angina pectoris requiring medication,
• history of or present CHF (NYHA II–IV),
• other cardiomyopathy,
• cardiac arrhythmia requiring medication,
• clinically significant cardiac valvular disease,
• poorly controlled hypertension (hypertension controlled by standard medication eligible) and
• clinically significant pericardial effusion.

The safety of continuation or resumption of trastuzumab in patients who have previously experienced cardiac toxicity has not been prospectively studied. According to the narrative reports of cardiac events, about half of the events had resolved completely by the time of the interim analysis. Please see

Table 7 and

Table 8 below.

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 HERZUMA^®. In patients who receive anthracycline containing chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last administration of HERZUMA^®, or longer if a continued decrease of LVEF is observed.

A high index of clinical suspicion is warranted for discontinuing treatment in the setting of cardiopulmonary symptoms. Close monitoring of cardiac function should be carried out for all patients and adequate treatment for CHF should be administered regardless of the discontinuation of HERZUMA^® therapy. Please see Table 2 in DOSAGE AND ADMINISTRATION: Dose Holding, Monitoring of Cardiac Function, for information on continuation and discontinuation of HERZUMA^® based on interval LVEF assessments.

HERA

In the HERA trial, cardiac monitoring (electrocardiogram [ECG], left ventricular ejection fraction [LVEF], signs/symptoms and cardiac questionnaire) was performed at baseline and regularly throughout the study. The assessment schedule for cardiac monitoring was at months 3 and 6 and then every 6 months until month 36 (3 years from the date of therapy) and in month 60 (5 years from the date of therapy). In addition, LVEF was measured at 48 months (4 years from the date of therapy) and followed up every 12 months from year 6 to year 10.

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.

Table 5 Absolute Numbers and Rates of Cardiac Endpoints in HERA (Median follow-up of 12 months)

Table 6 Absolute Numbers and Rates of Cardiac Endpoints in HERA (Median follow-up of 8 years)

Table 7 Median Time to Return to Baseline LVEF/ Stabilizations of LVEF in the HERA Trial (Median follow-up of 8 years) - Primary Cardiac Endpoint

Table 8 Median Time to Return to Baseline LVEF/ Stabilizations of LVEF in the HERA Trial (Median follow-up of 8 years) - Secondary Cardiac Endpoint

A significant drop in left ventricular ejection fraction (LVEF) is defined as an absolute decrease of 10 EF points or more from baseline and to below 50%, measured by MUGA scan or echocardiogram.

A primary cardiac endpoint was defined as the occurrence at any time after randomization but prior to any new therapy for recurrent disease of symptomatic congestive heart failure of NYHA class III or IV, confirmed by a cardiologist and a significant drop in LVEF, or cardiac death.

A secondary cardiac endpoint was defined as asymptomatic (NYHA class I) or mildly symptomatic (NYHA class II) cardiac dysfunction with a significant LVEF drop. In addition events which did not meet the above criteria for a secondary cardiac endpoint but which in the opinion of the Cardiac Advisory Board should be classed as secondary cardiac endpoints were included.

After a median follow-up of 3.6 years the incidences of severe CHF, symptomatic CHF and at least one significant LVEF decrease (an absolute decline of at least 10% from baseline LVEF and to less than 50%) after 1 year of trastuzumab therapy was 0.8%, 1.9% and 9.8%, respectively.

After a median follow-up of 8 years the incidence of severe CHF (NYHA 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%. At least one LVEF assessment was missing for 20.8% of patients in the observation only arm and 32.0% of patients in the trastuzumab 1-year arm. During the follow-up until month 60, at least one LVEF assessment was missed for 18.0% of patients in the observation only arm and 17.9% of patients in the trastuzumab 1-year arm.

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% (14/83) of cardiac endpoints occurred after completion of trastuzumab in the trastuzumab one-year arm.

