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 most common adverse reactions ( ≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea.
The most common adverse reactions ( ≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue. The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%).
In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies], the most common ( ≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%).
Clinical Trials Experience in Metastatic Breast Cancer
Table 6 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.
Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule
|Percent of Patients|
|ABRAXANE 260 mg/m² over 30 min
|Paclitaxel Injection 175 mg/m² over 3 hb
|< 2.0 x 109/L||80||82|
|< 0.5 x 109/L||9||22|
|< 100 x 109/L||2||3|
|< 50 x 109/L||< 1||< 1|
|< 11 g/dL||33||25|
|< 8 g/dL||1||< 1|
|Neutropenic Sepsis||< 1||< 1|
|Vital Sign Changes During Administration|
|Bradycardia||< 1||< 1|
|Severe Cardiovascular Eventsd||3||4|
|Patients with Normal Baseline||35||30|
|Myalgia / Arthralgia|
|Severe Symptomsd||0||< 1|
|Severe Symptomsd||3||< 1|
|Severe Symptomsd||< 1||1|
|Severe Symptomsd||< 1||0|
|Hepatic (Patients with Normal Baseline)|
|Alkaline Phosphatase Elevations||36||31|
|AST (SGOT) Elevations||39||32|
|Injection Site Reaction||< 1||1|
|aBased on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2.
bPaclitaxel injection patients received premedication.
cIncludes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing.
dSevere events are defined as at least grade 3 toxicity.
Adverse Event Experiences by Body System
Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm³ (Grade 4) in 9% of the patients treated with a dose of 260 mg/m² compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m² . Pancytopenia has been observed in clinical trials.
Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.
Hypersensitivity Reactions (HSRs)
Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all < 1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.
Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in < 1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation.
Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported.
Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia.
Dyspnea (12%), cough (7%), and pneumothorax ( < 1%) were reported after treatment with ABRAXANE.
The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy.
No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial.
Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m²). These effects generally have been reversible.
The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days.
Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.
Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities.
Other Clinical Events
Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported.
Clinical Trials Experience in Non-Small Cell Lung Cancer
Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m² on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m², following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose- and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment.
The following common ( ≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatintreated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group).
Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.
Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups
|ABRAXANE (100 mg/m² weekly) plus carboplatin||Paclitaxel Injection (200 mg/m² every 3 weeks) plus carboplatin|
|1508 patients assessed in ABRAXANE/carboplatin-treated group
2514 patients assessed in paclitaxel injection/carboplatin-treated group
3513 patients assessed in paclitaxel injection/carboplatin-treated group
Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.
Table 8: Selected Adverse Reactions with a Difference of ≥ 5% for All Grade Toxicity or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups
|System Organ Class||MedDRA v 12.1 Preferred Term||ABRAXANE (100 mg/m² weekly) + carboplatin (N=514)||Paclitaxel Injection (200 mg/m² every 3 weeks) + carboplatin (N=524)|
|Grade 1-4 Toxicity
|Grade 3-4 Toxicity
|Grades 1-4 Toxicity
|Grade 3-4 Toxicity
|Nervous system disorders||Peripheral neuropathya||48||3||64||12|
|General disorders and administration site conditions||Edema peripheral||10||0||4||< 1|
|Respiratory thoracic and mediastinal disorders||Epistaxis||7||0||2||0|
|Musculoskeletal and connective||Arthralgia||13||< 1||25||2|
|tissue disorders||Myalgia||10||< 1||19||2|
|aPeripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).|
For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE.
Clinical Trials Experience in Adenocarcinoma of the Pancreas
Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%.
Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 14 ( ≥ 5%) or for Grade 3-4 ( ≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients.
Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence ( ≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm
|ABRAXANE(125 mg/m²)/ Gemcitabined||Gemcitabine|
|a405 patients assessed in ABRAXANE/gemcitabine-treated group
b388 patients assessed in gemcitabine-treated group
c404 patients assessed in ABRAXANE/gemcitabine-treated group
dNeutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group.
Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group.
Table 10: Selected Adverse Reactions with a Higher Incidence ( ≥ 5% for All Grade Toxicity or ≥ 2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm
|System Organ Class||Adverse Reaction||ABRAXANE (125 mg/m²) and gemcitabine
|All Grades||Grade 3 or Higher||All Grades||Grade 3 or Higher|
|General disorders and administration site conditions||Fatigue||248 (59%)||77 (18%)||183 (46%)||37 (9%)|
|Peripheral edema||194 (46%)||13 (3%)||122 (30%)||12 (3%)|
|Pyrexia||171 (41%)||12 (3%)||114 (28%)||4 (1%)|
|Asthenia||79 (19%)||29 (7%)||54 (13%)||17 (4%)|
|Mucositis||42 (10%)||6 (1%)||16 (4%)||1 ( < 1%)|
|Gastrointestinal disorders||Nausea||228 (54%)||27 (6%)||192 (48%)||14 (3%)|
|Diarrhea||184 (44%)||26 (6%)||95 (24%)||6 (1%)|
|Vomiting||151 (36%)||25 (6%)||113 (28%)||15 (4%)|
|Skin and subcutaneous tissue disorders||Alopecia||212 (50%)||6 (1%)||21 (5%)||0|
|Rash||128 (30%)||8 (2%)||45 (11%)||2 ( < 1%)|
|Nervous system disorders||Peripheral neuropathya||227 (54%)||70 (17%)||51 (13%)||3 (1%)|
|Dysgeusia||68 (16%)||0||33 (8%)||0|
|Headache||60 (14%)||1 ( < 1%)||38 (9%)||1 ( < 1%)|
|Metabolism and nutrition disorders||Decreased appetite||152 (36%)||23 (5%)||104 (26%)||8 (2%)|
|Dehydration||87 (21%)||31 (7%)||45 (11%)||10 (2%)|
|Hypokalemia||52 (12%)||18 (4%)||28 (7%)||6 (1%)|
|Respiratory, thoracic and mediastinal disorders||Cough||72 (17%)||0||30 (7%)||0|
|Epistaxis||64 (15%)||1 ( < 1%)||14 (3%)||1 ( < 1%)|
|Infections and infestations||Urinary tract infections b||47 (11%)||10 (2%)||20 (5%)||1 ( < 1%)|
|Musculoskeletal and connective tissue disorders||Pain in extremity||48 (11%)||3 (1%)||24 (6%)||3 (1%)|
|Arthralgia||47 (11%)||3 (1%)||13 (3%)||1 ( < 1%)|
|Myalgia||44 (10%)||4 (1%)||15 (4%)||0|
|Psychiatric disorders||Depression||51 (12%)||1 ( < 1%)||24 (6%)||0|
|aPeripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope).
bUrinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal.
Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included:
Infections & infestations: oral candidiasis, pneumonia
Vascular disorders: hypertension
Cardiac disorders: tachycardia, congestive cardiac failure
Eye disorders: cystoid macular edema
Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.
Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent.
Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died.
Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations
Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. 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. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE.
Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.
There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.
There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE.
Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus.
Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE.
Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline.
Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.
There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.
Injection Site Reaction
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration.
Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported.
Other Clinical Events
Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.
There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.
No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness.