Herceptin I.V.

The most serious adverse reactions caused by HERCEPTIN include cardiomyopathy, hypersensitivity reactions including anaphylaxis, infusion reactions, pulmonary events, and exacerbation of chemotherapy-induced neutropenia. Please refer to the BOXED WARNINGS and/or WARNINGS sections for detailed descriptions of these reactions. The most common adverse reactions associated with HERCEPTIN use are fever, diarrhea, infections, chills, increased cough, headache, rash, and insomnia.

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 adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Additional adverse reactions have been identified during post-marketing 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 HERCEPTIN exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to HERCEPTIN.

Where specific percentages are noted, these data are based on clinical studies of HERCEPTIN alone or in combination with chemotherapy in clinical trials. Data in Table 4 are based on the experience with the recommended dosing regimen for HERCEPTIN in a randomized controlled clinical trial of 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. Data regarding serious adverse events are based on experience in 958 patients enrolled in all clinical trials of HERCEPTIN conducted prior to marketing approval.

Cardiac Failure/Dysfunction

For a description of cardiac toxicities, see BOXED WARNINGS : CARDIOMYOPATHY and WARNINGS : Cardiotoxicity .

Anemia and Leukopenia

In a randomized, controlled trial (see CLINICAL STUDIES ), the per-patient incidences of anemia (30% vs. 21%) and leukopenia (53% vs. 37%) were higher in patients receiving HERCEPTIN in combination with chemotherapy as compared to those receiving chemotherapy alone. The majority of these cytopenic events were mild to moderate in intensity, reversible, and none resulted in discontinuation of therapy with HERCEPTIN.

In a randomized, controlled trial conducted in the post-marketing setting, there were also increased incidences of NCI-CTC Grade 3/4 neutropenia (32% [29/92] vs. 22% [21/94]) and of febrile neutropenia (23% [21/91] vs. 17% [16/94]) in patients randomized to HERCEPTIN in combination with myelosuppressive chemotherapy as compared to chemotherapy alone (see ADVERSE REACTIONS : Infection ).

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

In a randomized, controlled trial (see CLINICAL STUDIES), the incidence of infections, primarily mild upper respiratory infections of minor clinical significance or catheter infections, was higher (46% vs. 30%) in patients receiving HERCEPTIN in combination with chemotherapy as compared to those receiving chemotherapy alone.

In a randomized, controlled trial conducted in the post-marketing setting, the reported incidence of febrile neutropenia was higher (23% [21/92] vs. 17% [16/94]) in patients receiving HERCEPTIN in combination with myelosuppressive chemotherapy as compared to chemotherapy alone.

In the postmarketing setting, there have also been reports of febrile neutropenia and infection with neutropenia culminating in death associated with the use of HERCEPTIN and myelosuppressive chemotherapy (see WARNINGS : Exacerbation of Chemotherapy-Induced Neutropenia ).

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, hypotention, elevated blood pressure, rash and asthenia. The symptoms occurred infrequently with subsequent HERCEPTIN infusions. (See BOXED WARNINGS : INFUSION REACTIONS and WARNINGS : Infusion Reactions .)

Additional adverse reactions have been identified during postmarketing 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 HERCEPTIN exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to HERCEPTIN.

Hypersensitivity Reactions Including Anaphylaxis

Pulmonary Events

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

Glomerulopathy

In the postmarketing 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 glomeruloclerosis and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure.

Other Serious Adverse Events

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

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

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

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

Endocrine :  hypothyroidism

Hematological :  pancytopenia, acute leukemia, coagulation disorder, lymphangitis

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

Musculoskeletal :  pathological fractures, bone necrosis, myopathy

Nervous :  convulsion, ataxia, confusion, manic reaction

Respiratory :  apnea, pneumothorax, asthma, hypoxia, laryngitis

Skin :  herpes zoster, skin ulceration

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

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.

The data reflect the percentage of patients whose test results were considered positive for antibodies to HERCEPTIN in the HAHA assay for Trastuzumab, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including 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.