Joint Analysis: NSABP B-31 and NCCTG N9831

Cardiac dysfunction adverse events were defined in both B-31 and N9831 as symptomatic cardiac events and asymptomatic LVEF events. Symptomatic cardiac events were reviewed and confirmed by the cardiac committee of each study and included the occurrence of symptomatic congestive heart failure with objective findings and confirmation by imaging, deaths due to cardiac causes (CHF, MI, or documented primary arrhythmia) and probable cardiac deaths (sudden death without documented etiology). Asymptomatic LVEF events were defined as absolute drop in LVEF ≥10% to < 55% or an absolute drop in LVEF of ≥5% to below the institution’s lower limit of normal (LLN). In study B-31, 15.5% of patients discontinued trastuzumab due to asymptomatic LVEF decrease (12.2%), CHF (2.2%) or Cardiac diagnosis other than CHF (1.1%) in the trastuzumab + chemotherapy arm; no patients in the chemotherapy alone arm discontinued treatment for these reasons. In all analyses the rate of cardiac dysfunction was higher in patients in the trastuzumab + chemotherapy arm compared with those in the chemotherapy alone arm. From the paclitaxel baseline to the six month, nine month and eighteen month assessment, the average change in LVEF was more pronounced in the trastuzumab + chemotherapy arm (-4.2%, -5.1% and -3.1% in the trastuzumab + chemotherapy alone arm, respectively versus -0.5%, -0.4% and -0.9% in the chemotherapy alone arm, respectively).

Table 9 Joint Analysis: (NSABP B-31 and NCCTG N9831)

The Incidence and Type of Cardiac Events (Median Duration of More Than 8 Years** Safety Follow up)

At 3 years, the cardiac event rate in patients receiving AC→TH (doxorubicin plus cyclophosphamide followed by paclitaxel + trastuzumab) was estimated at 3.2%, compared with 0.9% in AC→T treated patients. Between 5 and 7 years of follow-up, an additional patient in each treatment group experienced a cardiac event; the cardiac event rate at 9 years follow-up in patients receiving AC→TH was estimated at 3.2%, compared with 1.0% in AC→T treated patients.

Table 10 summarizes the follow-up information for 84 patients (52 from study B-31 and 32 from study N9831) for whom symptomatic CHF was adjudicated and confirmed by the study committee.

Table 10 Joint Analysis (NSABP B-31 and NCCTG N9831)

Follow-Up of Symptomatic CHF Events (Median Duration of More Than 8 Years* Safety Follow up)

(Patients from the Joint Safety Population with Symptomatic CHF Confirmed by Study Committee)

Following initiation of paclitaxel therapy, 344 patients treated with AC→TH (18.5%) experienced an LVEF percentage decrease of ≥ 10 points from paclitaxel baseline to < 50 points, compared with 82 patients treated with AC→T (7.0%) at a median follow-up of 8.1 years for the AC→TH group. The per patient incidence of new onset cardiac dysfunction, after initiation of paclitaxel therapy, as determined by LVEF, remained unchanged compared to the analysis performed at a median follow up of 2.0 years in the AC→TH group.

An independent clinical review was performed on 62 patients with symptomatic congestive heart failure in the trastuzumab + chemotherapy arm to assess treatment and resolution status. Most patients were treated with oral medications commonly used to manage congestive heart failure. Complete or partial LVEF recovery was documented in 56 patients (90.3%), with complete recovery in 17 of these patients (27.4%) and partial recovery in 39 of these patients (62.9%), compared to 6 patients (9.7%) experiencing no recovery. This analysis also showed evidence of reversibility of left ventricular dysfunction in 64.5% of patients who experienced a symptomatic CHF in the AC→TH group being asymptomatic at the latest follow up.

Risk factors for a cardiac event included trastuzumab treatment, increased age, prior or current use of anti-hypertensive medications and low LVEF prior to or following the initiation of paclitaxel treatment. In the trastuzumab + chemotherapy arm, the risk of a cardiac event increased with the number of these risk factors present. In study B-31, there was no association between the incidence of cardiac events and either radiation to the left side of the chest or smoking.

BCIRG-006

In study BCIRG-006, cardiac events were defined as congestive heart failure (CHF; grade 3 or 4 cardiac left ventricular function [CLVF], per the NCI-CTC, v 2.0), grade 3 or 4 cardiac arrhythmia, grade 3 or 4 cardiac ischemia/infarction, cardiac death and serious adverse events with cardiac etiology not pre-defined as a cardiac event in the protocol but assessed as being a significant cardiac event by the Independent Cardiac Review Panel (ICRP). Asymptomatic LVEF events were defined as an absolute decline in LVEF value of >15 % from baseline to a value that was below the institution’s lower limit of normal (LLN). [Note: asymptomatic LVEF events defined in HERA as: a drop in LVEF of at least 10 EF points from baseline and to below 50%, and in the JA as: absolute drop in LVEF ≥10% to < 55% or an absolute drop in LVEF of ≥5% to below the institution’s LLN.]

