NDC 0006-5033 Ontruzant

Trastuzumab

NDC Product Code 0006-5033

NDC CODE: 0006-5033

Proprietary Name: Ontruzant What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Trastuzumab What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Trastuzumab is used alone or with other medications to treat certain types of breast cancer. It is also used along with other medications to treat certain types of stomach cancer. The types of cancers trastuzumab is used to treat are tumors that produce more than the normal amount of a certain substance called HER2 protein. This medication is called a monoclonal antibody. It works by attaching to the HER2 cancer cells and blocking them from dividing and growing. It may also destroy the cancer cells or signal the body (immune system) to destroy the cancer cells.

NDC Code Structure

  • 0006 - Merck Sharp & Dohme Corp.

NDC 0006-5033-02

Package Description: 1 VIAL, SINGLE-DOSE in 1 CARTON > 1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-DOSE (0006-5033-01)

NDC Product Information

Ontruzant with NDC 0006-5033 is a a human prescription drug product labeled by Merck Sharp & Dohme Corp.. The generic name of Ontruzant is trastuzumab. The product's dosage form is injection, powder, lyophilized, for solution and is administered via intravenous form.

Labeler Name: Merck Sharp & Dohme Corp.

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Ontruzant Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • TRASTUZUMAB 150 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • TREHALOSE DIHYDRATE (UNII: 7YIN7J07X4)
  • HISTIDINE MONOHYDROCHLORIDE MONOHYDRATE (UNII: X573657P6P)
  • HISTIDINE (UNII: 4QD397987E)
  • POLYSORBATE 20 (UNII: 7T1F30V5YH)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.
  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • HER2/neu Receptor Antagonist - [EPC] (Established Pharmacologic Class)
  • HER2/Neu/cerbB2 Antagonists - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Merck Sharp & Dohme Corp.
Labeler Code: 0006
FDA Application Number: BLA761100 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: BLA - A product marketed under an approved Biologic License Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 04-15-2020 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Ontruzant Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Other

CardiomyopathyAdministration of trastuzumab products can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline-containing chemotherapy regimens.Evaluate left ventricular function in all patients prior to and during treatment with Ontruzant. Discontinue Ontruzant treatment in patients receiving adjuvant therapy and withhold Ontruzant in patients with metastatic disease for clinically significant decrease in left ventricular function
[see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

Infusion Reactions; Pulmonary ToxicityAdministration of trastuzumab products can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of administration. Interrupt Ontruzant infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue Ontruzant for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome
[see Warnings and Precautions (5.2, 5.4)].

Embryo-Fetal ToxicityExposure to trastuzumab products during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception
[see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)].

  • Adjuvant Treatment, Breast Cancer:Administer according to one of the following doses and schedules for a total of 52 weeks of Ontruzant therapy:
  • During and following paclitaxel, docetaxel, or docetaxel and carboplatin:
  • Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel and carboplatin).
  • One week following the last weekly dose of Ontruzant, administer Ontruzant at 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three weeks.
  • As a single agent within three weeks following completion of multi-modality, anthracycline-based chemotherapy regimens:
  • Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes
  • Subsequent doses at 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three weeks [see Dosage and Administration (2.3)].Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions (6.1)].
  • Metastatic Treatment, Breast Cancer:Administer Ontruzant, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a 90-minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as 30-minute intravenous infusions until disease progression.
  • Metastatic Gastric Cancer:Administer Ontruzant at an initial dose of 8 mg/kg as a 90-minute intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three weeks until disease progression [see Dosage and Administration (2.3)].

