Ogivri

Ogivri Adverse Reactions

trastuzumab

Manufacturer:

Biocon

Distributor:

DKSH

Marketer:

Meda Pharma
Full Prescribing Info
Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the monograph: Cardiomyopathy [see Precautions].
Infusion Reactions [see Precautions].
Embryo-Fetal Toxicity [see Precautions].
Pulmonary Toxicity [see Precautions].
Exacerbation of Chemotherapy-induced Neutropenia [see Precautions].
The most common adverse reactions in patients receiving trastuzumab products 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 trastuzumab product treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage & Administration].
In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were increased (≥ 5% difference) in patients receiving trastuzumab products as compared to patients receiving chemotherapy alone 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 trastuzumab product treatment 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 or another drug and may not reflect the rates observed in practice.
Adjuvant Breast Cancer Studies: The data as follows reflect exposure to one-year trastuzumab 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 11 as follows, from Study 3, reflect exposure to trastuzumab 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 trastuzumab arms of Study 3 at a median duration of follow-up of 12.6 months in the trastuzumab arm, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian. (See Table 11.)

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In Study 3, a comparison of 3-weekly trastuzumab treatment for two years versus one year was also performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year trastuzumab treatment arm (8.1% versus 4.6% in the one-year trastuzumab treatment arm). More patients experienced at least one adverse reaction of Grade 3 or higher in the 2-year trastuzumab treatment arm (20.4%) compared with the one-year trastuzumab treatment arm (16.3%).
The safety data from Studies 1 and 2 were obtained from 3655 patients, of whom 2000 received trastuzumab; the median treatment duration was 51 weeks. The median age was 49 years (range: 24 to 80); 84% of patients were White, 7% Black, 4% Hispanic, and 3% Asian.
In Study 1, only Grade 3 to 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 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab 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 to 5 non-hematologic toxicities, selected Grade 2 to 5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, sensory neuropathy) and Grade 1 to 5 cardiac toxicities occurring during chemotherapy and/or trastuzumab treatment. The following non-cardiac adverse reactions of Grade 2 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab 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 trastuzumab 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 incidence of CHF in the TCH arm.
Metastatic Breast Cancer Studies: The data as follows reflect exposure to trastuzumab in one randomized, open-label study, Study 5, of 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 12 are based on Studies 5 and 6.
Among the 464 patients treated in Study 5, the median age was 52 years (range: 25 to 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 trastuzumab followed by 2 mg/kg weekly. The percentages of patients who received trastuzumab 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 to 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 trastuzumab followed by 2 mg/kg weekly. The percentages of patients who received trastuzumab treatment for ≤6 months and ≤12 months were 31% and 16%, respectively. (See Table 12.)

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Metastatic Gastric Cancer: The data as follows are based on the exposure of 294 patients to trastuzumab in combination with a fluoropyrimidine (capecitabine or 5-FU) and cisplatin (Study 7). In the trastuzumab plus chemotherapy arm, the initial dose of trastuzumab 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 to 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 trastuzumab treatment was 21 weeks; median number of trastuzumab infusions administered was eight. (See Table 13.)

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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.
Cardiomyopathy: 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 trastuzumab 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 trastuzumab 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 trastuzumab therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving trastuzumab and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients receiving one-year trastuzumab monotherapy compared to observation in Study 3 (see Table 14, Figures 5 and 6). 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. (See Table 14 and Figures 5, 6 and 7.)

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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 Association classification system (I-IV, where IV is the most severe level of cardiac failure). In the metastatic breast cancer trials, the probability of cardiac dysfunction was highest in patients who received trastuzumab concurrently with anthracyclines.
In Study 7, 5.0% of patients in the trastuzumab plus chemotherapy arm compared to 1.1% of patients in the chemotherapy alone arm had LVEF value below 50% with a ≥ 10% absolute decrease in LVEF from pretreatment values.
Infusion Reactions: During the first infusion with trastuzumab, 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 trastuzumab infusion); permanent discontinuation of trastuzumab 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 trastuzumab 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.
Anemia: In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [Study 5]), of selected NCI-CTC Grade 2 to 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 trastuzumab and chemotherapy compared with those receiving chemotherapy alone. Following the administration of trastuzumab as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was < 1%. In Study 7 (metastatic gastric cancer), on the trastuzumab 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%.
Neutropenia: In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4 to 5 neutropenia (1.7% vs. 0.8% [Study 2]) and of selected Grade 2 to 5 neutropenia (6.4% vs. 4.3% [Study 1]) were increased in patients receiving trastuzumab 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 trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In Study 7 (metastatic gastric cancer) on the trastuzumab 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 neutropenia 5.1% compared to 2.8%.
Infection: The overall incidences of infection (46% vs. 30% [Study 5]), of selected NCI-CTC Grade 2 to 5 infection/febrile neutropenia (24.3% vs. 13.4% [Study 1]) and of selected Grade 3 to 5 infection/febrile neutropenia (2.9% vs. 1.4%) [Study 2]) were higher in patients receiving trastuzumab 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 trastuzumab to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC Grade 3 to 4 infections 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 trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone.
Pulmonary Toxicity: Adjuvant Breast Cancer among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC Grade 2 to 5 pulmonary toxicity (14.3% vs. 5.4% [Study 1]) and of selected NCI-CTC Grade 3 to 5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 0.9% [Study 2]) was higher in patients receiving trastuzumab and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2 to 5: 11.8% vs. 4.6% [Study 1]; NCI-CTC Grade 2 to 5: 2.4% vs. 0.2% [Study 2]).
Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving trastuzumab compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving trastuzumab, 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 trastuzumab 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 trastuzumab 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, noncardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see Precautions.
Thrombosis/Embolism: In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving trastuzumab 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]).
Diarrhea: Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2 to 5 diarrhea (6.7% vs. 5.4% [Study 1]) and of NCI-CTC Grade 3 to 5 diarrhea (2.2% vs. 0% [Study 2]), and of Grade 1 to 4 diarrhea (7% vs. 1% [Study 3; one-year trastuzumab treatment at 12.6 months median duration of follow-up]) were higher in patients receiving trastuzumab as compared to controls. In Study 4, the incidence of Grade 3 to 4 diarrhea was higher [5.7% ACTH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1 to 4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving trastuzumab. Of patients receiving trastuzumab as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving trastuzumab in combination with chemotherapy for treatment of metastatic breast cancer.
Renal Toxicity: In Study 7 (metastatic gastric cancer) on the trastuzumab-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 trastuzumab-containing arm compared to 1.7% on the chemotherapy only arm. Treatment discontinuation for renal insufficiency/failure was 2% on the trastuzumab-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 trastuzumab 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. The detection 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 in the studies described in Pharmacology: Pharmacodynamics: Clinical Studies under Actions with the incidence of antibodies in other studies or to other trastuzumab products may be misleading. Among 903 women with metastatic breast cancer, human anti-human antibody (HAHA) to trastuzumab 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.
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