Table 11 summarizes symptomatic cardiac events reported at any time during the study.

Table 11 Symptomatic Cardiac Events per the Independent Cardiac Review Panel (ICRP) Occurring at Any Time during the Study (Safety Population) 5 Year Follow Up

At 5.5 years, the rates of symptomatic cardiac or LVEF events were 1.0%, 2.3%, and 1.1% in the AC→T (doxorubicin plus cyclophosphamide, followed by docetaxel), AC→TH (doxorubicin plus cyclophosphamide, followed by docetaxel plus trastuzumab), and TCH (docetaxel, carboplatin and trastuzumab) treatment arms, respectively. For symptomatic CHF (Grade 3 - 4), the 5-year rates were 0.6%, 1.9%, and 0.4% in the AC→T, AC→TH, and TCH treatment arms, respectively. The overall risk of developing symptomatic cardiac events was similar for patients in AC→T and TCH arms. There was an increased risk of developing a symptomatic cardiac event for patients in the AC→TH arm, where the cumulative rate of symptomatic cardiac or LVEF events was 2.3% compared to approximately 1% in the two comparator arms (AC→T and TCH, respectively).

In BCIRG-006 study, 155 patients treated with AC→TH (14.4%) experienced an LVEF decrease of ≥ 10% from baseline to < 50%, compared with 79 (7.6%) patients treated with AC→T and 63 (6.0%) patients treated with TCH.

Table 12 presents the incidence of symptomatic and asymptomatic LVEF events.

Table 12 Asymptomatic and Symptomatic LVEF Declines by Baseline Events, Using the Same Assessment Method as Baseline (Safety Population) 5 Year Follow Up

Metastatic Breast Cancer (MBC)

HERZUMA^® and anthracyclines should not be given concurrently in the MBC setting.

In particular, moderate to severe cardiac dysfunction has been observed in MBC patients treated with trastuzumab in combination with an anthracycline (doxorubicin or epirubicin) and cyclophosphamide (see ADVERSE REACTIONS). The clinical status of patients in the trials who developed congestive heart failure were classified for severity using the New York Heart Association classification system (I-IV¹ where IV is the most severe level of cardiac failure).

(See Table 13).

Table 13 Incidence and Severity of Cardiac Dysfunction in Metastatic Breast Cancer Patients

In a subsequent trial with prospective monitoring of cardiac function, the incidence of symptomatic heart failure was 2.2% in patients receiving trastuzumab and docetaxel, compared with 0% in patients receiving docetaxel alone. In the MBC trials, the probability of cardiac dysfunction was highest in patients who received trastuzumab concurrently with anthracyclines. The MBC data suggest that advanced age may increase the probability of cardiac dysfunction.

Pre-existing cardiac disease or prior cardiotoxic therapy (e.g., anthracycline or radiation therapy) to the chest may decrease the ability to tolerate therapy with trastuzumab; however, the data is not adequate to evaluate correlation between cardiac dysfunction observed with trastuzumab and these factors in patients with HER2 positive MBC.

Hematologic

Exacerbation of Chemotherapy-Induced Neutropenia: In randomized, controlled clinical trials in both adjuvant and MBC designed to assess the impact of the addition of trastuzumab on chemotherapy, the per-patient incidences of moderate to severe neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy compared with those receiving chemotherapy alone.

Using NCI-CTC criteria, in the adjuvant HERA trial, 0.4% of patients treated with trastuzumab experienced a shift of 3 or 4 grades from baseline, compared with 0.6% in the observation arm.

In the adjuvant studies, NSABP B-31 and NCCTG N9831, there were 6 deaths due to septicemia or severe neutropenia. Five deaths occurred on the chemotherapy alone arm: 2

¹ New York Heart Association Functional Classification

Class I: Patients with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain.

Class II: Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or anginal pain.

Class III: Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea or anginal pain.

Class IV: Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.

patients died of pneumonia with febrile neutropenia and 3 patients died of septicemia. One death occurred on the trastuzumab + chemotherapy arm and the patient died of infection/neutropenic fever with lung infiltrates. All except 2 septicemia deaths occurred during protocol treatment period.

In the post-market setting in MBC, deaths due to sepsis in patients with severe neutropenia have been reported in patients receiving trastuzumab and myelosuppressive chemotherapy, although in controlled MBC clinical trials (pre- and post-market), the incidence of septic death was not significantly increased.

