Herceptin

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

• Herceptin^®

Possible serious side effects include:

• Heart failure
• Pulmonary toxicity
• Serious allergic reactions
• Fetal toxicity
• Decreased red and/or white blood cells,
• Herpes simplex infections
• Urinary tract infections
• Depression
• Neutropenia
• Anemia
• Leukopenia
• Sepsis
• Glomerulonephritis

Trastuzumab can cause serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during treatment or within 24 hours of treatment. The infusion should be interrupted if patients develop shortness of breath or significant reduction in blood pressure, and patients should be monitored until symptoms completely resolve.

Trastuzumab should be stopped if any of the following occurs:

• Anaphylaxis
• Angioedema
• Interstitial pneumonia
• Acute respiratory distress syndrome

Use of trastuzumab during pregnancy can cause oligohydramnios and oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and death of the baby.

Herceptin comes as a liquid that's injected into a vein by a healthcare professional.

The medicine must be given slowly, and it may take up to 90 minutes to receive your full dose.

Your dose and length of treatment will depend on your medical condition.

For treating breast cancer that has spread, Herceptin is typically given once a week.

For preventing the return of breast cancer, Herceptin is typically given once a week along with other chemotherapy treatments.

Then, it's administered once every three weeks once treatment with the other therapies ends.

The medicine is given for up to 52 weeks to prevent the return of breast cancer.

For stomach cancer, Herceptin is usually given once every three weeks.

Herceptin Overdose

Herceptin is administered in a clinical setting, so you're unlikely to experience an overdose.

Still, if you suspect an overdose, contact a poison control center or emergency room immediately.

You can get in touch with a poison control center at 800-222-1222.

Missed Dose of Herceptin

Call your doctor if you miss an appointment to receive your dose of Herceptin.

Mechanism of Action

Monoclonal antibody, inhibits growth of tumor cells that overexpress HER2

Pharmacokinetics

Half-life: 6 days

Peak plasma: 377 mcg/mL

Vd: 44 mL/kg

Pharmacogenomics

Mediates antibody-dependent cellular cytotoxicity against cells that overproduce HER2, and lacks effect on cells not overexpressing HER2

HER2 testing should be performed

Patients with breast cancers with intensive staining (3+) should definitely receive anti-HER2 therapy; the clinical relevance of 2+ staining is uncertain

Genetic testing laboratories

• The following companies currently offer IHC and/or FISH testing for HER2 overexpression
• Dako (http://www.dakousa.com/)
• Ventana Medical Systems (http://www.ventanamed.com/)
• Vysis/Abbott Molecular (http://www.abbottmolecular.com/)
• Invitrogen (http://www.invitrogen.com/)

Incompatibilities

Dextrose solutions

Not to be mixed with other drugs

IV Preparation

Prepare each vial by reconstituting powder with 20 mL of supplied diluent (bacteriostatic water for injection [BWFI]; contains 1.1% benzyl alcohol as a preservative)

If patient has known hypersensitivity to benzyl alcohol, drug may be reconstituted with sterile water for injection (SWI), but use SWI-reconstituted drug immediately

Reconstituted vial yields 21 mg/mL

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

Do not shake; swirl the vial gently to aid reconstitution

Slight foaming of the product may be present upon reconstitution; allow the vial to stand undisturbed for ~5 minutes

The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow

Further dilution

• Withdraw calculated dose from reconstituted vial and add to infusion bag containing 250 mL 0.9% NaCl
• Gently invert the bag to mix the solution

IV Administration

Not for IV push or bolus administration

Administer initial IV infusion over 90 min

Subsequent weekly IV infusions may be administered over 30 min if prior infusions are well tolerated

Missed dose

• Missed dose by ≤1 week: Usual maintenance dose (weekly schedule: 2 mg/kg; 3-weekly schedule: 6 mg/kg) should be administered as soon as possible; do not wait until the next planned cycle; give subsequent scheduled doses 7 or 21 days later accordingly
• Missed dose by >1 week: Reloading dose should be administered over ~90 minutes (weekly schedule: 4 mg/kg; three-weekly schedule: 8 mg/kg), as soon as possible; do not wait until the next planned cycle; give subsequent scheduled doses 7 or 21 days later accordingly

Storage

Do not freeze

Unopened vials: Stable at 2-8°C (36-46°F) prior to reconstitution

Reconstituted vials with BWFI: Once reconstituted with BWFI, may be stored in refrigerator (2-8°C) for 28 days

