Adheroza Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ............................................................................................................ 2

Table of Contents ............................................................................................................................. 2

Part 1: Healthcare Professional Information .................................................................................... 5

1 Indications ............................................................................................................................ 5

1.1 Pediatrics ................................................................................................................. 6

1.2 Geriatrics ................................................................................................................. 6

2 Contraindications ................................................................................................................. 6

3 Serious Warnings and Precautions Box ................................................................................ 7

4 Dosage and Administration .................................................................................................. 8

4.1 Dosing Considerations ............................................................................................. 8

4.2 Recommended Dose and Dosage Adjustment ........................................................ 9

4.3 Reconstitution ....................................................................................................... 11

4.4 Administration ....................................................................................................... 13

4.5 Missed Dose .......................................................................................................... 14

5 Overdose ............................................................................................................................ 14

6 Dosage Forms, Strengths, Composition, and Packaging .................................................... 15

7 Warnings and Precautions ................................................................................................. 16

General ............................................................................................................................ 16

Cardiovascular ................................................................................................................. 16

Driving and Operating Machinery ................................................................................... 26

Hematologic .................................................................................................................... 26

Immune ........................................................................................................................... 27

Reproductive Health ............................................................................................................... 29

Repsiratory .......................................................................... Error! Bookmark not defined.

7.1 Special Populations................................................................................................ 29

7.1.1 Pregnancy ........................................................................................................ 29

7.1.2 Breastfeeding .................................................................................................. 30

7.1.3 Pediatrics ......................................................................................................... 30

7.1.4 Geriatrics ......................................................................................................... 30

8 Adverse Reactions ................................................................... Error! Bookmark not defined.

8.1 Adverse Reaction Overview ................................................................................... 31

8.2 Clinical Trial Adverse Reactions ............................................................................. 32

8.3 Less Common Clinical Trial Adverse Reactions ...................................................... 74

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ............................................................................................................ 80

8.5 Post-Market Adverse Reactions ............................................................................ 80

9 Drug Interactions................................................................................................................ 82

9.2 Drug Interactions Overview ................................................................................... 82

9.3 Drug-Behaviour Interactions ................................................................................. 82

9.4 Drug-Drug Interactions .......................................................................................... 82

9.5 Drug-Food Interactions .......................................................................................... 82

9.6 Drug-Herb Interactions .......................................................................................... 82

9.7 Drug-Laboratory Test Interactions ......................................................................... 82

10 Clinical Pharmacology ........................................................................................................ 83

10.1 Mechanism of Action ............................................................................................. 83

10.2 Pharmacodynamics ............................................................................................... 86

10.3 Pharmacokinetics .................................................................................................. 86

10.4 Immunogenicity ..................................................................................................... 88

11 Storage, Stability and Disposal ........................................................................................... 89

12 Special Handling Instructions ............................................................................................. 89

Part 2: Scientific Information ......................................................................................................... 91

13 Pharmaceutical Information .............................................................................................. 91

14 Clinical Trials ....................................................................................................................... 92

14.1 Clinical Trials by Indication .................................................................................... 92

Early Breast Cancer (EBC) ........................................................................................................ 92

Metastatic Breast Cancer (MBC) .......................................................................................... 103

Metastatic Gastric Cancer (MGC) ......................................................................................... 106

15 Microbiology .................................................................................................................... 110

16 Non-Clinical Toxicology .................................................................................................... 110

17 Supporting Product Monographs ..................................................................................... 120

Patient Medication Information – Breast Cancer ........................................................................ 121

Patient Medication Information – Gastric Cancer ....................................................................... 127

Part 1: Healthcare Professional Information

ADHEROZA (trastuzumab for injection) is a biosimilar biologic drug (biosimilar) to Herceptin®(trastuzumab). A biosimilar is a biologic drug that was granted authorization based on a demonstration of similarity to a version previously authorized in Canada, known as the reference biologic drug.

1 Indications

ADHEROZA (trastuzumab for injection) is indicated for:

Early Breast Cancer (EBC)

• 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 14 Clinical Trials.

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)

• the treatment of patients with MBC whose tumours overexpress HER2.

