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Back To Vidyya Prescribing Information:

Herceptin


WARNING
CARDIOMYOPATHY:

HERCEPTIN® (Trastuzumab) administration can result in the development of ventricular dysfunction and congestive heart failure. Left ventricular function should be evaluated in all patients prior to and during treatment with HERCEPTIN. Discontinuation of HERCEPTIN treatment should be strongly considered in patients who develop a clinically significant decrease in left ventricular function. The incidence and severity of cardiac dysfunction was particularly high in patients who received HERCEPTIN in combination with anthracyclines and cyclophosphamide. (See WARNINGS.)

HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS
INFUSION REACTIONS
PULMONARY EVENTS

HERCEPTIN administration can result in severe hypersensitivity reactions (including anaphylaxis), infusion reactions, and pulmonary events. Rarely, these have been fatal. In most cases, symptoms occurred during or within 24 hours of administration of HERCEPTIN. HERCEPTIN infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of HERCEPTIN treatment should be strongly considered for patients who develop anaphylaxis, angioedema, or acute respiratory distress syndrome. (See WARNINGS.)

DESCRIPTION

HERCEPTIN® (Trastuzumab) is a recombinant DNA-derived humanized monoclonal antibody that selectively binds with high affinity in a cell-based assay (Kd = 5 nM) to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2.1,2 The antibody is an IgG1 kappa that contains human framework regions with the complementarity-determining regions of a murine antibody (4D5) that binds to HER2.

The humanized antibody against HER2 is produced by a mammalian cell (Chinese Hamster Ovary) [CHO] suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product.

HERCEPTIN is a sterile, white to pale yellow, preservative-free lyophilized powder for intravenous (IV) administration. The nominal content of each HERCEPTIN vial is 440 mg Trastuzumab, 9.9 mg L-histidine HCl, 6.4 mg L-histidine, 400 mg -trehalose dihydrate, and 1.8 mg polysorbate 20, USP. Reconstitution with only 20 mL of the supplied Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative, yields a multi-dose solution containing 21 mg/mL Trastuzumab, at a pH of approximately 6.

CLINICAL PHARMACOLOGY

General

The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor.1 HER2 protein overexpression is observed in 25%–30% of primary breast cancers. HER2 protein overexpression can be determined using an immunohistochemistry-based assessment of fixed tumor blocks.3

Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumorcells that overexpress HER2.4-6

Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity (ADCC).7,8 In vitro, HERCEPTIN-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.

Pharmacokinetics

The pharmacokinetics of Trastuzumab were studied in breast cancer patients with metastatic disease. Short duration intravenous infusions of 10 to 500 mg once weekly demonstrated dose-dependent pharmacokinetics. Mean half-life increased and clearance decreased with increasing dose level. The half-life averaged 1.7 and 12 days at the 10 and 500 mg dose levels, respectively. Trastuzumab’s volume of distribution was approximately that of serum volume (44 mL/kg). At the highest weekly dose studied (500 mg), mean peak serum concentrations were 377 microgram/mL.

In studies using a loading dose of 4 mg/kg followed by a weekly maintenance dose of 2 mg/kg, a mean half-life of 5.8 days (range = 1 to 32 days) was observed. Between Weeks 16 and 32, Trastuzumab serum concentrations reached a steady state with a mean trough and peak concentrations of approximately 79 microgram/mL and 123 microgram/mL, respectively.

Detectable concentrations of the circulating extracellular domain of the HER2 receptor (shed antigen) are found in the serum of some patients with HER2 overexpressing tumors. Determination of shed antigen in baseline serum samples revealed that 64% (286/447) of patients had detectable shed antigen, which ranged as high as 1880 ng/mL (median = 11 ng/mL). Patients with higher baseline shed antigen levels were more likely to have lower serum trough concentrations. However, with weekly dosing, most patients with elevated shed antigen levels achieved target serum concentrations of Trastuzumab by Week 6.

Data suggest that the disposition of Trastuzumab is not altered based on age or serum creatinine (up to 2.0 mg/dL). No formal interaction studies have been performed.

