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ABRAXANE® for Injectable Suspension
(paclitaxel) Protein-bound Particles for Injectable Suspension
WARNING
NEUTROPENIA
Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm³. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
Note: An albumin form of paclitaxel may substantially affect a drug's functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.
ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is paclitaxel formulated as albumin-bound nanoparticles with a mean particle size of approximately 130 nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous state. ABRAXANE is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single-use vial contains 100 mg of paclitaxel (bound to human albumin) and approximately 900 mg of human albumin (containing sodium caprylate and sodium acetyltryptophanate). Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel formulated as albumin-bound particles. ABRAXANE is free of solvents.
The active agent in ABRAXANE is paclitaxel, a microtubule inhibitor. The chemical name for paclitaxel is 5β,20-Epoxy- 1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.
Paclitaxel has the following structural formula:
 |
Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and a molecular weight of 853.91. It is highly lipophilic, insoluble in water, and melts at approximately 216°C to 217°C.
ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.
ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.
ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.
After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m² administered intravenously over 30 minutes every 3 weeks.
The recommended dose of ABRAXANE is 100 mg/m² administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 day cycle immediately after ABRAXANE [see Clinical Studies].
The recommended dose of ABRAXANE is 125 mg/m² administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies].
For patients with mild hepatic impairment (total bilirubin greater than ULN and less than or equal to 1.5 x ULN and aspartate aminotransferase [AST] less than or equal to 10 x ULN), no dose adjustments are required, regardless of indication.
Do not administer ABRAXANE to patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment.
Do not administer ABRAXANE to patients with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN regardless of indication as these patients have not been studied.
Recommendations for dosage adjustment for the first course of therapy are shown in Table 1.
Table 1: Recommendations for Starting Dose in Patients
with Hepatic Impairment
| SGOT (AST) Levels | Bilirubin Levels | ABRAXANE Dosea | ||||
| MBC | NSCLCc | Pancreaticc Adenocarcinoma | ||||
| Mild | < 10x ULN | AND | > ULN to ≤ 1. 5 x ULN | 260 mg/m² | 100 mg/m² | 125 mg/m² |
| Moderate | < 10x ULN | AND | > 1.5 to ≤ 3 x ULN | 200 mg/m² b | 80 mg/m² b | not recommended |
| Severe | < 10x ULN | AND | > 3 to ≤ 5 x ULN | 200 mg/m² b | 80 mg/m² b | not recommended |
| > 10x ULN | OR | > 5 x ULN | not recommended | not recommended | not recommended | |
| MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell
Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 260 mg/m² for patients with metastatic breast cancer or 100 mg/m² for patients with non-small cell lung cancer in subsequent courses should be considered if the patient tolerates the reduced dose for two cycles. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer. |
||||||
Patients who experience severe neutropenia (neutrophils less than 500 cells/mm³ for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m² for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m². For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS Â and ADVERSE REACTIONS].
Table 2: Permanent Dose Reductions for Hematologic and
Neurologic Adverse Drug Reactions in NSCLC
| Adverse Drug Reaction | Occurrence | Weekly ABRAXANE Dose (mg/m²) | Every 3-Week Carboplatin Dose (AUC mg«min/mL) |
| Neutropenic Fever (ANC less than 500/mm³ with fever > 38°C) OR Delay of next cycle by more than 7 days for ANC less than 1500/mm³ OR ANC less than 500/mm³ for more than 7 days | First | 75 | 4.5 |
| Second | 50 | 3 | |
| Third | Discontinue Treatment | ||
| Platelet count less than 50,000/mm³ | First | 75 | 4.5 |
| Second | Discontinue Treatment | ||
| Severe sensory Neuropathy - Grade 3 or 4 | First | 75 | 4.5 |
| Second | 50 | 3 | |
| Third | Discontinue Treatment | ||
Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3.
Table 3: Dose Level Reductions for Patients with
Adenocarcinoma of the Pancreas
| Dose Level | ABRAXANE (mg/m²) | Gemcitabine (mg/m²) |
| Full dose | 125 | 1000 |
| 1st dose reduction | 100 | 800 |
| 2nd dose reduction | 75 | 600 |
| If additional dose reduction required | Discontinue | Discontinue |
Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4.