  • 150 mg Single-dose vialReconstitution: Reconstitute each 150 mg vial of Ontruzant with 7.4 mL of Sterile Water for Injection (SWFI) (not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab-dttb that delivers 7.15 mL (150 mg trastuzumab-dttb).
  • Use appropriate aseptic technique when performing the following reconstitution steps:
  • Using a sterile syringe, slowly inject 7.4 mL of SWFI (not supplied) into the vial containing the lyophilized powder of Ontruzant, which has a cake-like appearance. The stream of diluent should be directed into the cake. The reconstituted vial yields a solution for single-dose use, containing 21 mg/mL trastuzumab-dttb.
  • Gently swirl and invert the vial to aid reconstitution. DO NOT SHAKE.
  • Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow.
  • Use the Ontruzant solution immediately following reconstitution with SWFI, as it contains no preservative and is intended for single-dose only. If not used immediately, store the reconstituted Ontruzant solution for up to 24 hours at 2° to 8°C (36° to 46°F); discard any unused Ontruzant after 24 hours. Do not freeze.Dilution:Determine the dose (mg) of Ontruzant [see Dosage and Administration (2.1)].
  • Calculate the volume of the 21 mg/mL reconstituted Ontruzant solution needed
  • Withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION.Gently invert the bag to mix the solution.
  • The solution of Ontruzant for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2° to 8°C (36° to 46°F) for no more than 24 hours prior to use. Discard after 24 hours. This storage time is additional to the time allowed for the reconstituted vials. Do not freeze.

  • Cardiac Monitoring: Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:
  • Baseline LVEF measurement immediately prior to initiation of Ontruzant
  • LVEF measurements every 3 months during and upon completion of Ontruzant
  • Repeat LVEF measurement at 4 week intervals if Ontruzant is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration (2.3)]LVEF measurements every 6 months for at least 2 years following completion of Ontruzant as a component of adjuvant therapy.
  • In Study 1, 15% (158/1031) of patients discontinued trastuzumab due to clinical evidence of myocardial dysfunction or significant decline in LVEF after a median follow-up duration of 8.7 years in the AC-TH (anthracycline, cyclophosphamide, paclitaxel, and trastuzumab) arm. In Study 3 (one-year trastuzumab treatment), the number of patients who discontinued trastuzumab due to cardiac toxicity at 12.6 months median duration of follow-up was 2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) of patients in the TCH (docetaxel, carboplatin, trastuzumab) arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) of patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued trastuzumab due to cardiac toxicity.
  • Among 64 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy, one patient died suddenly without documented etiology, and 33 patients were receiving cardiac medication at last follow-up. Approximately 24% of the surviving patients had recovery to a normal LVEF (defined as ≥ 50%) and no symptoms on continuing medical management at the time of last follow-up. Incidence of congestive heart failure (CHF) is presented in Table 1. The safety of continuation or resumption of Ontruzant in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied.
  • Table 1
  • A Median follow-up duration for studies 1 and 2 combined was 8.3 years in the AC → TH arm.
  • B Anthracycline (doxorubicin) and cyclophosphamide.
  • C Includes 1 patient with fatal cardiomyopathy and 1 patient with sudden death without documented etiology.
  • D Includes NYHA II-IV and cardiac death at 12.6 months median duration of follow-up in the one-year trastuzumab arm.
  • Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies
  • Incidence of CHF
  • Study
  • Regimen
  • Trastuzumab
  • Control
  • 1 & 2aACb → Paclitaxel + Trastuzumab
  • 3.2% (64/2000)c1.3% (21/1655)
  • 3dChemo → Trastuzumab
  • 2% (30/1678)
  • 0.3% (5/1708)
  • 4
  • ACb → Docetaxel + Trastuzumab
  • 2% (20/1068)
  • 0.3% (3/1050)
  • 4
  • Docetaxel + Carbo + Trastuzumab
  • 0.4% (4/1056)
  • 0.3% (3/1050)
  • In Study 3 (one-year trastuzumab treatment), at a median follow-up duration of 8 years, the incidence of severe CHF (NYHA III & IV) was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%.
  • Table 2
  • A Congestive heart failure or significant asymptomatic decrease in LVEF.
  • B Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
  • C Includes 1 patient with fatal cardiomyopathy.
  • Incidence of Cardiac Dysfunctiona in Metastatic Breast Cancer Studies
  • Incidence
  • NYHA I-IV
  • NYHA III−IV
  • Study
  • Event
  • Trastuzumab
  • Control
  • Trastuzumab
  • Control
  • 5 (AC)bCardiac Dysfunction
  • 28%
  • 7%
  • 19%
  • 3%
  • 5 (paclitaxel)
  • Cardiac Dysfunction
  • 11%
  • 1%
  • 4%
  • 1%
  • 6
  • Cardiac Dysfunctionc7%
  • N/A
  • 5%
  • N/A
  • In Study 4, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the trastuzumab containing regimens (AC-TH: 0.3% (3/1068) and TCH: 0.2% (2/1056)) as compared to none in AC-T.

