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 a,a-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 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 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 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
a AC = anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
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 treatment effect. (See CLINICAL STUDIES: 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
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 HercepTestTM; , 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. 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.) None known. 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
aOpen-label, single-agent Phase II study (94% received prior anthracyclines).
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. 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 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 µg/mL Trastuzumab. Human peripheral blood lymphocytes treated in vitro at concentrations of up to 5000 µg/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 20‚50 of gestation) and late (Days 120‚150 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. A total of 958 patients have received HERCEPTIN 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.
Table 4
Other serious adverse events The following other serious adverse events occurred in at least one of the 958 patients treated with HERCEPTIN: 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 There is no experience with overdosage in human clinical trials. Single doses higher than 500 mg have not been tested. 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 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: a. 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. b. 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. c. 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. 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). HERCEPTIN 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
Last Updated: 12/10/2001 Date created: September 26, 2003
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