The benefits of treatment with ADHEROZA in patients who do not overexpress HER2 (HER2 overexpression 0 as defined by a validated immunohistochemical [IHC] assay) or who exhibit lower- level overexpression (HER2 overexpression 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 4 Dosage and Administration, 4.1 Dosing Considerations, Selection of Patients / Diagnostic Tests).

ADHEROZA 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 ADHEROZA in combination with pertuzumab and docetaxel, consult the Product Monograph for pertuzumab.

Metastatic Gastric Cancer (MGC)

• use 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.

ADHEROZA should only be administered to patients with MGC whose tumours have HER2 overexpression as defined by IHC2+ confirmed by FISH+, or IHC 3+ as determined by an accurate and validated assay.

1.1 Pediatrics

Pediatrics (< 18 years of age): The safety and effectiveness of ADHEROZA in pediatric patients (< 18 years of age) have not been established; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (> 65 years of age): The reported clinical experience is not adequate to determine whether older patients respond differently to trastuzumab treatment than younger patients (see 7 Warnings and Precautions, 7.1 Special Populations 7.1.4 Geriatrics).

2 Contraindications

• ADHEROZA (trastuzumab) is contraindicated in patients who are hypersensitive to this drug, Chinese Hamster Ovary (CHO) cell proteins or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 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

There is a risk of medication errors between ADHEROZA (trastuzumab) and trastuzumab emtansine or trastuzumab deruxtecan. In order to minimize this risk, check the vial labels to ensure that the drug being prepared and administered is ADHEROZA (trastuzumab) and not trastuzumab emtansine or trastuzumab deruxtecan. ADHEROZA should be prescribed using both the trade name and non-proprietary name (see 4 Dosage and Administration, 4.1 Dosing Considerations).

Cardiotoxicity

ADHEROZA (trastuzumab) 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. 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 was particularly high in patients who received trastuzumab concurrently with anthracyclines and cyclophosphamide (see 7 Warnings and Precautions, Cardiovascular).

Evaluate left ventricular function in all patients prior to and during treatment with ADHEROZA (see 7 Warnings and Precautions, Cardiovascular).

Infusion Reactions; Pulmonary Toxicity

ADHEROZA administration can result in serious infusion reactions and pulmonary toxicity. Fatal infusion reactions have been reported. In most cases, symptoms occurred during or within 24 hours of administration of trastuzumab. ADHEROZA infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinue ADHEROZA for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome (see 7 Warnings and Precautions).

Embryo-Fetal Toxicity

Exposure to ADHEROZA during pregnancy can result in impairment of fetal renal growth and/or renal function impairment resulting in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, intrauterine growth retardation and neonatal death (see 7 Warnings and Precautions, 7.1 Special Populations, 7.1.1 Pregnancy).

4 Dosage and Administration

4.1 Dosing Considerations

• There is a risk of medication errors between ADHEROZA (trastuzumab) and trastuzumab emtansine or trastuzumab deruxtecan. In order to prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is ADHEROZA (trastuzumab) and not trastuzumab emtansine or trastuzumab deruxtecan. Ensure that the recommended ADHEROZA (trastuzumab) dose is administered (see 4.2 Recommended Dose and Dosage Adjustment).
• ADHEROZA should be prescribed using both the trade name and non-proprietary name. Do not substitute ADHEROZA for or with trastuzumab emtansine or trastuzumab deruxtecan.
• 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.

Selection of Patients / Diagnostic Tests

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

ADHEROZA 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, the HercepTest® kit (registered Trade-Mark of Genentech, Inc.) also utilizes a scale of 0 to 3+. A reading of 3+ with HercepTest® is likely to correspond to that of a 2+ or 3+ with the investigative clinical trial assay. A 2+ reading with the HercepTest® 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 ADHEROZA, the risk of cardiac dysfunction (see 7 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 14 Clinical Trials section.

Metastatic Gastric Cancer (MGC)

ADHEROZA 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 ADHEROZA 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.

4.2 Recommended Dose and Dosage Adjustment

Early Breast Cancer (EBC)

3-Weekly Schedule: The recommended initial loading dose is 8 mg/kg ADHEROZA (trastuzumab) administered as a 90-minute infusion. The recommended maintenance dose is 6 mg/kg ADHEROZA 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 4.3 Reconstitution, Preparation for Administration).

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

See 14 Clinical Trials for chemotherapy combination dosing.