Reconstituted vials with SWI: Vials reconstituted with unpreserved SWI (not supplied) should be used immediately and not stored

Diluted solution: May be refrigerated (2-8°C) for up to 24 hr

The following adverse reactions are discussed in greater detail in other sections of the label:

• Cardiomyopathy [see WARNINGS AND PRECAUTIONS]
• Infusion Reactions [see WARNINGS AND PRECAUTIONS]
• Embryo-Fetal Toxicity [see WARNINGS AND PRECAUTIONS]
• Pulmonary Toxicity [see WARNINGS AND PRECAUTIONS]
• Exacerbation of Chemotherapy-Induced Neutropenia [see WARNINGS AND PRECAUTIONS]

The most common adverse reactions in patients receiving Herceptin in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of Herceptin treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see DOSAGE AND ADMINISTRATION].

In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were increased (≥ 5% difference) in the Herceptin arm as compared to the chemotherapy alone arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in discontinuation of treatment on the Herceptin containing arm in the absence of disease progression were infection, diarrhea, and febrile neutropenia.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to one-year Herceptin therapy across three randomized,open-label studies, Studies 1, 2, and 3, with (n = 3678) or without (n = 3363) trastuzumab in the adjuvant treatment of breast cancer

The data summarized in Table 3 below, from Study 3, reflect exposure to Herceptin in 1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18.Among the 3386 patients enrolled in the observation and one-year Herceptin arms of Study 3 at a median duration of follow-up of 12.6 months in the Herceptin arm, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian.

Table 3 : Adverse Reactions for Study 3a, All Gradesb

In Study 3, a comparison of 3-weekly Herceptin treatment for two years versus one year was also performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year Herceptin treatment arm (8.1% versus 4.6% in the one-year Herceptin treatment arm). More patients experienced at least one adverse reaction of Grade 3 or higher in the 2-year Herceptin treatment arm 330 (20.4%) compared with the one-year Herceptin treatment arm (16.3%).

The safety data from Studies 1 and 2 were obtained from 3655 patients, of whom 2000 received Herceptin; the median treatment duration was 51 weeks. The median age was 49 years (range: 24−80); 84% of patients were White, 7% Black, 4% Hispanic, and 3% Asian.

In Study 1, only Grade 3−5 adverse events, treatment-related Grade 2 events, and Grade 2−5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2−5 occurred at an incidence of at least 2% greater among patients receiving Herceptin plus chemotherapy as compared to chemotherapy alone: fatigue(29.5% vs. 22.4%), infection (24.0% vs. 12.8%), hot flashes (17.1% vs. 15.0%), anemia (12.3% vs. 6.7%), dyspnea (11.8% vs. 4.6%), rash/desquamation (10.9% vs. 7.6%), leukopenia (10.5% vs.8.4%), neutropenia (6.4% vs. 4.3%), headache (6.2% vs. 3.8%), pain (5.5% vs. 3.0%), edema (4.7% vs. 2.7%), and insomnia (4.3% vs. 1.5%). The majority of these events were Grade 2 in severity.

In Study 2, data collection was limited to the following investigator-attributed treatment-related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3−5 non-hematologic toxicities, selected Grade 2−5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, and sensory neuropathy) and Grade 1−5 cardiac toxicities occurring during chemotherapy and/or Herceptin treatment. The following non-cardiac adverse reactions of Grade 2−5 occurred at an incidence of at least 2% greater among patients receiving Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (12.2% vs. 9.1%), nail changes (11.5% vs. 6.8%), dyspnea (2.4% vs. 0.2%), and diarrhea (2.2% vs. 0%). The majority of these events were Grade 2 in severity.

Safety data from Study 4 reflect exposure to Herceptin as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n =1056]. The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms.The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy period. Among these patients, the median age was 49 years (range 22 to 74 years). In Study 4, the toxicity profile was similar to that reported in Studies 1, 2, and 3 with the exception of a low 358 incidence of CHF in the TCH arm.

The data below reflect exposure to Herceptin in one randomized, open-label study, Study 5, of 361 chemotherapy with (n = 235) or without (n = 234) trastuzumab in patients with metastatic breast cancer, and one single-arm study (Study 6; n = 222) in patients with metastatic breast cancer. Data in Table 4 are based on Studies 5 and 6.

Among the 464 patients treated in Study 5, the median age was 52 years (range: 25−77 years).Eighty-nine percent were White, 5% Black, 1% Asian, and 5% other racial/ethnic groups.All patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for ≥ 6 months and ≥ 12 months were 58% and 9%, respectively.