Adjuvant Breast Cancer StudiesThe data below reflect exposure to one-year trastuzumab therapy across three randomized, open-label studies, Studies 1, 2, and 3, with (n = 3678) or without (n = 3363) trastuzumab in the adjuvant treatment of breast cancer.
The data summarized in Table 3 below, from Study 3, reflect exposure to trastuzumab in 1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18. Among the 3386 patients enrolled in the observation and one-year trastuzumab arms of Study 3 at a median duration of follow-up of 12.6 months in the trastuzumab arm, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian.
Table 3
a Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm.
b The incidence of Grade 3 or higher adverse reactions was <1% in both arms for each listed term.
c Higher level grouping term.
Adverse Reactions for Study 3a, All GradesbOne year Trastuzumab
Observation
Adverse Reaction
(n = 1678)
(n = 1708)
CardiacHypertension
64 (4%)
35 (2%)
Dizziness
60 (4%)
29 (2%)
Ejection Fraction Decreased
58 (3.5%)
11 (0.6%)
Palpitations
48 (3%)
12 (0.7%)
Cardiac Arrhythmiasc40 (3%)
17 (1%)
Cardiac Failure Congestive
30 (2%)
5 (0.3%)
Cardiac Failure
9 (0.5%)
4 (0.2%)
Cardiac Disorder
5 (0.3%)
0 (0%)
Ventricular Dysfunction
4 (0.2%)
0 (0%)
Respiratory Thoracic Mediastinal DisordersCough
81 (5%)
34 (2%)
Influenza
70 (4%)
9 (0.5%)
Dyspnea
57 (3%)
26 (2%)
URI
46 (3%)
20 (1%)
Rhinitis
36 (2%)
6 (0.4%)
Pharyngolaryngeal Pain
32 (2%)
8 (0.5%)
Sinusitis
26 (2%)
5 (0.3%)
Epistaxis
25 (2%)
1 (0.06%)
Pulmonary Hypertension
4 (0.2%)
0 (0%)
Interstitial Pneumonitis
4 (0.2%)
0 (0%)
Gastrointestinal DisordersDiarrhea
123 (7%)
16 (1%)
Nausea
108 (6%)
19 (1%)
Vomiting
58 (3.5%)
10 (0.6%)
Constipation
33 (2%)
17 (1%)
Dyspepsia
30 (2%)
9 (0.5%)
Upper Abdominal Pain
29 (2%)
15 (1%)
Musculoskeletal & Connective Tissue DisordersArthralgia
137 (8%)
98 (6%)
Back Pain
91 (5%)
58 (3%)
Myalgia
63 (4%)
17 (1%)
Bone Pain
49 (3%)
26 (2%)
Muscle Spasm
46 (3%)
3 (0.2%)
Nervous System DisordersHeadache
162 (10%)
49 (3%)
Paraesthesia
29 (2%)
11 (0.6%)
Skin & Subcutaneous Tissue DisordersRash
70 (4%)
10 (0.6%)
Nail Disorders
43 (2%)
0 (0%)
Pruritus
40 (2%)
10 (0.6%)
General DisordersPyrexia
100 (6%)
6 (0.4%)
Edema Peripheral
79 (5%)
37 (2%)
Chills
85 (5%)
0 (0%)
Asthenia
75 (4.5%)
30 (2%)
Influenza-like Illness
40 (2%)
3 (0.2%)
Sudden Death
1 (0.06%)
0 (0%)
InfectionsNasopharyngitis
135 (8%)
43 (3%)
UTI
39 (3%)
13 (0.8%)
Immune System DisordersHypersensitivity
10 (0.6%)
1 (0.06%)
Autoimmune Thyroiditis
4 (0.3%)
0 (0%)
In Study 3, a comparison of 3-weekly trastuzumab treatment for two years versus one year was also performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year trastuzumab treatment arm (8.1% versus 4.6% in the one-year trastuzumab treatment arm). More patients experienced at least one adverse reaction of Grade 3 or higher in the 2-year trastuzumab treatment arm (20.4%) compared with the one-year trastuzumab treatment arm (16.3%).
The safety data from Studies 1 and 2 were obtained from 3655 patients, of whom 2000 received trastuzumab; the median treatment duration was 51 weeks. The median age was 49 years (range: 24 to 80); 84% of patients were White, 7% Black, 4% Hispanic, and 3% Asian.
In Study 1, only Grade 3 to 5 adverse events, treatment-related Grade 2 events, and Grade 2−5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab plus chemotherapy as compared to chemotherapy alone: fatigue (29.5% vs. 22.4%), infection (24.0% vs. 12.8%), hot flashes (17.1% vs. 15.0%), anemia (12.3% vs. 6.7%), dyspnea (11.8% vs. 4.6%), rash/desquamation (10.9% vs. 7.6%), leukopenia (10.5% vs. 8.4%), neutropenia (6.4% vs. 4.3%), headache (6.2% vs. 3.8%), pain (5.5% vs. 3.0%), edema (4.7% vs. 2.7%), and insomnia (4.3% vs. 1.5%). The majority of these events were Grade 2 in severity.
In Study 2, data collection was limited to the following investigator-attributed treatment-related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3 to 5 non-hematologic toxicities, selected Grade 2 to 5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, and sensory neuropathy) and Grade 1 to 5 cardiac toxicities occurring during chemotherapy and/or trastuzumab treatment. The following non-cardiac adverse reactions of Grade 2 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab plus chemotherapy as compared to chemotherapy alone: arthralgia (12.2% vs. 9.1%), nail changes (11.5% vs. 6.8%), dyspnea (2.4% vs. 0.2%), and diarrhea (2.2% vs. 0%). The majority of these events were Grade 2 in severity.
Safety data from Study 4 reflect exposure to trastuzumab as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056]. The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms. The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy period. Among these patients, the median age was 49 years (range 22 to 74 years). In Study 4, the toxicity profile was similar to that reported in Studies 1, 2, and 3 with the exception of a low incidence of CHF in the TCH arm.