Table 4: Dose Recommendation and Modifications for
Neutropenia and/or Thrombocytopenia
| Cycle Day | ANC (cells/mm³) | Platelet count (cells/mm³) | ABRAXANE / Gemcitabine | |
| Day 1 | < 1500 | OR | < 100,000 | Delay doses until recovery |
| Day 8 | 500 to < 1000 | OR | 50,000 to < 75,000 | Reduce 1 dose level |
| < 500 | OR | < 50,000 | Withhold doses | |
| Day 15: If Day 8 doses were reduced or given without modification: | ||||
| 500 to < 1000 | OR | 50,000 to < 75,000 | Reduce 1 dose level from Day 8 | |
| < 500 | OR | < 50,000 | Withhold doses | |
| Day 15: If Day 8 doses were withheld: | ||||
| ≥ 1000 | OR | ≥ 75,000 | Reduce 1 dose level from Day 1 | |
| 500 to < 1000 | OR | 50,000 to < 75,000 | Reduce 2 dose levels from Day 1 | |
| < 500 | OR | < 50,000 | Withhold doses | |
| ANC = Absolute Neutrophil Count | ||||
Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5.
Table 5: Dose Modifications for Other Adverse Drug
Reactions in Patients with Adenocarcinoma of the Pancreas
| Adverse Drug Reaction | ABRAXANE | Gemcitabine |
| Febrile Neutropenia: Grade 3 or 4 | Withhold until fever resolves and ANC ≥ 1500; resume at next lower dose level | |
| Peripheral Neuropathy: Grade 3 or 4 | Withhold until improves to ≤ Grade 1; resume at next lower dose level | No dose reduction |
| Cutaneous Toxicity: Grade 2 or 3 | Reduce to next lower dose level; discontinue treatment if toxicity persists | |
| Gastrointestinal Toxicity: Grade 3 mucositis or diarrhea | Withhold until improves to ≤ Grade 1; resume at next lower dose level | |
ABRAXANE is a cytotoxic drug and, as with other potentially toxic paclitaxel compounds, caution should be exercised in handling ABRAXANE. The use of gloves is recommended. If ABRAXANE (lyophilized cake or reconstituted suspension) contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure to paclitaxel, events may include tingling, burning and redness. If ABRAXANE contacts mucous membranes, the membranes should be flushed thoroughly with water.
Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Limiting the infusion of ABRAXANE to 30 minutes, as directed, reduces the likelihood of infusion-related reactions [see ADVERSE REACTIONS].
Premedication to prevent hypersensitivity reactions is generally not needed prior to the administration of ABRAXANE. Premedication may be needed in patients who have had prior hypersensitivity reactions to ABRAXANE. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug [see WARNINGS AND PRECAUTIONS].
ABRAXANE is supplied as a sterile lyophilized powder for reconstitution before use. AVOID ERRORS, READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION.
1. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP.
2. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL.
 |
3. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized cake as this will result in foaming.
4. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized cake/powder.
5. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any cake/powder occurs. Avoid generation of foam.
6. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides.
Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel.
The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion.
Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient and slowly withdraw the dosing volume of the reconstituted suspension from the vial(s) into a syringe: Dosing volume (mL)=Total dose (mg)/5 (mg/mL).
Inject the appropriate amount of reconstituted ABRAXANE into an empty, sterile intravenous bag [plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type intravenous bag]. The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer ABRAXANE infusions. The use of medical devices containing silicone oil as a lubricant (ie, syringes and intravenous bags) to reconstitute and administer ABRAXANE may result in the formation of proteinaceous strands.
Visually inspect the reconstituted ABRAXANE suspension in the intravenous bag prior to administration. Discard the reconstituted suspension if proteinaceous strands, particulate matter or discoloration are observed.
Unopened vials of ABRAXANE are stable until the date indicated on the package when stored between 20°C to 25°C (68°F to 77°F) in the original package. Neither freezing nor refrigeration adversely affects the stability of the product.
Reconstituted ABRAXANE in the vial should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 24 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original carton to protect it from bright light. Discard any unused portion.