The pathophysiologic basis for exacerbation of neutropenia has not been determined; the effect of trastuzumab on the pharmacokinetics of chemotherapeutic agents has not been fully evaluated. If neutropenia occurs, the appropriate management should be instituted as per local practice/guidelines and the labelled instructions for chemotherapy agents should be followed with regard to dose interruption or dose reduction (see DOSAGE AND ADMINISTRATION: Recommended Dose and Dosage Adjustment, Dose Reduction).

Hypersensitivity Reactions Including Anaphylaxis, Infusion-Associated Reactions and Pulmonary Events

Administration of HERZUMA^® can result in severe hypersensitivity reactions (including anaphylaxis), infusion reactions and pulmonary events. In rare cases, these reactions have been fatal. See discussion below.

There are no data regarding the most appropriate method of identification of patients who may safely be retreated with trastuzumab after experiencing a severe reaction. Trastuzumab has been readministered to some patients who fully recovered from a previous severe reaction. Prior to readministration of trastuzumab the majority of these patients were prophylactically treated with pre-medications including antihistamines and/or corticosteroids. While some of these patients tolerated retreatment, others had severe reactions again despite the use of prophylactic pre-medications.

Hypersensitivity Reactions Including Anaphylaxis: Severe hypersensitivity reactions have been infrequently reported in patients treated with trastuzumab. Signs and symptoms include anaphylaxis, urticaria, bronchospasm, angioedema, and/or hypotension. In some cases, the reactions have been fatal. The onset of symptoms generally occurred during an infusion, but there have also been reports of symptom onset after the completion of an infusion. Reactions were most commonly reported in association with the initial infusion. In HERA 1 observation and 10 trastuzumab treated patients experienced hypersensitivity. Eight out of the 10 events were considered related to trastuzumab treatment. The incidence of allergic reactions in the Joint Analysis (chemotherapy alone versus trastuzumab + chemotherapy: 3.6% versus 3.1% in study B-31 and 1.1% versus 0.3% in study N9831) was comparable between the two treatment arms in both studies. In study BCIRG-006, the incidence of allergic reactions according to the NCI-CTC v 2.0 classification was 9.4%, 12.3% and 14.9% in AC→T, AC→TH and TCH arms, respectively.

Infusional administration of HERZUMA^® should be interrupted in all patients with severe hypersensitivity reactions. In the event of a hypersensitivity reaction, appropriate medical therapy should be administered, which may include epinephrine, corticosteroids,

diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms.

Infusion-Related Reactions (IRRs): IRRs are known to occur with trastuzumab. Pre-medication may be used to reduce risk of occurrence of IRRs.

Serious IRRs to infusions of trastuzumab including dyspnea, hypotension, hypertension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress, supraventricular tachyarrhythmia and urticaria have been reported (see ADVERSE REACTIONS). Patients should be observed for IRRs. Interruption of an IV infusion may help control such symptoms and the infusion may be resumed when symptoms abate. These symptoms can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as diphenhydramine. Serious reactions have been treated successfully with supportive therapy such as oxygen, beta-agonists and corticosteroids (see ADVERSE REACTIONS). The appropriate management of patients with uncontrolled hypertension or history of hypertension should be considered prior to infusion with HERZUMA^®.

These severe reactions were usually associated with the first infusion of trastuzumab and generally occurred during or immediately following the infusion. For some patients, symptoms later worsened and led to further pulmonary complications. 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 or pulmonary symptoms more than six hours after the start of the infusion of trastuzumab. Patients should be warned of the possibility of such a late onset and should be instructed to contact their physician if those symptoms occur. In rare cases, these reactions are associated with a clinical course culminating in a fatal outcome. Patients who are experiencing dyspnea 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.

Pulmonary Events: Severe pulmonary events leading to death have been reported with the use of trastuzumab in the adjuvant breast cancer clinical studies and the post-market MBC setting. These events may occur as part of an infusion-related reaction or with a delayed onset (See Infusion-Related Reactions subsection of WARNINGS AND PRECAUTIONS), and were reported to occur at varying latencies, from within 24 hours to over 30 days, since the start of treatment with trastuzumab. Cases of interstitial lung disease (which often present with dyspnea) including lung infiltrates, pneumonitis, pleural effusion, respiratory distress, acute pulmonary edema, respiratory insufficiency, acute respiratory distress syndrome, and pneumonia 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 with dyspnea at rest due to complications of advanced malignancy and co-morbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated with HERZUMA^®.