Metastatic Breast Cancer StudiesThe data below reflect exposure to trastuzumab in one randomized, open-label study, Study 5, of chemotherapy with (n = 235) or without (n = 234) trastuzumab in patients with metastatic breast cancer, and one single-arm study (Study 6; n = 222) in patients with metastatic breast cancer. Data in Table 4 are based on Studies 5 and 6.
Among the 464 patients treated in Study 5, the median age was 52 years (range: 25 to 77 years). Eighty-nine percent were White, 5% Black, 1% Asian, and 5% other racial/ethnic groups. All patients received 4 mg/kg initial dose of trastuzumab followed by 2 mg/kg weekly. The percentages of patients who received trastuzumab treatment for ≥ 6 months and ≥ 12 months were 58% and 9%, respectively.
Among the 352 patients treated in single agent studies (213 patients from Study 6), the median age was 50 years (range 28 to 86 years), 86% were White, 3% were Black, 3% were Asian, and 8% in other racial/ethnic groups. Most of the patients received 4 mg/kg initial dose of trastuzumab followed by 2 mg/kg weekly. The percentages of patients who received trastuzumab treatment for ≥ 6 months and ≥ 12 months were 31% and 16%, respectively.
Table 4
       a Data for trastuzumab single agent were from 4 studies, including 213 patients from Study 6.
       b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients in Uncontrolled Studies or at Increased Incidence in the Trastuzumab Arm (Studies 5 and 6)
Single Agentan = 352
Trastuzumab +Paclitaxeln = 91
PaclitaxelAlonen = 95
Trastuzumab +ACbn = 143
ACb Alonen = 135
Body as a WholePain
47%
61%
62%
57%
42%
Asthenia
42%
62%
57%
54%
55%
Fever
36%
49%
23%
56%
34%
Chills
32%
41%
4%
35%
11%
Headache
26%
36%
28%
44%
31%
Abdominal pain
22%
34%
22%
23%
18%
Back pain
22%
34%
30%
27%
15%
Infection
20%
47%
27%
47%
31%
Flu syndrome
10%
12%
5%
12%
6%
Accidental injury
6%
13%
3%
9%
4%
Allergic reaction
3%
8%
2%
4%
2%
CardiovascularTachycardia
5%
12%
4%
10%
5%
Congestive heart failure
7%
11%
1%
28%
7%
DigestiveNausea
33%
51%
9%
76%
77%
Diarrhea
25%
45%
29%
45%
26%
Vomiting
23%
37%
28%
53%
49%
Nausea and vomiting
8%
14%
11%
18%
9%
Anorexia
14%
24%
16%
31%
26%
Heme & LymphaticAnemia
4%
14%
9%
36%
26%
Leukopenia
3%
24%
17%
52%
34%
MetabolicPeripheral edema
10%
22%
20%
20%
17%
Edema
8%
10%
8%
11%
5%
MusculoskeletalBone pain
7%
24%
18%
7%
7%
Arthralgia
6%
37%
21%
8%
9%
NervousInsomnia
14%
25%
13%
29%
15%
Dizziness
13%
22%
24%
24%
18%
Paresthesia
9%
48%
39%
17%
11%
Depression
6%
12%
13%
20%
12%
Peripheral neuritis
2%
23%
16%
2%
2%
Neuropathy
1%
13%
5%
4%
4%
RespiratoryCough increased
26%
41%
22%
43%
29%
Dyspnea
22%
27%
26%
42%
25%
Rhinitis
14%
22%
5%
22%
16%
Pharyngitis
12%
22%
14%
30%
18%
Sinusitis
9%
21%
7%
13%
6%
SkinRash
18%
38%
18%
27%
17%
Herpes simplex
2%
12%
3%
7%
9%
Acne
2%
11%
3%
3%
< 1%
UrogenitalUrinary tract infection
5%
18%
14%
13%
7%