Among the 352 patients treated in single agent studies (213 patients from Study 6), the median age was 50 years (range 28−86 years), 86% were White, 3% were Black, 3% were Asian, and 8% in other racial/ethnic groups. Most of the patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for ≥ 6 months 373 and ≥ 12 months were 31% and 16%, respectively.

Table 4 : Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients in Uncontrolled Studies or at Increased Incidence in the Herceptin Arm (Studies 5 and 6)

The data below are based on the exposure of 294 patients to Herceptin in combination with a fluoropyrimidine (capecitabine or 5-FU) and cisplatin (Study 7). In the Herceptin plus chemotherapy arm, the initial dose of Herceptin 8 mg/kg was administered on Day 1 (prior to chemotherapy) followed by 6 mg/kg every 21 days until disease progression. Cisplatin was administered at 80 mg/m2 on Day 1 and the fluoropyrimidine was administered as either capecitabine 1000 mg/m2 orally twice a day on Days 1–14 or 5-fluorouracil 800 mg/m2/day as a continuous intravenous infusion Days 1 through 5. Chemotherapy was administered for six 21-day cycles. Median duration of Herceptin treatment was 21 weeks; median number of Herceptin infusions administered was eight.

Table 5: Study 7: Per Patient Incidence of Adverse Reactions of All Grades (Incidence ≥ 5% between Arms) or Grade 3/4 (Incidence > 1% between Arms) and Higher Incidence in Herceptin Arm

The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast cancer, metastatic breast cancer, metastatic gastric cancer, or post-marketing experience.

Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In Study 3, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year Herceptin arm); and in Studies 1 and 2, 7.9 years in the AC-T arm, 8.3 years in the AC-TH arm. In Studies 1 and 2, 6% of all randomized patients with post-AC LVEF evaluation were not permitted to initiate Herceptin following completion of AC chemotherapy due to cardiac dysfunction (LVEF < LLN or ≥ 16 point decline in LVEF from baseline to end of AC). Following initiation of Herceptin therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving Herceptin and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients receiving one-year Herceptin monotherapy compared to observation in Study 3 (see Table 6, Figures 1 and 2). The per-patient incidence of new-onset cardiac dysfunction, as measured by LVEF, remained similar when compared to the analysis performed at a median follow-up of 2.0 years in the AC-TH arm. This analysis also showed evidence of reversibility of left ventricular dysfunction, with 64.5% of patients who experienced symptomatic CHF in the AC-TH group being asymptomatic at latest follow-up, and 90.3% having full or partial LVEF recovery.

Table 6a: Per-patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4

Figure 1: Studies 1 and 2: Cumulative Incidence of Time to First LVEF 412 Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is initiation of paclitaxel or Herceptin + paclitaxel therapy.

Figure 2 :Study 3: Cumulative Incidence of Time to First LVEF 420 Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization.

Figure 3 :Study 4: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to 428 Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization.

The incidence of treatment emergent congestive heart failure among patients in the metastatic 433 breast cancer trials 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 2). In the metastatic breast cancer trials, the probability of cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracyclines.

In Study 7, 5.0% of patients in the Herceptin plus chemotherapy arm compared to 1.1% of 438 patients in the chemotherapy alone arm had LVEF value below 50% with a ≥10% absolute decrease in LVEF from pretreatment values.

During the first infusion with Herceptin, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of Herceptin infusion); permanent discontinuation of Herceptin for infusion reactions was required in < 1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusion reactions occurred in 21% and 35% of patients, and were severe in 1.4% and 9%of patients, on second or subsequent Herceptin infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported.

In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [Study 5]), of selected NCI-CTC Grade 2–5 anemia (12.3% vs. 6.7% [Study 1]), and of anemia requiring transfusions (0.1% vs. 0 patients [Study 2]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. Following the administration of Herceptin as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was < 1%. In Study 7 (metastatic gastric cancer), on the Herceptin containing arm as compared to the chemotherapy alone arm, the overall incidence of anemia was 28% compared to 21% and of NCI CTC Grade 3/4 anemia was 12.2% compared to 10.3%.

In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4−5 neutropenia (1.7% vs. 0.8% [Study 2]) and of selected Grade 2−5 neutropenia(6.4% vs. 4.3% [Study 1]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In Study 7 (metastatic gastric cancer) on the Herceptin containing arm as compared to the chemotherapy alone arm, the incidence of NCI-CTC Grade 3/4 neutropenia was 36.8% compared to 28.9%; febrile 470 neutropenia 5.1% compared to 2.8%.