Mean serum trough concentrations of Trastuzumab, when administered in combination with paclitaxel, were consistently elevated approximately 1.5-fold as compared with serum concentrations of Trastuzumab used in combination with anthracycline plus cyclophosphamide. In primate studies, administration of Trastuzumab with paclitaxel resulted in a reduction in Trastuzumab clearance. Serum levels of Trastuzumab in combination with cisplatin, doxorubicin or epirubicin plus cyclophosphamide did not suggest any interactions; no formal drug interaction studies were performed.

CLINICAL STUDIES

The safety and efficacy of HERCEPTIN® (Trastuzumab) were studied in a randomized, controlled clinical trial in combination with chemotherapy (469 patients) and an open-label single agent clinical trial (222 patients). Both trials studied patients with metastatic breast cancer whose tumors overexpress the HER2 protein. Patients were eligible if they had 2+ or 3+ levels of overexpression (based on a 0–3+ scale) by immunohistochemical assessment of tumor tissue performed by a central testing lab.

A multicenter, randomized, controlled clinical trial was conducted in 469 patients with metastatic breast cancer who had not been previously treated with chemotherapy for metastatic disease. Patients were randomized to receive chemotherapy alone or in combination with HERCEPTIN given intravenously as a 4 mg/kg loading dose followed by weekly doses of HERCEPTIN at 2 mg/kg. For those who had received prior anthracycline therapy in the adjuvant setting, chemotherapy consisted of paclitaxel (175 mg/m2 over 3 hours every 21 days for at least six cycles); for all other patients, chemotherapy consisted of anthracycline plus cyclophosphamide (AC: doxorubicin 60 mg/m2 or epirubicin 75 mg/m2 plus 600 mg/m2 cyclophosphamide every 21 days for six cycles). Compared with patients in the AC subgroups (n = 281), patients in the paclitaxel subgroups (n = 188) were more likely to have had the following: poor prognostic factors (premenopausal status, estrogen or progesterone receptor negative tumors, positive lymph nodes), prior therapy (adjuvant chemotherapy, myeloablative chemotherapy, radiotherapy), and a shorter disease-free interval.

Compared with patients randomized to chemotherapy alone, the patients randomized to HERCEPTIN and chemotherapy experienced a significantly longer median time to disease progression, a higher overall response rate (ORR), a longer median duration of response, and a higher one-year survival rate. (See Table 1.) These treatment effects were observed both in patients who received HERCEPTIN plus paclitaxel and in those who received HERCEPTIN plus AC, however the magnitude of the effects was greater in the paclitaxel subgroup. The degree of HER2 overexpression was a predictor of treatment effect. (See CLINICAL STUDIES: HER2 protein overexpression.)

Table 1

Phase III Clinical Efficacy in First-Line Treatment

  Combined Results Paclitaxel subgroup AC subgroup
  HERCEPTIN
+
All Chemotherapy
All Chemotherapy HERCEPTIN
+
Paclitaxel
Paclitaxel HERCEPTIN
+
ACa
AC
 

(n = 235)

(n = 234)

(n = 92)

(n = 96)

(n = 143)

(n = 138)

Primary Endpoint
Time to Progressionb, c
Median (months)

7.2

4.5

6.7

2.5

7.6

5.7

95% confidence interval

6.9, 8.2

4.3, 4.9

5.2, 9.9

2.0, 4.3

7.2, 9.1

4.6, 7.1

p-value (log rank)

 < 0.0001

< 0.0001 0.002

Secondary Endpoints
Overall Response Rateb

Rate (percent)

45

29

38

15

50

38

95% confidence interval

39, 51

23, 35

28, 48

8, 22

42, 58

30, 46

p-value (c2-test) < 0.001 <  0.001 0.10
Duration of Responseb, c
Median (months) 8.3 5.8 8.3 4.3

8.4

6.4

25%, 75% quantile 5.5, 14.8 3.9, 8.5 5.1, 11.0 3.7, 7.4 5.8, 14.8 4.5, 8.5
1-Year Survivalc
Percent alive 79 68 73 61 83 73
95% confidence interval 74, 84 62, 74 66, 80 51, 71 77, 89 66, 82
p-value (Z-test) < 0.01 0.08 0.04

a AC  = anthracycline (doxorubicin or epirubicin) and cyclophosphamide.