Metastatic Gastric CancerThe data below are based on the exposure of 294 patients to trastuzumab in combination with a fluoropyrimidine (capecitabine or 5-FU) and cisplatin (Study 7). In the trastuzumab plus chemotherapy arm, the initial dose of trastuzumab 8 mg/kg was administered on Day 1 (prior to chemotherapy) followed by 6 mg/kg every 21 days until disease progression. Cisplatin was administered at 80 mg/m2 on Day 1 and the fluoropyrimidine was administered as either capecitabine 1000 mg/m2 orally twice a day on Days 1 to 14 or 5-fluorouracil 800 mg/m2/day as a continuous intravenous infusion Days 1 through 5. Chemotherapy was administered for six 21-day cycles. Median duration of trastuzumab treatment was 21 weeks; median number of trastuzumab infusions administered was eight.
Table 5
Study 7: Per Patient Incidence of Adverse Reactions of All Grades (Incidence ≥ 5% between Arms) or Grade 3/4 (Incidence > 1% between Arms) and Higher Incidence in Trastuzumab Arm
Trastuzumab + FC (N = 294)N (%)
FC(N = 290)N (%)
Body System/Adverse Event
All GradesGrades 3/4All GradesGrades 3/4Investigations     Neutropenia
230 (78)
101 (34)
212 (73)
83 (29)
     Hypokalemia
83 (28)
28 (10)
69 (24)
16 (6)
     Anemia
81 (28)
36 (12)
61 (21)
30 (10)
     Thrombocytopenia
47 (16)
14 (5)
33 (11)
8 (3)
Blood and Lymphatic System Disorders     Febrile Neutropenia
-
15 (5)
-
8 (3)
Gastrointestinal Disorders     Diarrhea
109 (37)
27 (9)
80 (28)
11 (4)
     Stomatitis
72 (24)
2 (1)
43 (15)
6 (2)
     Dysphagia
19 (6)
7 (2)
10 (3)
1 (≤ 1)
Body as a Whole     Fatigue
102 (35)
12 (4)
82 (28)
7 (2)
     Fever
54 (18)
3 (1)
36 (12)
0 (0)
     Mucosal Inflammation
37 (13)
6 (2)
18 (6)
2 (1)
     Chills
23 (8)
1 (≤ 1)
0 (0)
0 (0)
Metabolism and Nutrition Disorders     Weight Decrease
69 (23)
6 (2)
40 (14)
7 (2)
Infections and Infestations     Upper Respiratory Tract Infections
56 (19)
0 (0)
29 (10)
0 (0)
     Nasopharyngitis
37 (13)
0 (0)
17 (6)
0 (0)
Renal and Urinary Disorders     Renal Failure and Impairment
53 (18)
8 (3)
42 (15)
5 (2)
Nervous System Disorders     Dysgeusia
28 (10)
0 (0)
14 (5)
0 (0)
The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast cancer, metastatic breast cancer, metastatic gastric cancer, or post-marketing experience.