Other severe events reported rarely in the post-market MBC setting include pneumonitis and pulmonary fibrosis. All of the confirmed cases of pulmonary fibrosis received to date are characterized by one or more significant confounding factors including pre-existing lung disease and prior/concomitant chemotherapy such as cyclophosphamide. However, a causal relationship between trastuzumab and pulmonary fibrosis cannot be excluded.

Immune

Immunogenicity:

Samples for assessment of human anti-human antibody (HAHA) were not collected in studies of adjuvant breast cancer. Of 903 patients that have been evaluated in the MBC trials, human anti-human antibody (HAHA) to trastuzumab was detected in 1 patient, who had no allergic manifestations.

Respiratory

Refer to Pulmonary Events subsection of WARNINGS AND PRECAUTIONS.

Thrombosis/Embolism

Thrombosis/embolism has been observed in patients who receive trastuzumab + chemotherapy in both the adjuvant and metastatic treatment setting, and in rare cases, has been fatal (see ADVERSE REACTIONS section).

Ability to Drive and Use Machines

Trastuzumab has a minor influence on the ability to drive and use machines. Dizziness and somnolence may occur during treatment with HERZUMA^®. Patients experiencing infusion-related symptoms should be advised not to drive or use machines until symptoms resolve completely.

Selection of Patients / Diagnostic Tests

Early Breast Cancer (EBC)/Metastatic Breast Cancer (MBC)

HERZUMA^® should only be used in patients whose tumours overexpress HER2 as determined by immunohistochemistry. CICH or FISH testing for HER2 status also may be used, provided that the testing is done in experienced laboratories that have validated the test.

To ensure accurate and reproducible results, the protocol described in the package insert of an appropriate diagnostic test needs to be strictly followed. However, based on the current scientific knowledge, no standard test can be recommended at this time. There is no standard method of staining and no standard for the type of antibodies used. The grading for overexpression is subjective, and the signal may fade with time on stored slides.

The test method for HER2 overexpression used to determine eligibility of patients for inclusion in the MBC clinical trials employed immunohistochemical staining for HER2 of fixed material from tissue biopsy using the murine monoclonal antibodies CB11 and 4D5. Patients classified as staining 2+ or 3+ were included, while those staining 0 or 1+ were excluded. Greater than 70% of patients enrolled exhibited 3+ overexpression. The data suggest that beneficial effects were greater among those patients with higher levels of overexpression of HER2.

In the studies, an investigative clinical trial assay was employed which utilized a 0 to 3+ scale. The degree of HER2 overexpression indicated by different test methods may not correlate with that used as the eligibility criterion for inclusion in the clinical trials. For example, a validated IHC assay utilizes a scale of 0 to 3+. A reading of 3+ with the validated IHC assay is likely to correspond to that of a 2+ or 3+ with the investigative clinical trial assay. A 2+ reading with the validated IHC assay would likely incorporate a significant number of patients who were scored as 1+ by the investigative clinical trial assay. These patients (1+) would not have met the inclusion criteria. Test methods having increased sensitivity, relative to the investigative clinical trial assay, may alter the benefit-to-risk ratio compared to that seen in the clinical trials. In deciding which patients should receive HERZUMA^®, the risk of cardiac dysfunction (see WARNINGS and PRECAUTIONS) must be weighed against the potential benefits of treatment, especially for those not in the high range of HER2 overexpression.

For inclusion criteria in terms of HER2 expression in clinical trials in EBC see Clinical Trials -Reference Biologic Drug section.

Metastatic Gastric Cancer (MGC)

HERZUMA^® should only be administered to patients with MGC whose tumours have HER2 overexpression as determined by validated immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) testing. The testing should be done in experienced laboratories that have validated the test.

Patients are eligible for HERZUMA^® treatment if they demonstrate strong HER2 protein overexpression, defined by a 3+ score by IHC, or a 2+ score by IHC and a positive FISH result.

8.1 Special Populations

8.1.1 Women and Men of Reproductive Potential:

Fertility

It is not known whether HERZUMA^® can affect reproductive capacity. Animal reproduction studies revealed no evidence of impaired fertility or harm to the foetus (see NON-CLINICAL TOXICOLOGY – REFERENCE BIOLOGIC DRUG, Reproductive Toxicity).