The suspension for infusion when prepared as recommended in an infusion bag should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) and protected from bright light for a maximum of 24 hours.
The total combined refrigerated storage time of reconstituted ABRAXANE in the vial and in the infusion bag is 24 hours. This may be followed by storage in the infusion bag at ambient temperature (approximately 25°C) and lighting conditions for a maximum of 4 hours.
Discard any unused portion.
For injectable suspension: lyophilized powder containing 100 mg of paclitaxel formulated as albumin-bound particles in single-use vial for reconstitution.
Product No.: 103450
NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.
Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light.
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see REFERENCES]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
REFERENCES
1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.
Manufactured for: Celgene Corporation, Summit, NJ 07901. Revised: July 2015
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 [see Clinical Trials Experience in Metastatic Breast Cancer below].
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 [see Clinical Trials Experience in Non-Small Cell Lung Cancer below]. 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%).
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 | ||
| ABRAXANE260 mg/m² over 30 min (n=229) |
Paclitaxel Injection175 mg/m² over 3 hb (n=225) |
|
| Bone Marrow | ||
| Neutropenia | ||
| < 2.0 x 109/L | 80 | 82 |
| < 0.5 x 109/L | 9 | 22 |
| Thrombocytopenia | ||
| < 100 x 109/L | 2 | 3 |
| < 50 x 109/L | < 1 | < 1 |
| Anemia | ||
| < 11 g/dL | 33 | 25 |
| < 8 g/dL | 1 | < 1 |
| Infections | 24 | 20 |
| Febrile Neutropenia | 2 | 1 |
| Neutropenic Sepsis | < 1 | < 1 |
| Bleeding | 2 | 2 |
| Hypersensitivity Reactionc | ||
| All | 4 | 12 |
| Severea | 0 | 2 |
| Cardiovascular | ||
| Vital Sign Changes During Administration | ||
| Bradycardia | < 1 | < 1 |
| Hypotension | 5 | 5 |
| Severe Cardiovascular Eventsd | 3 | 4 |
| Abnormal ECG | ||
| All Patients | 60 | 52 |
| Patients with Normal Baseline | 35 | 30 |
| Respiratory | ||
| Cough | 7 | 6 |
| Dyspnea | 12 | 9 |
| Sensory Neuropathy | ||
| Any Symptoms | 71 | 56 |
| Severe Symptomsd | 10 | 2 |
| Myalgia / Arthralgia | ||
| Any Symptoms | 44 | 49 |
| Severe Symptomsd | 8 | 4 |
| Asthenia | ||
| Any Symptoms | 47 | 39 |
| Severe Symptomsd | 8 | 3 |
| Fluid Retention/Edema | ||
| Any Symptoms | 10 | 8 |
| Severe Symptomsd | 0 | < 1 |
| Gastrointestinal | ||
| Nausea | ||
| Any Symptoms | 30 | 22 |
| Severe Symptomsd | 3 | < 1 |
| Vomiting | ||
| Any Symptoms | 18 | 10 |
| Severe Symptomsd | 4 | 1 |
| Diarrhea | ||
| Any Symptoms | 27 | 15 |
| Severe Symptomsd | < 1 | 1 |
| Mucositis | ||
| Any Symptoms | 7 | 6 |
| Severe Symptomsd | < 1 | 0 |
| Alopecia | 90 | 94 |
| Hepatic (Patients with Normal Baseline) | ||
| Bilirubin Elevations | 7 | 7 |
| Alkaline Phosphatase Elevations | 36 | 31 |
| AST (SGOT) Elevations | 39 | 32 |
| Injection Site Reaction | < 1 | 1 |
| a Based on worst grade by NCI Common
Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity. |
||
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.
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.
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.
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 of 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 | |||
| Grades 1-4 (%) | Grade 3-4 (%) | Grades 1-4 (%) | Grade 3-4 (%) | |
| Anemia1,2 | 98 | 28 | 91 | 7 |
| Neutropenia1,3 | 85 | 47 | 83 | 58 |
| Thrombocytopenia1,3 | 68 | 18 | 55 | 9 |
| 1 508 patients assessed in
ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 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 tissue disorders | Arthralgia | 13 | < 1 | 25 | 2 |
| Myalgia | 10 | < 1 | 19 | 2 | |
| a Peripheral 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.