Metastatic Breast Cancer (MBC)

Weekly schedule: The recommended initial loading dose is 4 mg/kg ADHEROZA administered as a 90-minute infusion. The recommended weekly maintenance dose is 2 mg/kg ADHEROZA and can be administered as a 30-minute infusion if the initial loading dose was well tolerated. ADHEROZA may be administered in an outpatient setting. Do not administer as an IV push or bolus (see 4.3 Reconstitution, Preparation for Administration).

Metastatic Gastric Cancer (MGC)

3-Weekly Schedule: The recommended initial loading dose is 8 mg/kg ADHEROZA administered as a 90-minute infusion. The recommended maintenance dose is 6 mg/kg ADHEROZA 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 4.3 Reconstitution, Preparation for Administration).

Duration of Treatment

Patients with MBC or MGC should be treated with ADHEROZA until progression of disease or unmanageable toxicity.

Patients with EBC should be treated for 1 year or until disease recurrence or unmanageable toxicity, whichever occurs first (see 7 Warnings and Precautions, Cardiovascular). Extending treatment in EBC beyond one year is not recommended (see 14 Clinical Trials, Early Breast Cancer (EBC), HERA).

Dose Modification

If the patient develops an infusion-related reaction (IRR), the infusion rate of ADHEROZA may be slowed or interrupted.

No reductions in the dose of trastuzumab were made during clinical trials. Patients may continue therapy with ADHEROZA 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.

Dose Holding

Monitoring of Cardiac Function (also see 7 Warnings and Precautions, Cardiovascular, Cardiotoxicity).

^a Based on NSABP B-31 trial protocol. Modified to include recommendations for cardiology consultation or treatment of cardiac dysfunction (or both) when appropriate, as indicated in the subsequent footnotes.

^b Consider cardiac assessment and initiation of angiotensin converting-enzyme inhibitor therapy.

^c After two holds, consider permanent discontinuation of ADHEROZA.

^d Initiate angiotensin converting-enzyme inhibitor therapy and refer to cardiologist. LLN = lower limit of normal; MUGA = multiple-gated acquisition scan; ECHO = echocardiography.*Source: Mackey JR, Clemons M, Côté MA, et al. Cardiac management during adjuvant trastuzumab therapy: recommendations of the Canadian Trastuzumab Working Group. Curr Oncol. 2008 Jan;15(1):24-35.

For the frequency of cardiac monitoring see 7 Warnings and Precautions, Cardiovascular, Cardiotoxicity.

Health Canada has not authorized an indication for pediatric use (see 1 Indications).

4.3 Reconstitution

Table 3 – Reconstitution

Preparation for Administration:

Use appropriate aseptic technique.

150 mg/vial:

Each 150 mg single-use vial of ADHEROZA should be reconstituted with 7.2 mL of Sterile Water for Injection (SWFI) (not supplied) to yield a single-use solution containing 21 mg/mL trastuzumab.

420 mg/vial:

Each 420 mg multi-dose vial of ADHEROZA should be reconstituted with 20 mL of Bacteriostatic Water for Injection (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 ADHEROZA must be labelled in the area marked “Do not use after:” with the future date that is 28 days from the date of reconstitution.

If the patient has a known hypersensitivity to benzyl alcohol, ADHEROZA must be reconstituted with Sterile Water for Injection (see 7 Warnings and Precautions).

ADHEROZA which has been reconstituted with SWFI must be used immediately and any unused portion discarded. Use of other reconstitution diluents should be avoided.

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

Reconstitution:

150 mg/vial:

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

420 mg/vial:

1. 1. Using a sterile syringe, slowly inject 20 mL of Bacteriostatic Water for Injection (BWFI) (supplied) in the vial containing the lyophilized ADHEROZA 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 ADHEROZA results in a colourless to pale yellow transparent solution and should be essentially free of visible particles.

Determine the volume in mL of ADHEROZA 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.

[Body Weight (kg) x Dose (4 mg/kg for loading OR 2 mg/kg for maintenance)]

Volume (mL) =

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:

[Body Weight (kg) x Dose (8mg/kg for loading OR 6 mg/kg for maintenance)]

Volume (mL) =

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 ADHEROZA and polypropylene bags have been observed.