The overall incidences of infection (46% vs. 30% [Study 5]), of selected NCI-CTC Grade 2−5 infection/febrile neutropenia (24.3% vs. 13.4% [Study 1]) and of selected Grade 3−5 infection/febrile neutropenia (2.9% vs. 1.4%) [Study 2]) were higher in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract.

In Study 4, the overall incidence of infection was higher with the addition of Herceptin to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC Grade 3−4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms.

In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone.

Adjuvant Breast Cancer

Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC Grade 2−5 pulmonary toxicity (14.3% vs. 5.4% [Study 1]) and of selected NCI-CTC Grade 3−5

pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 0.9% [Study 2]) was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2−5: 11.8% vs. 4.6% [Study 1]; NCI-CTC Grade 2−5: 2.4% vs. 0.2% [Study 2]).

Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving Herceptin compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving Herceptin, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone.

In Study 3, there were 4 cases of interstitial pneumonitis in the one-year Herceptin treatment arm compared to none in the observation arm at a median follow-up duration of 12.6 months.

Metastatic Breast Cancer

Among women receiving Herceptin for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see WARNINGS AND PRECAUTIONS.

In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving Herceptin and chemotherapy compared to chemotherapy alone in three studies (2.6% vs. 1.5% [Study 1], 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]).

Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2−5 diarrhea (6.7% vs. 5.4% [Study 1]) and of NCI-CTC Grade 3−5 diarrhea (2.2% vs. 0% [Study 2]), and of Grade 1−4 diarrhea (7% vs. 1% [Study 3; one-year Herceptin treatment at 12.6 months median duration of follow-up]) were higher in patients receiving Herceptin as compared to controls. In Study 4, the incidence of Grade 3−4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1−4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving Herceptin. Of patients receiving Herceptin as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving Herceptin in combination with chemotherapy for treatment of metastatic breast cancer.

In Study 7 (metastatic gastric cancer) on the Herceptin-containing arm as compared to the chemotherapy alone arm the incidence of renal impairment was 18% compared to 14.5%. Severe (Grade 3/4) renal failure was 2.7% on the Herceptin-containing arm compared to 1.7% on the chemotherapy only arm. Treatment discontinuation for renal insufficiency/failure was 2% on the Herceptin-containing arm and 0.3% on the chemotherapy only arm.

In the post-marketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18 months from initiation of Herceptin therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Among 903 women with metastatic breast cancer, human anti-human antibody (HAHA) to Herceptin was detected in one patient using an enzyme-linked immunosorbent assay (ELISA). This patient did not experience an allergic reaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer.

The incidence of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Herceptin with the incidence of antibodies to other products may be misleading.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Herceptin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Infusion reaction [see WARNINGS AND PRECAUTIONS]
• Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal
• abnormalities, and neonatal death [see WARNINGS AND PRECAUTIONS]
• Glomerulopathy [see Clinical Trials Experience]
• Immune thrombocytopenia

Cardiomyopathy

• Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see BOX WARNING: Cardiomyopathy].

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential that Herceptin exposure during pregnancy or within 7 months prior to conception can result in fetal harm. Advise female patients to contact their healthcare provider with a known or suspected pregnancy [see Use In Specific Populations].
• Advise women who are exposed to Herceptin during pregnancy or who become pregnant within 7 months following the last dose of Herceptin that there is a pregnancy exposure registry and a pregnancy pharmacovigilance program that monitor pregnancy outcomes. Encourage these patients to enroll in the MotHER Pregnancy Registry and report their pregnancy to Genentech [see Use In Specific Populations].
• Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of Herceptin [see Use In Specific Populations].

Heart Problems

• Herceptin treatment can result in heart problems, including those without symptoms (such as reduced heart function) and those with symptoms (such as congestive heart failure). The risk and seriousness of these heart problems were highest in people who received both Herceptin and a certain type of chemotherapy (anthracycline). One patient died in an adjuvant (early) breast cancer trial of significantly weakened heart muscle.
• Herceptin can cause serious heart problems, including:
  • A decline in heart function
  • Irregular heartbeats
  • High blood pressure
  • Serious heart attack
  • Death
• Your doctor will stop Herceptin therapy if you have weakening of the heart muscle or changes in the heart muscle structure.