b Assessed by an independent Response Evaluation Committee.

c Kaplan-Meier Estimate

HERCEPTIN was studied as a single agent in a multicenter, open-label, single-arm clinical trial in patients with HER2 overexpressing metastatic breast cancer who had relapsed following one or two prior chemotherapy regimens for metastatic disease. Of 222 patients enrolled, 66% had received prior adjuvant chemotherapy, 68% had received two prior chemotherapy regimens for metastatic disease, and 25% had received prior myeloablative treatment with hematopoietic rescue. Patients were treated with a loading dose of 4 mg/kg IV followed by weekly doses of HERCEPTIN at 2 mg/kg IV. The ORR (complete response + partial response), as determined by an independent Response Evaluation Committee, was 14%, with a 2% complete response rate and a 12% partial response rate. Complete responses were observed only in patients with disease limited to skin and lymph nodes. The degree of HER2 overexpression was a predictor of treatmenteffect. (See CLINICAL STUDIES: HER2 protein overexpression.)

HER2 Protein Overexpression

Relationship to Response: In the clinical studies described, patient eligibility was determined by testing tumor specimens for overexpression of HER2 protein. Specimens were tested with a research-use-only immunohistochemical assay (referred to as the Clinical Trial Assay, CTA) and scored as 0, 1+, 2+, or 3+ with 3+ indicating the strongest positivity. Only patients with 2+ or 3+ positive tumors were eligible (about 33% of those screened).

Data from both efficacy trials suggest that the beneficial treatment effects were largely limited to patients with the highest level of HER2 protein overexpression (3+). (See Table 2.)

Table 2

Treatment Effect versus Level of HER2 Expression

  Single-Arm Trial Treatment Subgroups in
Randomized Trial
  HERCEPTIN HERCEPTIN +
Paclitaxel
Paclitaxel HERCEPTIN +
AC
AC
Overall Response Rate
2+ overexpression 4%

(2/50)
21%

(5/24)
16%

(3/19)
40%

(14/35)
43%

(18/42)
3+ overexpression 17%

(29/172)
44%

(30/68)
14%

(11/77)
53%

(57/108)
36%

(35/96)
Median time to progression (months)
(95% CI)
2+ overexpression N/A a 4.4

(2.2, 6.6)
3.2

(2.0, 5.6)
7.8

(6.4, 10.1)
7.1

(4.8, 9.8)
3+ overexpression N/A a 7.1

(6.2, 12.0)
2.2

(1.8, 4.3)
7.3

(7.1, 9.2)
4.9

(4.5, 6.9)

a N/A = Not Assessed

Immunohistochemical Detection: In clinical trials, the Clinical Trial Assay (CTA) was used for immunohistochemical detection of HER2 protein overexpression. The DAKO HercepTest™, another immunohistochemical test for HER2 protein overexpression, has not been directly studied for its ability to predict HERCEPTIN treatment effect, but has been compared to the CTA on over 500 breast cancer histology specimens obtained from the National Cancer Institute Cooperative Breast Cancer Tissue Resource. Based upon these results and an expected incidence of 33% of 2+ or 3+ HER2 overexpression in tumors from women with metastatic breast cancer, one can estimate the correlation of the HercepTest™ results with CTA results. Of specimens testing 3+ (strongly positive) on the HercepTest™, 94% would be expected to test at least 2+ on the CTA (i.e., meeting the study entry criterion) including 82% which would be expected to test 3+ on the CTA (i.e., the reading most associated with clinical benefit). Of specimens testing 2+ (weakly positive) on the HercepTest™, only 34% would be expected to test at least 2+ on the CTA, including 14% which would be expected to test 3+ on the CTA.