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 1- 4 ( ≥ 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 | |||
| Grades 1-4 (%) | Grade 3-4 (%) | Grades 1-4 (%) | Grade 3-4 (%) | |
| Neutropeniaa,b | 73 | 38 | 58 | 27 |
| Thrombocytopeniab,c | 74 | 13 | 70 | 9 |
| a 405 patients assessed in
ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil 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 (N=421) |
Gemcitabine (N=402) |
||
| 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 |
| a Peripheral neuropathy is defined by the
MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococcal. |
|||||
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/gemcitabine 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.
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, left ventricular dysfunction, and atrioventricular block 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.
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.
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.
The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.
Included as part of the PRECAUTIONS section.
Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer.
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm³. In the case of severe neutropenia ( < 500 cells/mm³ for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC.
In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level > 1,500 cells/mm³ and platelets recover to a level > 100,000 cells/mm³.
In patients with NSCLC, resume treatment if recommended (see DOSAGE AND ADMINISTRATION, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm³ and platelet count of at least 100,000 cells/mm³ on Day 1 or to an ANC of at least 500 cells/mm³ and platelet count of at least 50,000 cells/mm³ on Days 8 or 15 of the cycle [see DOSAGE AND ADMINISTRATION].
In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm³ or platelets are less than 50,000 cells/mm³ and delay initiation of the next cycle if the ANC is less than 1500 cells/mm³ or platelet count is less than 100,000 cells/mm³ on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see DOSAGE AND ADMINISTRATION].
Sensory neuropathy is dose- and schedule-dependent [see ADVERSE REACTIONS]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see DOSAGE AND ADMINISTRATION].
Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see DOSAGE AND ADMINISTRATION].
Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine.
Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug.
Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression; such patients should be closely monitored for development of profound myelosuppression. ABRAXANE is not recommended in patients who have total bilirubin > 5 x ULN or AST > 10 x ULN. In addition, ABRAXANE is not recommended in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and AST ≤ 10 x ULN). The starting dose should be reduced for patients with moderate or severe hepatic impairment [see DOSAGE AND ADMINISTRATION, Use in Specific Populations and CLINICAL PHARMACOLOGY].
ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.
There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations].
Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology].
See FDA-approved patient labeling
The carcinogenic potential of ABRAXANE has not been studied.
Paclitaxel was clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). ABRAXANE was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.
Administration of paclitaxel formulated as albumin-bound particles to male rats at 42 mg/m² on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a body surface area basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A low incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12 mg/m²/week in this study (approximately 1 to 5% of the daily maximum recommended human exposure on a mg/m² basis). Testicular atrophy/degeneration was observed in single-dose toxicology studies in rodents administered paclitaxel formulated as albumin-bound particles at doses lower than the recommended human dose; doses were 54 mg/m² in rodents and 175 mg/m² in dogs.
Pregnancy Category D [see WARNINGS AND PRECAUTIONS].
There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE.
Administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m² (approximately 2% of the daily maximum recommended human dose on a mg/m² basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m² (approximately 1% of the daily maximum recommended human dose on a mg/m² basis).
It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.
Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE.
A subsequent pooled analysis was conducted in 981 patients receiving ABRAXANE monotherapy for metastatic breast cancer, of which 15% were 65 years of age or older and 2% were 75 years of age or older. A higher incidence of epistaxis, diarrhea, dehydration, fatigue and peripheral edema was found in patients 65 years of age or older.
Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old.
Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients.
The exposure to paclitaxel may be higher in patients with hepatic impairment than in patients with normal hepatic function. Reduce  ABRAXANE starting dose in patients with moderate to severe hepatic impairment. Do not administer ABRAXANE to patients with total bilirubin > 5 x ULN or AST > 10 x ULN [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Do not administer to patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment [see DOSAGE AND ADMINISTRATION].
Adjustment of the starting ABRAXANE dose is not required for patients with mild to moderate renal impairment (estimated creatinine clearance ≥ 30 to < 90 mL/min) [see CLINICAL PHARMACOLOGY]. There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance < 30 mL/min).