Contraception

Women of childbearing potential should be advised to use effective contraception during treatment with HERZUMA^® and for at least 7 months after treatment has concluded (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics)

8.1.2 Pregnant Women

Reproduction studies have been conducted in cynomolgus monkeys at doses up to 25 times the weekly human maintenance dose of 2 mg/kg trastuzumab and have revealed no evidence of impaired fertility or harm to the fetus (see NON-CLINICAL TOXICOLOGY – REFERENCE BIOLOGIC DRUG, Reproductive Toxicity). However, when assessing the risk of reproductive toxicity in humans, it is important to consider the significance of the rodent form of the HER2 receptor in normal embryonic development and the embryonic death in mutant mice lacking this receptor. Placental transfer of trastuzumab during the early (days 20-50 of gestation) and late (days 120-150 of gestation) fetal development period was observed.

HERZUMA^® can cause fetal harm when administered to a pregnant woman. In the post-market setting, cases of impairment of fetal renal growth and/or renal function impairment, intrauterine growth retardation and skeletal abnormalities in association with oligohydramnios during the second and third trimesters, some associated with fatal pulmonary hypoplasia of the fetus, have been reported in pregnant women receiving trastuzumab. Also, the causal role of trastuzumab cannot be excluded nor confirmed in two cases of interventricular septal defects reported in infants exposed to trastuzumab in utero. In one of these two cases, spontaneous closure of the defect occurred nine months postpartum. No follow up information regarding closure of the defect was available in the second case. HER2 is known to be expressed in many embryonic tissues. Women who become pregnant should be advised of the possibility of harm to the fetus. If a pregnant woman is treated with HERZUMA^®, close monitoring by a multidisciplinary team is desirable.

Women using HERZUMA^® during pregnancy should be monitored for oligohydramnios. If oligohydramnios occurs, fetal testing should be done that is appropriate for gestational age and consistent with community standards of care. Additional intravenous (IV) hydration has been helpful when oligohydramnios has occurred following administration of other chemotherapy agents; however, the effects of additional IV hydration with trastuzumab treatment are not known.

Animal reproduction studies revealed no evidence of impaired fertility or harm to the fetus. Because animal reproduction studies are not always predictive of human response, HERZUMA^® should not be used during pregnancy unless the potential benefit for the mother outweighs the potential risk to the fetus.

8.1.3 Breast-feeding

A study conducted in cynomolgus monkeys at doses 25 times the weekly human maintenance dose of 2 mg/kg trastuzumab 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 excreted in human milk. As human IgG is excreted in human milk, and the potential for absorption and harm to the infant is unknown, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of trastuzumab and the importance of the drug to the mother.

8.1.4 Pediatrics

The safety and effectiveness of trastuzumab in pediatric patients below the age of 18, have not been established.

8.1.5 Geriatrics (> 65 years of age)

Trastuzumab has been administered in clinical studies to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in MBC treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease and those receiving adjuvant therapy in studies NSABP B-31 and NCCTG N9831, and BCIRG-006. Age ≥ 60 years was associated with increased risk of shorter time to first symptomatic cardiac event in study BCIRG-006 (based on 35 cardiac events in 2066 patients) (for the definition of cardiac events in each study see

WARNINGS AND PRECAUTIONS, Cardiotoxicity, Early Breast Cancer). Limitations in data collection and differences in study design of the 4 studies of trastuzumab in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of trastuzumab in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (as measured by ORR, TTP, OS, and DFS) of trastuzumab treatment in older patients differ from those observed in patients <65 years of age, for either treatment of metastatic disease or adjuvant treatment of EBC.

In ToGA (BO18255) study in MGC, of the 294 patients treated with trastuzumab, 108 (37%) were 65 years of age or older, while 13 (4.4%) were 75 and over. No overall differences in safety or effectiveness were observed.

The risk of hematologic toxicities (leukopenia and thrombocytopenia) may be increased in geriatric patients.

Data suggest that the disposition of trastuzumab is not altered based on age (see ACTION AND CLINICAL PHARMACOLOGY: Pharmacokinetics). In clinical studies, geriatric patients (≥ 65 years of age) did not receive reduced doses of trastuzumab.

9 ADVERSE REACTIONS

The adverse drug reaction profiles reported in clinical studies that compared HERZUMA^® to the reference biologic drug were comparable. The description of adverse reactions in this section is based on clinical experience with the reference biologic drug.