4.4 Administration

Weekly Schedule: Treatment may be administered in an outpatient setting by administration of a 4 mg/kg loading dose of ADHEROZA 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 8 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 ADHEROZA may be administered over 30 minutes (see 4.2 Recommended Dose and Dosage Adjustment). Patients should still be observed for fever and chills or other infusion - associated symptoms (see 8 Adverse Reactions).

3-Weekly Schedule: Treatment may be administered in an outpatient setting by administration of an 8 mg/kg loading dose of ADHEROZA 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 8 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 ADHEROZA may be administered over 30 minutes (see 4.2 Recommended Dose and Dosage Adjustment). Patients should still be observed for fever and chills or other infusion -associated symptoms (see 8 Adverse Reactions).

ADHEROZA should not be mixed or diluted with other drugs. Infusions of ADHEROZA should not be administered or mixed with dextrose solutions.

4.5 Missed Dose

Weekly schedule: If the patient has missed a dose of ADHEROZA 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 ADHEROZA doses of 2 mg/kg should be administered 7 days later according to the weekly schedule.

If the patient has missed a dose of ADHEROZA by more than one week, a re-loading dose of ADHEROZA should be administered (4 mg/kg over approximately 90 minutes) as soon as possible. Subsequent maintenance ADHEROZA 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 ADHEROZA 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 ADHEROZA 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 ADHEROZA by more than one week, a re-loading dose of ADHEROZA should be administered (8 mg/kg over approximately 90 minutes) as soon as possible. Subsequent maintenance ADHEROZA doses of 6 mg/kg should be administered 21 days later according to the 3-weekly schedule.

5 Overdose

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

Ensure that the recommended ADHEROZA (trastuzumab) dose and NOT trastuzumab emtansine or trastuzumab deruxtecan dose is administered. For information on the risk of trastuzumab emtansine or trastuzumab deruxtecan overdose due to medication errors, see their respective Product Monographs.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6 Dosage Forms, Strengths, Composition, and Packaging

To help ensure the traceability of biologic products healthcare professionals should record 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:

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

150 mg/vial:

Each single-use vial of ADHEROZA contains 150 mg trastuzumab, 136.20 mg α,α-trehalose dihydrate, 3.36 mg L-histidine hydrochloride monohydrate, 2.16 mg L-histidine, and 0.60 mg polysorbate 20. Reconstitution with 7.2 mL of SWFI, not supplied, yields a single-use solution containing 21 mg/mL trastuzumab, at a pH of approximately 6.

420 mg/vial:

Each multi-dose vial of ADHEROZA contains 420 mg trastuzumab, 6.1 mg L-histidine, 9.5 mg L- histidine hydrochloride monohydrate, 1.7 mg polysorbate 20, and 381.8 mg α,α-trehalose dihydrate. Reconstitution with 20 mL of the supplied BWFI (in co-pack), containing 1.1% benzyl alcohol as a preservative, yields a multi-dose solution containing 21 mg/mL trastuzumab, at a pH of approximately 6.

Availability:

150 mg single-use vial:

ADHEROZA is supplied in a single-use vial as a lyophilized, sterile powder containing 150 mg trastuzumab per vial, under vacuum. Each carton contains one single-use vial of 150 mg

ADHEROZA.

420 mg multi-dose vial:

ADHEROZA is supplied in a multi-dose vial as a lyophilized, sterile powder containing 420 mg trastuzumab per vial, under vacuum. Each carton contains one vial of 420 mg ADHEROZA and one 20 mL vial of Bacteriostatic Water for Injection (BWFI), containing 1.1% benzyl alcohol. BWFI is supplied as a 20 mL vial of sterile solution containing 1.1% benzyl alcohol as an antimicrobial preservative.

7 Warnings and Precautions

See 3 Serious Warnings and Precautions Box.

General

Therapy with ADHEROZA 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 ADHEROZA with Sterile Water for Injection (SWFI). Use SWFI-reconstituted ADHEROZA immediately and discard the vial (see 4 Dosage and Administration).

Cardiovascular

Cardiotoxicity: Administration of ADHEROZA 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-marketing data.