Monitoring the Heart

• Your doctor will evaluate your heart function before and during treatment. For adjuvant breast cancer therapy, your doctor will also evaluate heart function after the end of treatment.
• Your doctor may run tests, such as an echocardiogram or a MUGA scan, and will review your health history to see how well the heart muscle is working.
• If you are taking Herceptin and have stopped treatment temporarily because of significant heart problems, your doctor should monitor your heart health more frequently.

Infusion Reactions

• Some patients have had serious infusion reactions and lung problems; infusion reactions leading to death have been reported
• Symptoms usually happen during or within 24 hours of taking Herceptin 
• Your infusion should be temporarily stopped if you experience shortness of breath or very low blood pressure
• Your doctor should monitor you until these symptoms completely go away
• Your doctor may have you completely stop Herceptin treatment if you have:
  • A severe allergic reaction
  • Swelling
  • Lung problems
  • Swelling of the lungs
  • Severe shortness of breath
• Infusion reaction symptoms consist of:

• Fever and chills
• Nausea
• Vomiting
• Pain (in some cases at tumor sites)
• Headache

• Dizziness
• Shortness of breath
• Very low blood pressure
• Rash
• Lack of energy and strength

Pregnancy

• Herceptin can cause harm to the fetus (unborn baby), in some cases death to the fetus, when taken by a pregnant woman
• You should use effective birth control methods while receiving Herceptin and for at least 6 months after you finish taking Herceptin 
• Nursing mothers taking Herceptin may want to stop nursing or stop Herceptin, depending on the importance of the drug to the mother

Lung Problems

Taking Herceptin Can Result in Serious and Potentially Deadly Lung Problems, Including:

• A severe shortness of breath
• Fluid in or around the lungs
• Weakening of the valve between the heart and the lungs
• Too little oxygen in the body
• Swelling of the lungs
• Scarring of the lungs

Problems like these may occur after an infusion reaction. If you have trouble breathing at rest due to existing lung disease, or large lung tumors appear, you may have more serious lung problems. Your doctor should stop Herceptin if you experience lung problems.

Additional Important Safety Information associated with Herceptin 

Worsening of Low White Blood Cell Counts Due to Chemotherapy

• Worsening of low white blood cell counts to serious and life-threatening levels and associated fever were higher in patients taking Herceptin in combination with chemotherapy when compared with those who received chemotherapy alone. The likelihood that a patient will die from infection was similar among patients who received Herceptin and those who did not

HER2 Testing

• You must have a HER2 test to determine if your cancer is HER2-positive before taking Herceptin, as benefit has only been shown in patients whose tumors are HER2-positive

• You should contact your doctor immediately for any of the following:
  • New onset or worsening shortness of breath
  • Cough
  • Swelling of the ankles/legs
  • Swelling of the face
  • Palpitations
  • Weight gain of more than 5 pounds in 24 hours
  • Dizziness or loss of consciousness
• If you are pregnant or of childbearing potential, you should know that Herceptin exposure can result in harm to the fetus (unborn baby)
• You should use effective birth control methods during treatment and for a minimum of six months following Herceptin 
• If you are nursing your baby, you should stop taking Herceptin or stop nursing

Herceptin is given intravenously (IV) by a healthcare provider in a medical setting (healthcare provider's office, or hospital). The first dose is usually given over 90 minutes. Subsequent maintenance doses may be given over 30 minutes if the first dose is well-tolerated. Herceptin is given once a week or every three weeks, depending on the chosen dosing regimen.

Your doctor will monitor the side effects you experience and your response to therapy, as well as:

• how well your heart, kidneys and liver are functioning
• your complete blood count (CBC)

Trastuzumab injection is used to treat HER2-overexpressing new or metastatic (cancer that has spread) breast cancer. It can be used alone or with other cancer medicines (eg, carboplatin, cyclophosphamide, docetaxel, doxorubicin, paclitaxel).

Trastuzumab injection is also used in combination with cisplatin and capecitabine or 5-fluorouracil to treat HER2-overexpressing metastatic (cancer that has spread) stomach and gastroesophageal (stomach and esophagus) cancer.

Trastuzumab prevents the growth of some tumors that produce extra amounts of a certain substance known as the HER2 protein. It should only be used in patients whose tumors have been shown to produce extra amounts of this protein (HER2 overexpression).

Trastuzumab is a monoclonal antibody. It interferes with the growth of cancer cells, which are eventually destroyed by the body. Since the growth of normal body cells may also be affected by trastuzumab, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, such as a skin rash, may not be serious but may cause concern. Some effects do not occur until months or years after the medicine is used.

