HERCEPTIN®
`Trastuzumab
`
`WARNING
`CARDIOMYOPATHY:
`HERCEPTIN 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 sever-
`ity of cardiac dysfunction was particularly high in patients who received HERCEPTIN in combination
`with anthracyclines and cyclophosphamide. (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 epider-
`mal growth factor receptor2 protein, HER2.1,2 The antibody is an IgG1 kappa that contains human frame-
`work 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) admin-
`istration. Each vial of HERCEPTIN contains 440mg Trastuzumab, 9.9mg L-histidineHCl, 6.4mg L-histi-
`dine, 400 mg a,a-trehalose dihydrate, and 1.8 mg polysorbate 20, USP. Reconstitution with 20 mL of the
`supplied Bacteriostatic Water for Injection, (BWFI) USP, containing 1.1%benzyl alcohol as a preservative,
`yields 21mL of a multi-dose solution containing 21mg/mL Trastuzumab, at a pH of approximately 6.
`
`CLINICAL PHARMACOLOGY
`General
`The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185kDa, which is struc-
`turally 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 tumor
`cells 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 pharmacokinet-
`ics. 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 approx-
`imately 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 con-
`centrations reached a steady-state with a mean trough and peak concentrations of approximately
`79microgram/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 inter-
`actions; no formal drug interaction studies were performed.
`
`CLINICAL STUDIES
`The safety and efficacy of HERCEPTIN were studied in a randomized, controlled clinical trial in combina-
`tion with chemotherapy (469patients) and an open-label single agent clinical trial (222 patients). Both tri-
`als studied patients with metastatic breast cancer whose tumors overexpressthe HER2 protein. Patients were
`eligible if they had 2+ or 3+ levels of overexpression (based on a 0–3+ scale) by immunohistochemical assess-
`ment of tumor tissue performed by a central testing lab.
`A multicenter, randomized, controlled clinical trial was conducted in 469patients with metastatic breast can-
`cer who had not been previously treated with chemotherapy for metastatic disease. Patients were random-
`ized 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 2mg/kg. For those who had received prior anthra-
`cycline therapy in the adjuvant setting, chemotherapy consisted of paclitaxel (175 mg/m2 over 3hours every
`21 days for at least six cycles); for all other patients, chemotherapy consisted of anthracycline plus cyclophos-
`phamide (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 sub-
`groups (n = 188) were more likely to have had the following: poor prognostic factors (premenopausal sta-
`tus, 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 time to disease progression, a higher overall response rate
`(ORR), a longer median duration of response, and a higher one-year survival rate. (See Table1.) These treat-
`ment 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 pro -
`tein overexpression.)
`
`Table 1
`Phase III Clinical Efficacy in First-Line Treatment
`
`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 inpatients
`with HER2 overexpressing metastatic breast cancer who had relapsed following one or two prior chemother-
`apy regimens for metastatic disease. Of 222 patients enrolled, 66% had received prior adjuvant chemother-
`apy, 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® (Trastuzumab) at 2mg/kg IV. The ORR (complete response+ par-
`tial response), as determined by an independent Response Evaluation Committee, was 14%, with a 2% com-
`plete 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 treatment
`effect. (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 immuno-
`histochemical assay (referred to as the Clinical Trial Assay, CTA) and scored as 0, 1+, 2+, or 3+ with 3+ indi-
`cating 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
`
`a N/A = Not Assessed
`
`Immunohistochemical Detection: In clinical trials, the Clinical Trial Assay (CTA) was used for immuno-
`histochemical detection of HER2 protein overexpression. The DAKO HercepTestTM, another immunohis-
`tochemical 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 spec-
`imens 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 HercepTestTM results with CTA results.
`Of specimens testing 3+ (strongly positive) on the HercepTestTM, 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 HercepTestTM, 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 informa-
`tion 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 dys-
`pnea, 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 were classified for severity using the New York
`Heart Association classification system (I-IV, where IV is the most severe level of cardiac failure).
`(SeeTable 3.)
`
`Table 3
`Incidence and Severity of Cardiac Dysfunction
`
`a Open-label, single-agent Phase 2 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 includ-
`ing 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 cautionshould 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 eval-
`uate 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.
`
`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.
`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 lev-
`els in clinical studies (see Pharmacokinetics).
`
`

`

`HERCEPTIN®
`Trastuzumab
`
`WARNING
`CARDIOMYOPATHY:
`HERCEPTIN 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 sever-
`ity of cardiac dysfunction was particularly high in patients who received HERCEPTIN in combination
`with anthracyclines and cyclophosphamide. (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 epider-
`mal growth factor receptor2 protein, HER2.1,2 The antibody is an IgG1 kappa that contains human frame-
`work 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) admin-
`istration. Each vial of HERCEPTIN contains 440mg Trastuzumab, 9.9mg L-histidineHCl, 6.4mg L-histi-
`dine, 400 mg a,a-trehalose dihydrate, and 1.8 mg polysorbate 20, USP. Reconstitution with 20 mL of the
`supplied Bacteriostatic Water for Injection, (BWFI) USP, containing 1.1%benzyl alcohol as a preservative,
`yields 21mL of a multi-dose solution containing 21mg/mL Trastuzumab, at a pH of approximately 6.