Because the half-life of trastuzumab, using a population pharmacokinetic method, is approximately 28.5 days [95% confidence interval (CI), 25.5 - 32.8 days], trastuzumab may persist in the circulation for approximately 24 weeks (range: 22 - 28 weeks) after stopping treatment with trastuzumab. 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 ADHEROZA 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 ADHEROZA 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 ADHEROZA. If LVEF drops 10 ejection points from baseline and/or to below 50%, ADHEROZA should be withheld and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, discontinuation of ADHEROZA 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 ADHEROZA 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 ADHEROZA. 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 ADHEROZA. 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 ADHEROZA, 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 ADHEROZA, it should be treated with the standard medications for this purpose. Discontinuation of ADHEROZA 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 ADHEROZA in patients who have previously experienced cardiac toxicity has not been prospectively studied.

Early Breast Cancer (EBC)

ADHEROZA 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 BCIRG006 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 ADHEROZA. In patients who receive anthracycline containing chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last administration of ADHEROZA, 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 ADHEROZA therapy. Please see Table 2 in 4 Dosage and Administration, 4.2 Recommended Dose and Dosage Adjustment, Dose Holding, Monitoring of Cardiac Function, for information on continuation and discontinuation of ADHEROZA 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, New York Heart Association (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.

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 arm, respectively versus -0.5%, -0.4% and -0.9% in the chemotherapy alone arm, respectively).

A = doxorubicin; C = cyclophosphamide; CHF = congestive heart failure; H = trastuzumab; LVEF = left ventricular ejection fraction; MI = myocardial infarction; T = paclitaxel.

*Asymptomatic LVEF per protocol events at any time after AC initiation: 1. Drop in LVEF of 10 points compared with AC baseline LVEF to below 55. or 2. Drop in LVEF of 5 points compared with AC baseline LVEF to below the lower limit of normal.

** In the joint analysis safety population, the median duration of follow-up was 8.1 years for the AC→T + H group and 8.5 years for the AC→T group

^a 16 AC→T patients had adjudicated and confirmed symptomatic CHF out of the 62 possible CHF patients reviewed by the study committees.

^b 62 AC→T + H patients had adjudicated and confirmed symptomatic CHF out of the 135 possible CHF patients reviewed by the study committees.

^c A patient received AC→T in studyB-31; not included here and had “emphysema” listed on autopsy.

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.

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.

BCIRG006

In study BCIRG006, 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.

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 BCIRG006 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.

Metastatic Breast Cancer (MBC)

ADHEROZA 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 8 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).

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.

^a Single agent studies H0551g, H0649g and H0650g.

^b Randomized Phase III study comparing chemotherapy plus trastuzumab to chemotherapy alone, where chemotherapy is either anthracycline/cyclophosphamide or paclitaxel.

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.

Driving and Operating Machinery

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

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 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-marketing 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-marketing), 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 4 Dosage and Administration, 4.2 Recommended Dose and Dosage Adjustment, Dose Modification).

Immune

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

Administration of ADHEROZA 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 ADHEROZA after experiencing a severe reaction. Trastuzumab has been readministered to some patients who fully recovered from a previous severe reaction. Prior to re-administration 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 BCIRG006, 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 ADHEROZA 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 8 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 8 Adverse Reactions). The appropriate management of patients with uncontrolled hypertension or history of hypertension should be considered prior to infusion with ADHEROZA.

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 ADHEROZA.

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-marketing MBC setting. These events may occur as part of an infusion-related reaction or with a delayed onset (see Infusion Related Reactions subsection of 7 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 ADHEROZA.

Other severe events reported rarely in the post-marketing 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.

Reproductive Health

Women of childbearing potential should be advised to use effective contraception during treatment with ADHEROZA and for at least 7 months after treatment has concluded (see 10 Clinical Pharmacology, 10.3 Pharmacokinetics).

• Fertility

It is not known whether ADHEROZA can affect reproductive capacity. Animal reproduction studies revealed no evidence of impaired fertility or harm to the foetus (see 16 Non-Clinical Toxicology, Reproductive and development toxicology).

Respiratory

Refer to Pulmonary Events subsection of 7 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 8 Adverse Reactions).

7.1 Special Populations

7.1.1 Pregnancy

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 16 Non-Clinical Toxicology, Reproductive and development toxicology). 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.

ADHEROZA can cause fetal harm when administered to a pregnant woman. In the post-marketing 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 ADHEROZA, close monitoring by a multidisciplinary team is desirable.