This medicine is to be given only by or under the immediate supervision of your doctor.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Dizziness
• fever or chills
• headache
• muscle aches
• nausea or vomiting
• skin rash
• sore throat
• stuffy or runny nose
• unusual tiredness or weakness

• Bloody nose
• cough
• diarrhea
• difficult or labored breathing
• ear congestion or pain
• fast or irregular heartbeat
• general feeling of discomfort or illness
• head congestion
• hoarseness or other voice changes
• increased cough
• joint pain
• loss of appetite
• nasal congestion
• pain or tenderness around the eyes and cheekbones
• shivering
• sneezing
• sweating
• swelling of the feet or lower legs
• tightness in the chest
• trouble with sleeping
• vomiting

• Blue lips and fingernails
• blurred vision
• chest pain
• confusion
• cough or hoarseness, accompanied by fever or chills
• faintness or lightheadedness when suddenly getting up from a lying or sitting position
• itching
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, feet, or sex organs
• lower back or side pain, accompanied by fever or chills
• painful or difficult urination, accompanied by fever or chills
• pale skin
• redness of the skin

• Black, tarry stools
• bloody or cloudy urine
• sores, ulcers, or white spots in the mouth
• unusual bleeding or bruising
• weight gain

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Difficulty in moving
• metallic taste in the tongue
• muscle pain or stiffness
• pain
• weight loss

• Numbness or tingling of the hands or feet

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Cardiomyopathy

Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy]. Herceptin can also cause asymptomatic decline in left ventricular ejection fraction (LVEF).

There is a 4–6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving Herceptin as a single agent or in combination therapy compared with those not receiving Herceptin. The highest absolute incidence occurs when Herceptin is administered with an anthracycline.

Withhold Herceptin for ≥ 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values [see Dosage and Administration (2.3)]. The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied.

Patients who receive anthracycline after stopping Herceptin may also be at increased risk of cardiac dysfunction [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

Cardiac Monitoring

Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:

• Baseline LVEF measurement immediately prior to initiation of Herceptin
• LVEF measurements every 3 months during and upon completion of Herceptin
• Repeat LVEF measurement at 4 week intervals if Herceptin is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration (2.3)]
• LVEF measurements every 6 months for at least 2 years following completion of Herceptin as a component of adjuvant therapy.

In Study 1, 15% (158/1031) of patients discontinued Herceptin due to clinical evidence of myocardial dysfunction or significant decline in LVEF after a median follow-up duration of 8.7 years in the AC-TH arm. In Study 3 (one-year Herceptin treatment), the number of patients who discontinued Herceptin due to cardiac toxicity at 12.6 months median duration of follow-up was 2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) of patients in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) of patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued Herceptin due to cardiac toxicity.

Among 64 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy, one patient died suddenly without documented etiology, and 33 patients were receiving cardiac medication at last follow-up. Approximately 24% of the surviving patients had recovery to a normal LVEF (defined as ≥50%) and no symptoms on continuing medical management at the time of last follow-up. Incidence of congestive heart failure (CHF) is presented in Table 1. The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied.

In Study 3 (one-year Herceptin treatment), at a median follow-up duration of 8 years, the incidence of severe CHF (NYHA III & IV) was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%.

In Study 4, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the Herceptin containing regimens (AC-TH: 0.3% (3/1068) and TCH: 0.2% (2/1056)) as compared to none in AC-T.

Infusion Reactions

Infusion reactions consist 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 [see Adverse Reactions (6.1)].

In post-marketing reports, serious and fatal infusion reactions have been reported. Severe reactions, which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable, including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction.

Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered (which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen). Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions.

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. Prior to resumption of Herceptin infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated Herceptin infusions, others had recurrent severe infusion reactions despite pre-medications.

Embryo-Fetal Toxicity

Herceptin can cause fetal harm when administered to a pregnant woman. In post marketing reports, use of Herceptin during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.

Verify the pregnancy status of females of reproductive potential prior to the initiation of Herceptin. Advise pregnant women and females of reproductive potential that exposure to Herceptin during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of Herceptin [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.3)].

Pulmonary Toxicity

Herceptin use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions (5.2)]. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity.

Exacerbation of Chemotherapy-Induced Neutropenia

In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3–4 neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received Herceptin and those who did not [see Adverse Reactions (6.1)].

Herceptin (trastuzumab) is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Herceptin is used to treat certain types of breast cancer or stomach cancer. Other cancer medicines are sometimes used in combination with Herceptin.