INDICATIONS AND USAGE

HERCEPTIN as a single agent is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease. HERCEPTIN in combination with paclitaxel is indicated for treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have not received chemotherapy for their metastatic disease. HERCEPTIN should only be used in patients whose tumors have HER2 protein overexpression. (See CLINICAL STUDIES: HER2 protein overexpression for information regarding HER2 protein testing and the relationship between the degree of overexpression and the treatment effect.)

CONTRAINDICATIONS

None known.

WARNINGS

Cardiotoxicity:

Signs and symptoms of cardiac dysfunction, such as dyspnea, increased cough, paroxysmal nocturnal dyspnea, peripheral edema, S3 gallop, or reduced ejection fraction, have been observed in patients treated with HERCEPTIN. Congestive heart failure associated with HERCEPTIN therapy may be severe and has been associated with disabling cardiac failure, death, and mural thrombosis leading to stroke. The clinical status of patients in the trials who developed congestive heart failure was classified for severity using the New York Heart Association classification system (I-IV, where IV is the most severe level of cardiac failure). (See Table 3.)

Table 3

Incidence and Severity of Cardiac Dysfunction

 


HERCEPTINa
alone


HERCEPTIN + Paclitaxelb



Paclitaxelb

HERCEPTIN +
Anthracycline+
cyclophosphamideb


Anthracycline +
cyclophosphamideb

 

n = 213

n = 91

n = 95

n = 143

n = 135

Any Cardiac Dysfunction

7%

11%

1%

28%

7%

Class III-IV

5%

4%

1%

19%

3%

a Open-label, single-agent Phase II study (94% received prior anthracyclines).

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

Candidates for treatment with HERCEPTIN should undergo thorough baseline cardiac assessment including history and physical exam and one or more of the following: EKG, echocardiogram, and MUGA scan. There are no data regarding the most appropriate method of evaluation for the identification of patients at risk for developing cardiotoxicity. Monitoring may not identify all patients who will develop cardiac dysfunction.

Extreme caution should be exercised in treating patients with pre-existing cardiac dysfunction.

Patients receiving HERCEPTIN should undergo frequent monitoring for deteriorating cardiac function.

The probability of cardiac dysfunction was highest in patients who received HERCEPTIN concurrently with anthracyclines. The 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 HERCEPTIN therapy; however, the data are not adequate to evaluate the correlation between HERCEPTIN-induced cardiotoxicity and these factors.

Discontinuation of HERCEPTIN therapy should be strongly considered in patients who develop clinically significant congestive heart failure. In the clinical trials, most patients with cardiac dysfunction responded to appropriate medical therapy often including discontinuation of HERCEPTIN. The safety of continuation or resumption of HERCEPTIN in patients who have previously experienced cardiac toxicity has not been studied. There are insufficient data regarding discontinuation of HERCEPTIN therapy in patients with asymptomatic decreases in ejection fraction; such patients should be closely monitored for evidence of clinical deterioration.

Hypersensitivity Reactions Including Anaphylaxis:

Severe hypersensitivity reactions have been infrequently reported in patients treated with HERCEPTIN. 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.

HERCEPTIN infusion 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.

There are no data regarding the most appropriate method of identification of patients who may safely be retreated with HERCEPTIN after experiencing a severe hypersensitivity reaction. HERCEPTIN has been readministered to some patients who fully recovered from a previous severe reaction. Prior to readministration of HERCEPTIN, 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.

Infusion Reactions:

In the postmarketing setting, rare occurrences of severe infusion reactions leading to a fatal outcome have been associated with the use of HERCEPTIN.

In clinical trials, infusion reactions consisted of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia. These reactions were usually mild to moderate in severity. (See ADVERSE REACTIONS.)

However, in postmarketing reports, more severe adverse reactions to HERCEPTIN infusion were observed and included bronchospasm, hypoxia, and severe hypotension. These severe reactions were usually associated with the initial infusion of HERCEPTIN and generally occurred during or immediately following the infusion. However, the onset and clinical course were variable. For some patients, symptoms progressively worsened and led to further pulmonary complications. (See PULMONARY EVENTS section of WARNINGS.) In other patients with acute onset of signs and symptoms, initial improvement was followed by clinical deterioration. Delayed post-infusion events with rapid clinical deterioration have also been reported. Rarely, severe infusion reactions culminated in death within hours or up to one week following an infusion.