Women using ADHEROZA 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 ADHEROZA 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, ADHEROZA should not be used during pregnancy unless the potential benefit for the mother outweighs the potential risk to the fetus.

7.1.2 Breastfeeding

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 ADHEROZA 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.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): The safety and effectiveness of ADHEROZA in pediatric patients below the age of 18, have not been established.

7.1.4 Geriatrics

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 BCIRG006. 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 7 Warnings and Precautions, Cardiovascular, Cardiotoxicity, Early Breast Cancer (EBC)). 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 10 Clinical Pharmacology, 10.3 Pharmacokinetics). In clinical studies, geriatric patients (≥ 65 years of age) did not receive reduced doses of trastuzumab.

8 Adverse Reactions

8.1 Adverse Reaction Overview

Early Breast Cancer (EBC)

HERA

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

Please see 7 Warnings and Precautions, Cardiovascular, Cardiotoxicity, Early Breast Cancer (EBC) - Table 5, Table 6, Table 7, Table 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.

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 7 Warnings and Precautions, Cardiovascular, Cardiotoxicity, Early Breast Cancer (EBC) 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 14 Clinical Trials). Please refer to 7 Warnings and Precautions section for detailed description of these reactions and Table 9 for a description of the incidence and type of cardiac events seen in the Joint Analysis.

The toxicity profile of trastuzumab in all four adjuvant trials (HERA, NSABP Study B-31, NCCTG Study N9831 and BCIRG006) appears to be similar. Cardiac dysfunction is the main concern with trastuzumab treatment (see 7 Warnings and Precautions).

Metastatic Breast Cancer (MBC)

In clinical trials conducted prior to marketing, a total of 958 patients received ADHEROZA (trastuzumab) alone or in combination with chemotherapy. Data in Table 20 are based on the experience with the recommended dosing regimen for ADHEROZA 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.

Metastatic Gastric Cancer (MGC)

The ToGA trial (BO18255) is a randomised, open-label multicentre, phase III study of trastuzumab in combination with a fluoropyrimidine (FP) and cisplatin versus chemotherapy alone in patients with HER2 positive MGC. There were only 3.4% of patients in each treatment group with locally advanced cancer. The majority of patients had metastatic disease.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Early Breast Cancer (EBC)

HERA

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

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.

Multiple occurrences of the same adverse event in one individual counted only once.

*69 out of the total 93 Cardiac Failure Congestive events reported in the 1-year trastuzumab arm occurred within 365 days from randomization.

^# Serious adverse reactions of cellulitis and erysipelas were also reported in the HERA study.

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

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

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.

^a NCIC CTC terminology

A = doxorubicin; C = cyclophosphamide; GI = gastrointestinal; H = trastuzumab; T = paclitaxel; WBC = white blood cell.

Note: Only Grade 3–5 events, treatment-related Grade 2 events, Grade 2–5 cardiac left ventricular dysfunction, and Grade 2–5 dyspnea were collected during and 3 months following protocol treatment.

The term “febrile neutropenia” refers to febrile neutropenia with no evidence of infection; decreased neutrophils were not intended to be collected.

* Adverse event term is itemized on the Adverse Event CRF.

^a NCIC CTC terminology

A = doxorubicin; AE = adverse event; C = cyclophosphamide; H = trastuzumab; T = paclitaxel; WBC= white blood cell.

Note: Only treatment-related Grade 4 and 5 hematologic toxicities, Grade 3–5 non-hematologic toxicities, Grade 1–5 cardiac toxicities, as well as Grade 2–5 arthralgia, myalgia, nail changes, neuropathy–motor, and neuropathy–sensory adverse events were collected during the treatment period. During the post-treatment follow-up period, only Grade 3–5 cardiac ischemia/infarction, thrombosis/embolism, pneumonitis/pulmonary infiltrates, and lymphatic events were collected.

*Adverse event term is itemized on the Adverse Event CRF.

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).

A=doxorubicin; C=cyclophosphamide; H=trastuzumab; T =docetaxel; C (in TCH)=carboplatin

Note: In the BCIRG-006 study, all grade hematological and non-hematological AEs, and cardiac AEs were collected, as well as laboratory data.

The toxicity profile of trastuzumab in all four adjuvant trials appears to be similar. Cardiac dysfunction is the main concern with trastuzumab treatment (see 7 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).