Usual Adult Dose of Herceptin for Breast Cancer:

For use in the treatment of metastatic breast cancer:
Administer trastuzumab, alone or in combination with paclitaxel.
Initial dose: 4 mg/kg IV infusion over 90 minutes
Subsequent therapy: 2 mg/kg IV infusion over 30 minutes once weekly until disease progression

Usual Adult Dose of Herceptin for Breast Cancer -- Adjuvant:

Administer according to one of the following doses and schedules:

1) Initiate trastuzumab during and following paclitaxel, docetaxel, or docetaxel/carboplatin:
Initial dose: 4 mg/kg IV infusion over 90 minutes then 2 mg/kg IV infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin).
Subsequent therapy: one week after the last weekly dose of trastuzumab, give trastuzumab as 6 mg/kg IV infusion over 30 to 90 minutes every 3 weeks for a total of 52 weeks of therapy.

or

2) Initiate trastuzumab as a single agent within 3 weeks following completion of all chemotherapy.
Initial dose: 8 mg/kg IV infusion over 90 minutes
Subsequent therapy: 6 mg/kg IV infusion over 30 to 90 minutes every 3 weeks for a total of 17 doses (52 weeks of therapy)

Usual Adult Dose of Herceptin for Esophageal Carcinoma:

For use in the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma:
Administer trastuzumab in combination with cisplatin and capecitabine or 5-fluorouracil.
Initial dose: 8 mg/kg IV infusion over 90 minutes
Subsequent therapy: 6 mg/kg IV infusion over 30 to 90 minutes every 3 weeks until disease progression

Usual Adult Dose of Herceptin for Gastric Cancer:

For use in the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma:
Administer trastuzumab in combination with cisplatin and capecitabine or 5-fluorouracil.
Initial dose: 8 mg/kg IV infusion over 90 minutes
Subsequent therapy: 6 mg/kg IV infusion over 30 to 90 minutes every 3 weeks until disease progression

Other drugs may interact with trastuzumab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.

Applies to trastuzumab: intravenous powder for injection

General

The most common adverse events were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, stomatitis, weight loss, thrombocytopenia, mucosal inflammation, nasopharyngitis, dysgeusia, and myalgia.[Ref]

Hematologic

Very common (10% or more): Neutropenia (up to 78%), leukopenia (up to 52%), anemia (up to 36%), febrile neutropenia (up to 23%), thrombocytopenia (16%), leukopenia (10.5%)
Frequency not reported: Hypoprothrombinemia[Ref]

Cardiovascular

Very common (10% or more): LVEF decrease (up to 44.3%), congestive heart failure (up to 28%), tachycardia (up to 10%), blood pressure decreased, blood pressure increased, heart beat irregular, palpitation, cardiac flutter, ejection fraction decreased, lymphedema, hot flush
Common (1% to 10%): Asymptomatic cardiac dysfunction, hypertension, thrombotic adverse event, palpitations, cardiac arrhythmias, supraventricular tachyarrhythmia, cardiomyopathy, hypotension, vasodilation
Uncommon (0.1% to 1%): Cardiac failure, cardiac disorder, ventricular dysfunction, pericardial effusion
Frequency not reported: Cardiogenic shock, pericarditis, bradycardia, gallop rhythm present, S3 gallop[Ref]

Hypersensitivity

Very common (10% or more): Infusion-related reactions (up to 54%)
Common (1% to 10%): Hypersensitivity, allergic reaction
Frequency not reported: Anaphylactic reaction, anaphylactic shock[Ref]

Respiratory

Very common (10% or more): Cough increased (up to 43%), dyspnea (up to 42%), rhinitis (up to 22%), Grade 2 to 5 pulmonary toxicity (14.3%), wheezing, epistaxis, rhinorrhea, oropharyngeal pain, cough
Common (1% to 10%): Upper respiratory infection, rhinitis, pharyngolaryngeal pain, asthma, lung disorder, pleural effusion
Uncommon (0.1% to 1%): Pneumonitis, pulmonary infiltrates, pulmonary hypertension, interstitial pneumonitis
Frequency not reported: Pulmonary insufficiency, pulmonary fibrosis, respiratory distress, respiratory failure, lung infiltration, acute pulmonary edema, acute respiratory distress syndrome, bronchospasm, hypoxia, oxygen saturation decreased, laryngeal edema, pulmonary edema, orthopnea
Postmarketing reports: Bronchospasm, hypoxia, pleural effusions, non-cardiogenic pulmonary edema[Ref]