9.1 Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Early Breast Cancer (EBC)

HERA

(adjuvant sequential: use of trastuzumab following surgery and after chemotherapy)

Please see WARNINGS AND PRECAUTIONS: Cardiovascular/Cardiotoxicity/Early Breast Cancer – Table 5~8 for a description of the absolute numbers and rates of cardiac endpoints in HERA as well as the median time to return to baseline LVEF/ stabilizations of LVEF in the HERA trial.

The HERA trial is a randomized, open label study in patients with HER2 positive EBC. Table 14 displays adverse events which were reported after 8 years of median follow up in ≥ 1% of patients, by study treatment.

Table 14 Adverse Events Reported in ≥ 1% of HERA Study Patients, by Study Treatment Final Analysis After 8 years of Median Follow Up According to MedDRA v 15.0 Classification

In HERA, after a median follow-up of 12 months, 1 observation and 10 trastuzumab treated patients experienced hypersensitivity. Eight out of the 10 events were considered related to trastuzumab treatment.

In total, in the trastuzumab 1 year arm, 124 patients (7%) withdrew from trastuzumab treatment due to adverse events, and 2 patients (<1%) withdrew from the post-treatment follow-up phase due to adverse events, based on the withdrawal criteria in the HERA study protocol.

Please see

Table 7 and

Table 8 in WARNINGS AND PRECAUTIONS: Cardiovascular, Cardiotoxicity, Early Breast Cancer for information on the median time to return to baseline LVEF and stabilizations of LVEF after 8 years of median follow up in the HERA trial.

Joint Analysis –NSABP Study B-31 and NCCTG Study N9831

(adjuvant concurrent: use of trastuzumab in combination with paclitaxel)

Cardiac failure/dysfunction, pulmonary events, and exacerbation of chemotherapy-induced neutropenia were the most serious adverse reactions in the two randomized, controlled adjuvant breast cancer studies (NSABP study B-31 and NCCTG study N9831, see CLINICAL STUDIES). Please refer to WARNINGS AND PRECAUTIONS section for detailed description of these reactions and for a description of the incidence and type of cardiac events seen in the Joint Analysis.

Adverse events according to the National Cancer Institute - Common Terminology Criteria NCI-CTC v 2.0 classification occurring at a frequency of ≥ 1% for NSABP-B31 and NCCTG N9831, are summarized in Table 15 and

Table 16 respectively.

Table 15 Adverse Events of Any Grade with Incidence ≥ 1% in Study B-31 (Final Analysis after Median Follow-up of 8.1 years in the AC - T+H Group) According to NCI-CTC v 2.0 Classification

Table 16 Adverse Events of Any Grade with Incidence ≥ 1% in Study N9831 (Final Analysis after Median Follow-up of 8.1 years in the AC - T+H Group) According to NCI-CTC v 2.0 Classification

BCIRG-006

(adjuvant concurrent: use of trastuzumab in combination with docetaxel)

Adverse events according to the National Cancer Institute - Common Terminology Criteria NCI-CTC v 2.0 classification occurring at a frequency of ≥ 1% for study BCIRG-006 are summarized in Table 17. For adverse events that could not be classified according to the NCI-CTC, the Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) coding dictionary was used (see Table 18).

Table 17 Adverse Events of Any Grade with Incidence ≥ 1% in Study BCIRG-006 (5 Year Follow Up) According to NCI-CTC v 2.0 Classification

Table 18 Adverse Events of Any Grade with Incidence ≥ 1% in Study BCIRG-006 (5 Year Follow Up) According to COSTART Classification

The toxicity profile of trastuzumab in all four adjuvant trials appears to be similar. Cardiac dysfunction is the main concern with trastuzumab treatment (see WARNINGS AND PRECAUTIONS).

Metastatic Breast Cancer (MBC)

In clinical trials conducted prior to marketing, a total of 958 patients received trastuzumab alone or in combination with chemotherapy. Data in

Table 20 are based on the experience with the recommended dosing regimen for trastuzumab in the randomized controlled clinical trial in 234 patients who received trastuzumab in combination with chemotherapy and the open-label study of trastuzumab as a single agent in 213 patients with HER2-overexpressing MBC.

Table 19 Adverse Events Occurring in ≥ 1% of Patients in Study H0649g (up to First Disease Progression on Study)

Table 20 Adverse Events Occurring in ≥ 1% of Patients in Study H0648g (up to First Disease Progression on Study)