ONS Connect - October 2008 - (Page 33)

Figure 1 Studies 1 and 2: Cumulative Incidence of Time to First LVEF Decline of patients randomized to Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Infection The overall incidences of Grade 2–5 infection/febrile neutropenia (22% vs. 14% [Study 1]) and of selected Grade 3–5 infection/febrile neutropenia (3.3% 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 marketing case reports suggest that Herceptin use during pregnancy increases the risk for oligohydramnios during the second and third trimester. If Herceptin is used during pregnancy or if a woman becomes pregnant while taking Herceptin, she should be apprised of the potential hazard was reported in women who received Herceptin during pregnancy, either alone or in combination with chemotherapy. In half of these women, amniotic fluid index increased after Herceptin was stopped. In one case, Herceptin was resumed after the amniotic fluid index Herceptin during pregnancy should be monitored for oligohydramnios. If oligohydramnios occurs, fetal testing should be done that is appropriate for gestational age and intravenous (IV) hydration has been helpful when oligohydramnios has occurred following administration of other chemotherapy agents; however, the effects of additional IV hydration with Herceptin treatment are not known. Reproduction studies in cynomolgus monkeys at doses up to 25 times the recommended weekly human dose of 2 mg/kg trastuzumab have revealed no evidence of 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. Placental transfer of trastuzumab observed in monkeys. [See Nonclinical Toxicology] predictive of human response, Herceptin should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Nursing Mothers It is not known whether Herceptin is excreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the breast milk of lactating cynomolgus monkeys given 12.5 times the recommended weekly human dose of 2 mg/kg of Herceptin. Infant monkeys with detectable serum levels of trastuzumab did not have any adverse effects on growth or development from birth to 3 months of age; however, trastuzumab levels in animal breast milk may not many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from Herceptin, a decision should be made whether to discontinue nursing, or discontinue drug, and the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Herceptin in pediatric patients has not been established. Geriatric Use Herceptin has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in data collection and differences in study design of the 4 studies of Herceptin in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of Herceptin in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Herceptin treatment in older patients is different from that observed in patients <65 years of age for metastatic disease and adjuvant treatment. OVERDOSAGE There is no experience with overdosage in human clinical trials. Single doses higher than 8 mg/kg have not been tested. PATIENT COUNSELING INFORMATION 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 Boxed Warning: Cardiomyopathy potential to use effective contraceptive methods during treatment and for a minimum of six months following Herceptin [see Pregnancy who are using Herceptin to enroll in the Cancer and Childbirth Registry [see Pregnancy]. HERCEPTIN® [trastuzumab] Manufactured by: Genentech, Inc. 4839802 therapy. Figure 2 Study 3: Cumulative Incidence of Time to First LVEF Decline of 50% with Death as a Competing Risk Event 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. Pulmonary Toxicity CTC Grade 2–5 pulmonary toxicity (14% vs. 5% [Study 1]) and spontaneous reported Grade 2 dyspnea (3.4% vs. 1% [Study 2]) was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI CTC vs. 0.1% [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 failure, as compared to 1 patient receiving chemotherapy alone. In Study 3, there were 4 cases of interstitial none in the control arm. women receiving Herceptin for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see Warnings and Precautions. Thrombosis/Embolism 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 (3.0% vs. 1.3% [Study 1], 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]). Diarrhea CTC Grade 2–5 diarrhea (6.2% vs. 4.8% [Study 1]) and of of Grade 1–4 diarrhea (7% vs. 1% [Study 3]) were higher in patients receiving Herceptin as compared to controls. In Study 4, the incidence of Grade 3–4 diarrhea was higher women receiving Herceptin. Of patients receiving Herceptin as a single agent for the treatment of metastatic incidence of diarrhea was observed in patients receiving Herceptin in combination with chemotherapy for treatment of metastatic breast cancer. Glomerulopathy 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 with all therapeutic proteins, there is a potential for Time 0 is the date of randomization. Figure 3 Study 4: Cumulative Incidence of Time to First LVEF Decline of Time 0 is the date of randomization. The incidence of treatment emergent congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart 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. Infusion Reactions 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 infusional toxicity 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. Infusional toxicity occurred in 21% and 35% of patients, and was severe in 1.4% and 9% of patients, on second or subsequent Herceptin infusions administered as monotherapy or in combination with chemotherapy, reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported. Anemia In randomized controlled clinical trials, the overall incidence of anemia anemia (12.5% vs. 6.6% [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 was <1%. Neutropenia In randomized controlled clinical trials in the adjuvant setting, the incidence of selected and of selected Grade 2–5 neutropenia (7.1% vs. 4.5 % [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 febrile neutropenia (23% vs. 17%) were also increased in experience an allergic reaction. Samples for assessment cancer. The incidence of antibody formation is highly dependent on the sensitivity and the specificity of the (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay me

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ONS Connect- October 2008 Contents Editor's Note Just In Up Front You Tell Us Up Close &�Professional Web Connect Five-Minute In-Service Capitol Connection Caregiver Care Straight Talk New Treatments, New Hope Working for You Calendar of Events Staying on Top

ONS Connect - October 2008

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