Immunologic

Very common (10% or more): Infection (up to 47%), herpes simplex (up to 38%), pharyngitis (up to 30%), sinusitis (up to 21%), upper respiratory tract infections (19%), urinary tract infection (up to 18%), antibody to trastuzumab (the active ingredient contained in Herceptin) (up to 14.6%), nasopharyngitis (13%), flu syndrome (up to 12%)
Common (1% to 10%): Nasopharyngitis, influenza, urinary tract infection, neutropenic sepsis, cystitis, herpes zoster, influenza, skin infection, rhinitis, erysipelas, cellulitis, pneumonia, post-operative wound infection
Uncommon (0.1% to 1%): Sepsis[Ref]

Renal

Postmarketing reports of pathological evidence of glomerulopathy included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure.[Ref]

Very common (10% or more): Renal failure and impairment (18%)
Common (1% to 10%): Grade 3 or 4 renal failure, renal disorder, hyperbilirubinemia
Frequency not reported: Glomerulonephritis membranous, glomerulonephropathy, renal failure
Postmarketing reports: Nephrotic syndrome with pathological evidence of glomerulopathy[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 76%), vomiting (up to 53%), diarrhea (up to 45%), abdominal pain (up to 34%), stomatitis (24%), nausea and vomiting (18%), lip swelling, pancreatitis, constipation, dyspepsia
Common (1% to 10%): Dysphagia, upper abdominal pain, hemorrhoids, dry mouth[Ref]

Nervous system

Very common (10% or more): Headache (up to 44%), fatigue (35%), insomnia (up to 29%), dizziness (up to 24%), paresthesia (up to 23%), peripheral neuritis (up to 23%), neuropathy (up to 13%), dysgeusia (10%), tremor, hypoesthesia
Common (1% to 10%): Peripheral neuropathy, hypertonia, somnolence, ataxia
Rare (less than 0.1%): Paresis
Frequency not reported: Brain edema[Ref]

Dermatologic

Very common (10% or more): Rash (up to 38%), nail changes (11.5%), acne (up to 11%), rash/desquamation (10.9%), erythema, swelling face, palmar-plantar erythrodysesthesia syndrome, nail disorder, alopecia, nail toxicity
Common (1% to 10%): Pruritus, dry skin, ecchymosis, hyperhidrosis, maculopapular rash, onychoclasis, dermatitis, contusion
Uncommon (0.1% to 1%): Urticaria
Frequency not reported: Angioedema[Ref]

Musculoskeletal

Very common (10% or more): Arthralgia (up to 37%), back pain (up to 34%), bone pain (up to 24%), muscle tightness, myalgia
Common (1% to 10%): Muscle spasm, neck pain, pain in extremity, arthritis[Ref]

Metabolic

Very common (10% or more): Anorexia (up to 31%) hypokalemia (28%), weight decrease (23%), weight increased, decreased appetite
Frequency not reported: Hyperkalemia
Postmarketing reports: Volume overload[Ref]

Other

Very common (10% or more): Asthenia (up to 62%), pain (up to 61%), fever (up to 56%), chills (up to 41%), peripheral edema (up to 22%), hot flashes (17.1%), accidental injury (up to 13%), mucosal inflammation (13%), edema (11%), chest pain, influenza-like symptoms
Common (1% to 10%): Edema peripheral, asthenia, malaise
Uncommon (0.1% to 1%): Deafness
Rare (less than 0.1%): Sudden death[Ref]

Hepatic

Common (1% to 10%): Hepatocellular injury, hepatitis, liver tenderness
Rare (less than 0.1%): Jaundice
Frequency not reported: Hepatic failure[Ref]

Ocular

Very common (10% or more): Conjunctivitis, lacrimation increased
Common (1% to 10%): Dry eye
Frequency not reported: Papilledema, retinal hemorrhage[Ref]

Genitourinary

Oligohydramnios sequence included pulmonary hypoplasia, skeletal abnormalities, and neonatal death.[Ref]

Common (1% to 10%): Breast inflammation/mastitis
Postmarketing reports: Oligohydramnios or oligohydramnios sequence[Ref]

Psychiatric

Very common (10% or more): Depression (up to 20%), insomnia
Common (1% to 10%): Anxiety, thinking abnormal[Ref]

Endocrine

Uncommon (0.1% to 1%): Autoimmune thyroiditis[Ref]

Oncologic

Frequency not reported: Malignant neoplasm progression, neoplasm progression[Ref]

Some side effects of Herceptin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Use is not recommended and a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Yes Comments: Breastfeeding should be avoided during therapy and for 7 months after the last dose.