`
`CLINICAL PHARMACOLOGY
`General
`The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185kDa, which is struc-
`turally 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 tumor
`cells 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 pharmacokinet-
`ics. 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 approx-
`imately 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 con-
`centrations reached a steady-state with a mean trough and peak concentrations of approximately
`79microgram/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 inter-
`actions; no formal drug interaction studies were performed.
`
`CLINICAL STUDIES
`The safety and efficacy of HERCEPTIN were studied in a randomized, controlled clinical trial in combina-
`tion with chemotherapy (469patients) and an open-label single agent clinical trial (222 patients). Both tri-
`als studied patients with metastatic breast cancer whose tumors overexpressthe HER2 protein. Patients were
`eligible if they had 2+ or 3+ levels of overexpression (based on a 0–3+ scale) by immunohistochemical assess-
`ment of tumor tissue performed by a central testing lab.
`A multicenter, randomized, controlled clinical trial was conducted in 469patients with metastatic breast can-
`cer who had not been previously treated with chemotherapy for metastatic disease. Patients were random-
`ized 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 2mg/kg. For those who had received prior anthra-
`cycline therapy in the adjuvant setting, chemotherapy consisted of paclitaxel (175 mg/m2 over 3hours every
`21 days for at least six cycles); for all other patients, chemotherapy consisted of anthracycline plus cyclophos-
`phamide (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 sub-
`groups (n = 188) were more likely to have had the following: poor prognostic factors (premenopausal sta-
`tus, 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 time to disease progression, a higher overall response rate
`(ORR), a longer median duration of response, and a higher one-year survival rate. (See Table1.) These treat-
`ment 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 pro -
`tein overexpression.)
`
`Table 1
`Phase III Clinical Efficacy in First-Line Treatment
`
`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 inpatients
`with HER2 overexpressing metastatic breast cancer who had relapsed following one or two prior chemother-
`apy regimens for metastatic disease. Of 222 patients enrolled, 66% had received prior adjuvant chemother-
`apy, 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® (Trastuzumab) at 2mg/kg IV. The ORR (complete response+ par-
`tial response), as determined by an independent Response Evaluation Committee, was 14%, with a 2% com-
`plete 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 treatment
`effect. (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 immuno-
`histochemical assay (referred to as the Clinical Trial Assay, CTA) and scored as 0, 1+, 2+, or 3+ with 3+ indi-
`cating 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
`
`a N/A = Not Assessed
`
`Immunohistochemical Detection: In clinical trials, the Clinical Trial Assay (CTA) was used for immuno-
`histochemical detection of HER2 protein overexpression. The DAKO HercepTestTM, another immunohis-
`tochemical 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 spec-
`imens 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 HercepTestTM results with CTA results.
`Of specimens testing 3+ (strongly positive) on the HercepTestTM, 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 HercepTestTM, 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 informa-
`tion 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 dys-
`pnea, 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 were classified for severity using the New York
`Heart Association classification system (I-IV, where IV is the most severe level of cardiac failure).
`(SeeTable 3.)
`
`Table 3
`Incidence and Severity of Cardiac Dysfunction
`
`a Open-label, single-agent Phase 2 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 includ-
`ing 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 cautionshould 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 eval-
`uate 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.
`
`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.
`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 lev-
`els 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® (Trastuzumab) 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 onepatient, 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 invitro at concentrations of up to 5000 mg/plate Trastuzumab, with and
`without metabolic activation, revealed no evidence of mutagenic potential. In an invivo mutagenic assay (the
`micronucleus assay), no evidence of chromosomal damage to mouse bone marrow cells was observed fol-
`lowing 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 25times the weekly human maintenance dose of 2mg/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 tis-
`sues including cardiac and neural tissues; in mutant mice lacking HER2, embryos died in early gestation.9
`Placental transfer of HERCEPTIN during the early (Days20–50 of gestation) and late (Days120–150 of ges-
`tation) 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 25times the weekly human
`maintenance dose of 2mg/kg HERCEPTIN demonstrated that Trastuzumab is secreted in the milk. The pres-
`ence 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 ade-
`quate to determine whether older patients respond differently from younger patients.
`
`ADVERSE REACTIONS
`A total of 958 patients have received HERCEPTIN alone or in combination with chemotherapy. Data in the
`table below are based on the experience with the recommended dosing regimen for HERCEPTIN in the ran-
`domized controlled clinical trial in 234 patients who received HERCEPTIN in combination with chemother-
`apy 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 ACsubgroup, compared
`with the treatment group receiving