There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.
ABRAXANE is a microtubule inhibitor that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
The pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of ABRAXANE at dose levels of 80 to 375 mg/m² were determined in clinical studies. Dose levels of mg/m² refer to mg of paclitaxel in ABRAXANE. Following intravenous administration of ABRAXANE, paclitaxel plasma concentrations declined in a biphasic manner, the initial rapid decline representing distribution to the peripheral compartment and the slower second phase representing drug elimination.
The drug exposure (AUCs) was dose proportional over 80 to 300 mg/m² and the pharmacokinetics of paclitaxel for ABRAXANE were independent of the duration of intravenous administration.
The pharmacokinetic data of 260 mg/m² ABRAXANE administered over a 30-minute infusion was compared to the pharmacokinetics of 175 mg/m² paclitaxel injection over a 3-hour infusion. Clearance was larger (43%) and the volume of distribution was higher (53%) for ABRAXANE than for paclitaxel injection. There were no differences in terminal half-lives.
Following ABRAXANE administration to patients with solid tumors, paclitaxel is evenly distributed into blood cells and plasma and is highly bound to plasma proteins (94%). In a within-patient comparison study, the fraction of unbound paclitaxel in plasma was significantly higher with ABRAXANE (6.2%) than with solvent-based paclitaxel (2.3%). This contributes to significantly higher exposure to unbound paclitaxel with ABRAXANE compared with solvent-based paclitaxel, when the total exposure is comparable. In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 μg/mL, indicated that the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel. The total volume of distribution is approximately 1741 L; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel.
In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α- hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3'-p-hydroxypaclitaxel and 6α, 3'-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4 [see DRUG INTERACTIONS].
At the clinical dose range of 80 to 300 mg/m², the mean total clearance of paclitaxel ranges from 13 to 30 L/h/m², and the mean terminal half-life ranges from 13 to 27 hours.
After a 30-minute infusion of 260 mg/m² doses of ABRAXANE, the mean values for cumulative urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1% of the total administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel.
Fecal excretion was approximately 20% of the total dose administered.
The effect of hepatic impairment on the pharmacokinetics of paclitaxel following ABRAXANE administration was studied in patients with advanced solid tumors. The results showed that mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 x ULN, AST ≤ 10 x ULN, n=8) had no clinically important effect on pharmacokinetics of paclitaxel. Patients with moderate (total bilirubin > 1.5 to ≤ 3 x ULN, AST ≤ 10 x ULN, n=7) or severe (total bilirubin > 3 to ≤ 5 x ULN, n=5) hepatic impairment had a 22% to 26% decrease in the maximum elimination rate of paclitaxel and approximately 20% increase in mean paclitaxel AUC compared with patients with normal hepatic function (total bilirubin ≤ ULN, AST ≤ ULN, n=130). [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].
Elimination of paclitaxel shows an inverse correlation with total bilirubin and a positive correlation with serum albumin. Pharmacokinetic/pharmacodynamic modeling indicates that there is no correlation between hepatic function (as indicated by the baseline albumin or total bilirubin level) and neutropenia after adjusting for ABRAXANE exposure. Pharmacokinetic data are not available for patients with total bilirubin > 5 x ULN or for patients with metastatic adenocarcinoma of the pancreas [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].
The effect of pre-existing mild (creatinine clearance ≥ 60 to < 90 mL/min, n=61) or moderate (creatinine clearance ≥ 30 to < 60 mL/min, n=23) renal impairment on the pharmacokinetics of paclitaxel following ABRAXANE administration was studied in patients with advanced solid tumors. Mild to moderate renal impairment had no clinically important effect on the maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel [see Use In Specific Populations].
Population pharmacokinetic analyses for ABRAXANE show that body weight (40 to 143 kg), body surface area (1.3 to 2.4 m²), gender, race (Asian vs. White), age (24 to 85 years) and type of solid tumors do not have a clinically important effect on the maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel.