Some severe reactions have been treated successfully with interruption of the HERCEPTIN infusion and supportive therapy including oxygen, intravenous fluids, beta-agonists, and corticosteroids.

There are no data regarding the most appropriate method of identification of patients who may safely be retreated with HERCEPTIN after experiencing a severe infusion reaction. HERCEPTIN has been readministered to some patients who fully recovered from the previous severe reaction. Prior to readministration of HERCEPTIN, 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.

Pulmonary Events:

Severe pulmonary events leading to death have been reported rarely with the use of HERCEPTIN in the postmarketing setting. Signs, symptoms and clinical findings include dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, and acute respiratory distress syndrome. These events may or may not occur as sequelae of infusion reactions. (See INFUSION REACTIONS section of WARNINGS.) Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, may be at greater risk of severe reactions.

Other severe events reported rarely in the postmarketing setting include pneumonitis and pulmonary fibrosis.

PRECAUTIONS

General: HERCEPTIN therapy should be used with caution in patients with known hypersensitivity to Trastuzumab, Chinese Hamster Ovary cell proteins, or any component of this product.

Patients with Cardiac Ventricular Dysfunction

Extreme caution should be exercised in treating patients with pre-existing cardiac dysfunction. (See WARNINGS.)

Patients with Pulmonary Disorders

Patients with either symptomatic intrinsic pulmonary disease (e.g., asthma, COPD) or patients with extensive tumor involvement of the lungs (e.g., lymphangitic spread of tumor, pleural effusions, parenchymal masses), resulting in dyspnea at rest, may be at increased risk for severe pulmonary adverse events. (See WARNINGS.)

Drug Interactions: There have been no formal drug interaction studies performed with HERCEPTIN in humans. Administration of paclitaxel in combination with HERCEPTIN resulted in a two-fold decrease in HERCEPTIN clearance in a non-human primate study and in a 1.5-fold increase in HERCEPTIN serum levels in clinical studies. (See PHARMACOKINETICS.)

Benzyl Alcohol: For patients with a known hypersensitivity to benzyl alcohol (the preservative in Bacteriostatic Water for Injection) reconstitute HERCEPTIN with Sterile Water for Injection (SWFI), USP. DISCARD THE SWFI-RECONSTITUTED HERCEPTIN VIAL FOLLOWING A SINGLE USE.

Immunogenicity: Of 903 patients who have been evaluated, human anti-human antibody (HAHA) to Trastuzumab was detected in one patient, who had no allergic manifestations.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Carcinogenesis: HERCEPTIN has not been tested for its carcinogenic potential.

Mutagenesis: No evidence of mutagenic activity was observed in Ames tests using six different test strains of bacteria, with and without metabolic activation, at concentrations of up to 5000 mg/mL Trastuzumab. Human peripheral blood lymphocytes treated in vitro at concentrations of up to 5000 mg/plate Trastuzumab, with and without metabolic activation, revealed no evidence of mutagenic potential. In an in vivo mutagenic assay (the micronucleus assay), no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg Trastuzumab.

Impairment of Fertility: A fertility study has been conducted in female cynomolgus monkeys at doses up to 25 times the weekly human maintenance dose of 2 mg/kg HERCEPTIN and has revealed no evidence of impaired fertility.

Pregnancy Category B: Reproduction studies have been conducted in cynomolgus monkeys at doses up to 25 times the weekly human maintenance dose of 2 mg/kg HERCEPTIN and have revealed no evidence of impaired fertility or harm to the fetus. However, HER2 protein expression is high in many embryonic tissues including cardiac and neural tissues; in mutant mice lacking HER2, embryos died in early gestation.9 Placental transfer of HERCEPTIN during the early (Days 2050 of gestation) and late (Days 120150 of gestation) fetal development period was observed in monkeys. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers: A study conducted in lactating cynomolgus monkeys at doses 25 times the weekly human maintenance dose of 2 mg/kg HERCEPTIN demonstrated that Trastuzumab is secreted in the milk. 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 3 months of age. It is not known whether HERCEPTIN is excreted in human milk. Because human IgG is excreted in human milk, and the potential for absorption and harm to the infant is unknown, women should be advised to discontinue nursing during HERCEPTIN therapy and for 6 months after the last dose of HERCEPTIN.

Pediatric Use: The safety and effectiveness of HERCEPTIN in pediatric patients have not been established.

Geriatric Use: HERCEPTIN has been administered to 133 patients who were 65 years of age or over. The risk of cardiac dysfunction may be increased in geriatric patients. The reported clinical experience is not adequate to determine whether older patients respond differently from younger patients.

 

ADVERSE REACTIONS

In clinical studies, a total of 958 patients have received HERCEPTIN® (Trastuzumab) alone or in combination with chemotherapy. Data in Table 4 are based on the experience with the recommended dosing regimen for HERCEPTIN in the randomized controlled clinical trial in 234 patients who received HERCEPTIN in combination with chemotherapy and four open-label studies of HERCEPTIN as a single agent in 352 patients at doses of 10-500 mg administered weekly.  

Cardiac Failure/Dysfunction: For a description of cardiac toxicities, see WARNINGS.

Anemia and Leukopenia: An increased incidence of anemia and leukopenia was observed in the treatment group receiving HERCEPTIN and chemotherapy, especially in the HERCEPTIN and AC subgroup, compared with the treatment group receiving chemotherapy alone. The majority of these cytopenic events were mild or moderate in intensity, reversible, and none resulted in discontinuation of therapy with HERCEPTIN.

Hematologic toxicity is infrequent following the administration of HERCEPTIN as a single agent, with an incidence of Grade III toxicities for WBC, platelets, hemoglobin all < 1%. No Grade IV toxicities were observed.

Diarrhea: Of patients treated with HERCEPTIN as a single agent, 25% experienced diarrhea. An increased incidence of diarrhea, primarily mild to moderate in severity, was observed in patients receiving HERCEPTIN in combination with chemotherapy.

Infection: An increased incidence of infections, primarily mild upper respiratory infections of minor clinical significance or catheter infections, was observed in patients receiving HERCEPTIN in combination with chemotherapy.

Infusion Reactions: During the first infusion with HERCEPTIN, a symptom complex most commonly consisting of chills and/or fever was observed in about 40% of patients in clinical trials. The symptoms were usually mild to moderate in severity and were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of HERCEPTIN infusion). HERCEPTIN discontinuation was infrequent. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, rash and asthenia. The symptoms occurred infrequently with subsequent HERCEPTIN infusions. (See WARNINGS for information on more severe reactions reported in the post-marketing setting.)

Hypersensitivity Reactions Including Anaphylaxis
Pulmonary Events:

In the postmarketing setting, severe hypersensitivity reactions (including anaphylaxis), infusion reactions, and pulmonary adverse events have been reported. These events include anaphylaxis, angioedema, bronchospasm, hypotension, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema and acute respiratory distress syndrome. For a detailed description, see WARNINGS.

Table 4

Adverse Events Occurring in > 5% of Patients or at
Increased Incidence in the HERCEPTIN Arm of the Randomized Study
(Percent of Patients)

  Single Agent
n = 352
HERCEPTIN + Paclitaxel
n = 91
Paclitaxel Alone
n = 95
HERCEPTIN + AC
n = 143
AC Alone
n = 135

Body as a Whole

Pain

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


Cardiovascular

Tachycardia

5

12

4

10

5

Congestive heart failure

7

11

1

28

7


Digestive

Nausea

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 & Lymphatic

Anemia

4

14

9

36

26

Leukopenia

3

24

17

52

34


Metabolic

Peripheral edema

10

22

20

20

17

Edema

8

10

8

11

5


Musculoskeletal

Bone pain

7

24

18

7

7

Arthralgia

6

37

21

8

9


Nervous

Insomnia

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


Respiratory

Cough 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


Skin

Rash

18

38

18

27

17

Herpes simplex

2

12

3

7

9

Acne

2

11

3

3

< 1


Urogenital

Urinary tract infection

5

18

14

13

7

Other serious adverse events

The following other serious adverse events occurred in at least one of the 958 patients treated with HERCEPTIN in clinical studies:

Body as a Whole: cellulitis, anaphylactoid reaction, ascites, hydrocephalus, radiation injury, deafness, amblyopia

Cardiovascular: vascular thrombosis, pericardial effusion, heart arrest, hypotension, syncope, hemorrhage, shock, arrhythmia

Digestive: hepatic failure, gastroenteritis, hematemesis, ileus, intestinal obstruction, colitis, esophageal ulcer, stomatitis, pancreatitis, hepatitis

Endocrine: hypothyroidism

Hematological: pancytopenia, acute leukemia, coagulation disorder, lymphangitis

Metabolic: hypercalcemia, hypomagnesemia, hyponatremia, hypoglycemia, growth retardation, weight loss

Musculoskeletal: pathological fractures, bone necrosis, myopathy

Nervous: convulsion, ataxia, confusion, manic reaction

Respiratory: apnea, pneumothorax, asthma, hypoxia, laryngitis

Skin: herpes zoster, skin ulceration

Urogenital: hydronephrosis, kidney failure, cervical cancer, hematuria, hemorrhagic cystitis, pyelonephritis

OVERDOSAGE

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

DOSAGE AND ADMINISTRATION

Usual Dose

The recommended initial loading dose is 4 mg/kg Trastuzumab administered as a 90-minute infusion. The recommended weekly maintenance dose is 2 mg/kg Trastuzumab and can be administered as a 30-minute infusion if the initial loading dose was well tolerated. HERCEPTIN® (Trastuzumab) may be administered in an outpatient setting. HERCEPTIN is to be diluted in saline for IV infusion. DO NOT ADMINISTER AS AN IV PUSH OR BOLUS (see ADMINISTRATION).

Preparation for Administration

The diluent provided has been formulated to maintain the stability and sterility of HERCEPTIN for up to 28 days. Other diluents have not been shown to contain effective preservatives for HERCEPTIN. Each vial of HERCEPTIN should be reconstituted with ONLY 20 mL of BWFI, USP, 1.1% benzyl alcohol preserved, as supplied, to yield a multi-dose solution containing 21 mg/mL Trastuzumab. Use of all 30 mL of diluent results in a lower-than-intended dose of HERCEPTIN. THE REMAINDER (approximately 10 mL) OF THE DILUENT SHOULD BE DISCARDED. Immediately upon reconstitution with BWFI, the vial of HERCEPTIN must be labeled 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 known hypersensitivity to benzyl alcohol, HERCEPTIN must be reconstituted with Sterile Water for Injection (see PRECAUTIONS). HERCEPTIN WHICH HAS BEEN RECONSTITUTED WITH SWFI MUST BE USED IMMEDIATELY AND ANY UNUSED PORTION DISCARDED. USE OF OTHER RECONSTITUTION DILUENTS SHOULD BE AVOIDED.

Shaking the reconstituted HERCEPTIN or causing excessive foaming during the addition of diluent may result in problems with dissolution and the amount of HERCEPTIN that can be withdrawn from the vial.

Use appropriate aseptic technique when performing the following reconstiution steps:

  1. Using a sterile syringe, slowly inject 20 mL of the diluent into the vial containing the lyophilized cake of Trastuzumab. The stream of diluent should be directed into the lyophilized cake.

  2. Swirl the vial gently to aid reconstitution. Trastuzumab may be sensitive to shear-induced stress, e.g., agitation or rapid expulsion from a syringe. DO NOT SHAKE.

  3. Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed for approximately 5 minutes. The solution should be essentially free of visible particulates, clear to slightly opalescent, and colorless to pale yellow.

Determine the number in mg of Trastuzumab needed, based on a loading dose of 4 mg Trastuzumab/kg body weight or a maintenance dose of 2 mg Trastuzumab/kg body weight. Calculate the volume of 21 mg/mL Trastuzumab solution and withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DEXTROSE (5%) SOLUTION SHOULD NOT BE USED. Gently invert the bag to mix the solution. The reconstituted preparation results in a colorless to pale yellow transparent solution. Parenteral drug products should be inspected visually for particulates and discoloration prior to administration.

