"June 12, 2012 -- The FDA on Monday approved a new drug for the treatment of a type of late-stage breast cancer. The drug helped stop cancer growth for about six months longer than existing medications.
Pertuzumab, to be marketed under"...
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]. The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied.
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]
- 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) patients in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) 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 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.
Table 1 : Incidence of Congestive Heart Failure
in Adjuvant Breast Cancer Studies
|Study||Regimen||Incidence of CHF|
|1 & 2a||ACb → Paclitaxel + Herceptin||3.2% (64/2000)c||1.3% (21/1655)|
|3d||Chemo → Herceptin||2% (30/1678)||0.3% (5/1708)|
|4||ACb→Docetaxel + Herceptin||2% (20/1068)||0.3% (3/1050)|
|4||Docetaxel + Carbo + Herceptin||0.4% (4/1056)||0.3% (3/1050)|
|a Median follow-up duration for studies 1 and
2 combined was 8.3 years in the AC→TH arm.
b Anthracycline (doxorubicin) and cyclophosphamide.
c Includes 1 patient with fatal cardiomyopathy and 1 patient with sudden death without documented etiology.
d Includes NYHA II-IV and cardiac death at 12.6 months median duration of follow-up in the one-year Herceptin arm.
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%.
Table 2: Incidence of Cardiac Dysfunctiona in
Metastatic Breast Cancer Studies
|NYHA I−IV||NYHA III−IV|
|5 (AC)b||Cardiac Dysfunction||28%||7%||19%||3%|
|5 (paclitaxel)||Cardiac Dysfunction||11%||1%||4%||1%|
|a Congestive heart failure or significant
asymptomatic decrease in LVEF.
b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
c Includes 1 patient with fatal cardiomyopathy.
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]
In postmarketing 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.
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. If the patient becomes pregnant while taking Herceptin or within 7 months following the last dose of Herceptin, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations].
Advise females of reproductive potential to avoid becoming pregnant while taking Herceptin. If contraceptive methods are being considered, use effective contraception during treatment and for at least 7 months after receiving the last dose of Herceptin [see Use in Specific Populations].
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 Infusion Reactions]. 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]
Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown. Due to differences in tumor histopathology, use FDA-approved tests for the specific tumor type (breast or gastric/gastroesophageal adenocarcinoma) to assess HER2 protein overexpression and HER2 gene amplification. Tests should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.
Several FDA-approved commercial assays are available to aid in the selection of breast cancer and metastatic gastric cancer patients for Herceptin therapy. Users should refer to the package inserts of specific assay kits for information on the Intended Use, and the validation and performance of each assay. Limitations in assay precision make it inadvisable to rely on a single method to rule out potential Herceptin benefit.
Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers. Study 7 demonstrated that gene amplification and protein overexpression were not as well correlated as with breast cancer.
Treatment outcomes for metastatic gastric cancer (Study 7), based on HER2 gene amplification (FISH) and HER2 protein overexpression (IHC) test results are provided in Table14.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Herceptin has not been tested for carcinogenic potential.
No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays, at concentrations of up to 5000 mcg/mL. In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg Herceptin.
A fertility study conducted in female cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of 2 mg/kg trastuzumab and has revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels. Studies to evaluate the effects of trastuzumab on male fertility have not been conducted.
Use In Specific Populations
Category D [see WARNINGS AND PRECAUTIONS]
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 of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.
These case reports described oligohydramnios in pregnant women who received Herceptin either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after Herceptin was stopped. In one case, Herceptin therapy resumed after the amniotic fluid index improved, and oligohydramnios recurred.
Monitor women exposed to Herceptin during pregnancy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of IV hydration in management of oligohydramnios due to Herceptin exposure is not known.
Advise women of the potential hazard to the fetus resulting from Herceptin exposure during pregnancy. If Herceptin is administered during pregnancy, or if a patient becomes pregnant while receiving Herceptin or within 7 months following the last dose of Herceptin, immediately report Herceptin exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed to Herceptin during pregnancy or within 7 months of conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720.
No teratogenic effects were observed in offspring from pregnant cynomolgus monkeys administered trastuzumab during the period of organogenesis at doses up to 25 times the recommended weekly human dose of 2 mg/kg. Trastuzumab administration to cynomolgus monkeys during early gestation (Days 20 to 50) or late gestation (Days 120 to 150) resulted in offspring with trastuzumab plasma levels of 15 to 28% of maternal plasma levels.
In mutant mice lacking HER2, embryos died in early gestation.
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 accurately reflect human breast milk levels.
Because 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, taking into account the elimination half-life of trastuzumab and the importance of the drug to the mother.
The safety and effectiveness of Herceptin in pediatric patients has not been established.
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.
In Study 7 (metastatic gastric cancer), of the 294 patients treated with Herceptin 108 (37%) were 65 years of age or older, while 13 (4.4%) were 75 and over. No overall differences in safety or effectiveness were observed.
Females Of Reproductive Potential
Herceptin can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to avoid becoming pregnant while taking Herceptin. If contraceptive methods are being considered, use effective contraception while receiving Herceptin and for at least 7 months following the last dose of Herceptin [see Use In Specific Populations].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 5/14/2015
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