Administration of carboplatin immediately after the completion of the ABRAXANE infusion to patients with NSCLC did not cause clinically meaningful changes in paclitaxel exposure. The observed mean AUCinf of free carboplatin was approximately 23% higher than the targeted value (6 min*mg/mL), but its mean half-life and clearance were consistent with those reported in the absence of paclitaxel.
Pharmacokinetic interactions between ABRAXANE and gemcitabine have not been studied in humans.
Data from 106 patients accrued in two single arm open label studies and from 460 patients enrolled in a randomized comparative study were available to support the use of ABRAXANE in metastatic breast cancer.
In one study, ABRAXANE was administered as a 30-minute infusion at a dose of 175 mg/m² to 43 patients with metastatic breast cancer. The second trial utilized a dose of 300 mg/m² as a 30-minute infusion in 63 patients with metastatic breast cancer. Cycles were administered at 3-week intervals. Objective responses were observed in both studies.
This multicenter trial was conducted in 460 patients with metastatic breast cancer. Patients were randomized to receive ABRAXANE at a dose of 260 mg/m² given as a 30-minute infusion, or paclitaxel injection at 175 mg/m² given as a 3-hour infusion. Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant setting, 40% in the metastatic setting and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study drug as second or greater than second-line therapy. Seventy-seven percent of the patients had been previously exposed to anthracyclines.
In this trial, patients in the ABRAXANE treatment arm had a statistically significantly higher reconciled target lesion response rate (the trial primary endpoint) of 21.5% (95% CI: 16.2% to 26.7%), compared to 11.1% (95% CI: 6.9% to 15.1%) for patients in the paclitaxel injection treatment arm. See Table 11. There was no statistically significant difference in overall survival between the two study arms.
Table 11: Efficacy Results
from Randomized Metastatic Breast Cancer Trial
| ABRAXANE 260 mg/m² | Paclitaxel Injection 175 mg/m² | ||
| Reconciled Target Lesion Response Rate (primary endpoint)a | |||
| All randomized patients | Response Rate [95% CI] | 50/233 (21.5%) [16.19% - 26.73%] |
25/227 (11.1%) [6.94% - 15.09%] |
| p-valueb | 0.003 | ||
| Patients who had failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapyc | Response Rate [95% CI] | 20/129 (15.5%) [9.26% - 21.75%] |
12/143 (8.4%) [3.85% - 12.94%] |
| a Reconciled Target Lesion Response Rate
(TLRR) was the prospectively defined protocol specific endpoint, based on independent
radiologic assessment of tumor responses reconciled with investigator responses
(which also included clinical information) for the first 6 cycles of therapy.
The reconciled TLRR was lower than the investigator Reported Response Rates,
which are based on all cycles of therapy. b From Cochran-Mantel-Haenszel test stratified by 1st line vs. > 1st line therapy. c Prior therapy included an anthracycline unless clinically contraindicated. |
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A multicenter, randomized, open-label study was conducted in 1052 chemonaive patients with Stage IIIb/IV non-small cell lung cancer to compare ABRAXANE in combination with carboplatin to paclitaxel injection in combination with carboplatin as first-line treatment in patients with advanced non-small cell lung cancer. 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. Treatment was administered until disease progression or development of an unacceptable toxicity. The major efficacy outcome measure was overall response rate as determined by a central independent review committee using RECIST guidelines (Version 1.0).
In the intent-to-treat (all-randomized) population, 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, and 73% were current or former smokers. Patients received a median of 6 cycles of treatment in both study arms.
Patients in the ABRAXANE/carboplatin arm had a statistically significantly higher overall response rate compared to patients in the paclitaxel injection/carboplatin arm [(33% versus 25%) see Table 12]. There was no statistically significant difference in overall survival between the two study arms.