No incompatibilities between HERCEPTIN and polyvinylchloride or polyethylene bags have been observed.

Administration

Treatment may be administered in an outpatient setting by administration of a 4 mg/kg Trastuzumab loading dose by intravenous (IV) infusion over 90 minutes. DO NOT ADMINISTER AS AN IV PUSH OR BOLUS. Patients should be observed for fever and chills or other infusion-associated symptoms (see ADVERSE REACTIONS). If prior infusions are well tolerated, subsequent weekly doses of 2 mg/kg Trastuzumab may be administered over 30 minutes.

HERCEPTIN should not be mixed or diluted with other drugs. HERCEPTIN infusions should not be administered or mixed with Dextrose solutions.

Stability and Storage

Vials of HERCEPTIN are stable at 2–8°C (36–46°F) prior to reconstitution. Do not use beyond the expiration date stamped on the vial. A vial of HERCEPTIN reconstituted with BWFI, as supplied, is stable for 28 days after reconstitution when stored refrigerated at 2–8°C (36–46°F), and the solution is preserved for multiple use. Discard any remaining multi-dose reconstituted solution after 28 days. If unpreserved SWFI (not supplied) is used, the reconstituted HERCEPTIN solution should be used immediately and any unused portion must be discarded. DO NOT FREEZE HERCEPTIN THAT HAS BEEN RECONSTITUTED.

The solution of HERCEPTIN for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, may be stored at 2–8°C (36–46°F) for up to 24 hours prior to use. Diluted HERCEPTIN has been shown to be stable for up to 24 hours at room temperature (2–25°C). However, since diluted HERCEPTIN contains no effective preservative, the reconstituted and diluted solution should be stored refrigerated (2–8°C).

HOW SUPPLIED

HERCEPTIN® (Trastuzumab) is supplied as a lyophilized, sterile powder nominally containing 440 mg Trastuzumab per vial under vacuum.

Each carton contains one vial of 440 mg HERCEPTIN® (Trastuzumab) and one 30 mL vial of Bacteriostatic
Water for Injection, USP, 1.1% benzyl alcohol.
NDC50242-134-60.

REFERENCES
  1. Coussens L, Yang-Feng TL, Liao Y-C, Chen E, Gray A, McGrath J, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 1985; 230:1132—9.

  2. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244:707—12.

  3. Press MF, Pike MC, Chazin VR, Hung G, Udove JA, Markowicz M, et al. Her-2/neuexpression in node-negative breast cancer: direct tissue quantitation by computerized image analysis and association of overexpression with increased risk of recurrent disease. Cancer Res 1993; 53:4960—70.

  4. Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 1989; 9:1165—72.

  5. Lewis GD, Figari I, Fendly B, Wong WL, Carter P, Gorman C, et al. Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother 1993; 37:255—63.

  6. Baselga J, Norton L, Albanell J, Kim Y-M, Mendelsohn J. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 1998; 58: 2825-31.

  7. Hotaling TE, Reitz B, Wolfgang-Kimball D, Bauer K, Fox JA. The humanized anti-HER2 antibody rhuMAb HER2 mediates antibody dependent cell-mediated cytotoxicity via FcgR III [abstract]. Proc Annu Meet Am Assoc Cancer Res 1996; 37:471.

  8. Pegram MD, Baly D, Wirth C, Gilkerson E, Slamon DJ, Sliwkowski MX, et al. Antibody dependent cell-mediated cytotoxicity in breast cancer patients in Phase III clinical trials of a humanized anti-HER2 antibody [abstract]. Proc Am Assoc Cancer Res 1997; 38:602.

  9. Lee, KS. Requirement for neuroregulin receptor, erbB2, in neural and cardiac development. Nature 1995; 379: 394-6.

HERCEPTIN® (Trastuzumab)

Manufactured by:
Genentech, Inc.
1 DNA Way
South San Francisco, CA 94080-4990

4817402


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