CardiomyopathySerial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In Study 3, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year trastuzumab arm); and in Studies 1 and 2, 7.9 years in the AC-T arm, 8.3 years in the AC-TH arm. In Studies 1 and 2, 6% of all randomized patients with post-AC LVEF evaluation were not permitted to initiate trastuzumab following completion of AC chemotherapy due to cardiac dysfunction (LVEF < LLN or ≥ 16 point decline in LVEF from baseline to end of AC). Following initiation of trastuzumab therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving trastuzumab and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients receiving one-year trastuzumab monotherapy compared to observation in Study 3 (see Table 6, Figures 1 and 2). The per-patient incidence of new-onset cardiac dysfunction, as measured by LVEF, remained similar when compared to the analysis performed at a median follow-up of 2.0 years in the AC-TH arm. This analysis also showed evidence of reversibility of left ventricular dysfunction, with 64.5% of patients who experienced symptomatic CHF in the AC-TH group being asymptomatic at latest follow-up, and 90.3% having full or partial LVEF recovery.
Table 6a       a For Studies 1, 2 and 3, events are counted from the beginning of trastuzumab treatment. For Study 4, events are counted from the date of randomization.
       b Studies 1 and 2 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC → T) or paclitaxel plus trastuzumab (AC → TH).
       c Median duration of follow-up for Studies 1 and 2 combined was 8.3 years in the AC → TH arm.
       d Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm.
       e Study 4 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC → T) or docetaxel plus trastuzumab (AC → TH); docetaxel and carboplatin plus trastuzumab (TCH).
Per-patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4
LVEF < 50%and Absolute Decrease from Baseline
Absolute LVEF Decrease
LVEF< 50%
≥ 10%decrease
≥ 16%decrease
< 20% and ≥ 10%
≥ 20%
Studies 1 & 2b,cAC→TH(n = 1856)
23.1%(428)
18.5%(344)
11.2%(208)
37.9%(703)
8.9%(166)
AC→T(n = 1170)
11.7%(137)
7.0%(82)
3.0%(35)
22.1%(259)
3.4%(40)
Study 3dTrastuzumab(n = 1678)
8.6%(144)
7.0%(118)
3.8%(64)
22.4%(376)
3.5%(59)
Observation(n = 1708)
2.7%(46)
2.0%(35)
1.2%(20)
11.9%(204)
1.2%(21)
Study 4eTCH(n = 1056)
8.5%(90)
5.9%(62)
3.3%(35)
34.5