Table 12: Efficacy Results from Randomized Non-Small
Cell Lung Cancer Trial (Intent-to-Treat Population)
| ABRAXANE (100 mg/m² weekly) + carboplatin (N=521) |
Paclitaxel Injection (200 mg/m² every 3 weeks) + carboplatin (N=531) |
|
| Overall Response Rate (ORR) | ||
| Confirmed complete or partial overall response, n (%) | 170 (33%) | 132 (25%) |
| 95% CI | 28.6, 36.7 | 21.2, 28.5 |
| P-value (Chi-Square test) | 0.005 | |
| Median DoR in months (95% CI) | 6.9 (5.6, 8.0) | 6.0 (5.6, 7.1) |
| Overall Response Rate by Histology | ||
| Carcinoma/Adenocarcinoma | 66/254 (26%) | 71/264 (27%) |
| Squamous Cell Carcinoma | 94/229 (41%) | 54/221 (24%) |
| Large Cell Carcinoma | 3/9 (33%) | 2/13 (15%) |
| Other | 7/29 (24%) | 5/33 (15%) |
| CI = confidence interval; DoR= Duration of response | ||
A multicenter, multinational, randomized, open-label study was conducted in 861 patients comparing ABRAXANE plus gemcitabine versus gemcitabine monotherapy as first-line treatment of metastatic adenocarcinoma of the pancreas. Key eligibility criteria were Karnofsky Performance Status (KPS) ≥ 70, normal bilirubin level, transaminase levels ≤ 2.5 times the upper limit of normal (ULN) or ≤ 5 times the ULN for patients with liver metastasis, no prior cytotoxic chemotherapy in the adjuvant setting or for metastatic disease, no ongoing active infection requiring systemic therapy, and no history of interstitial lung disease. Patients with rapid decline in KPS ( ≥ 10%) or serum albumin ( ≥ 20%) during the 14 day screening period prior to study randomization were ineligible.
A total of 861 patients were randomized (1:1) to the ABRAXANE/gemcitabine arm (N=431) or to the gemcitabine arm (N=430). Randomization was stratified by geographic region (Australia, Western Europe, Eastern Europe, or North America), KPS (70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no). Patients randomized to ABRAXANE/gemcitabine received ABRAXANE 125 mg/m² as an intravenous infusion over 30-40 minutes followed by gemcitabine 1000 mg/m² as an intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-day cycle. Patients randomized to gemcitabine received 1000 mg/m² as an intravenous infusion over 30-40 minutes weekly for 7 weeks followed by a 1-week rest period in Cycle 1 then as 1000 mg/m² on Days 1, 8 and 15 of each subsequent 28-day cycle. Patients in both arms received treatment until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall survival (OS). Additional outcome measures were progression-free survival (PFS) and overall response rate (ORR), both assessed by independent, central, blinded radiological review using RECIST (version 1.0).
In the intent to treat (all randomized) population, the median age was 63 years (range 27-88 years) with 42% ≥ 65 years of age; 58% were men; 93% were White and KPS was 90-100 in 60%. Disease characteristics included 46% of patients with 3 or more metastatic sites; 84% of patients had liver metastasis; and the location of the primary pancreatic lesion was in the head of pancreas (43%), body (31%), or tail (25%).
Results for overall survival, progression-free survival, and overall response rate are shown in Table 13.
Table 13: Efficacy Results from Randomized Study in
Patients with Adenocarcinoma of the Pancreas (ITT Population)
| ABRAXANE(125 mg/m²) and gemcitabine (N = 431) |
Gemcitabine (N = 430) |
|
| Overall Survival | ||
| Number of deaths, n (%) | 333 (77) | 359 (83) |
| Median Overall Survival (months) | 8.5 | 6.7 |
| 95% CI | 7.9, 9.5 | 6.0, 7.2 |
| HR (95% CI) a | 0.72 (0.62, 0.83) | |
| P-valueb | < 0.0001 | |
| Progression-free Survivalc | ||
| Death or progression, n (%) | 277 (64) | 265 (62) |
| Median Progression-free Survival (months) | 5.5 | 3.7 |
| 95% CI | 4.5, 5.9 | 3.6, 4.0 |
| HR (95% CI) a | 0.69 (0.58, 0.82) | |
| P-valueb | < 0.0001 | |
| Overall Response Ratec | ||
| Confirmed complete or partial overall response, n (%) | 99 (23) | 31 (7) |
| 95% CI | 19.1, 27.2 | 5.0, 10.1 |
| P-value d | < 0.0001 | |
| CI = confidence interval, HR= hazard ratio of ABRAXANE
plus gemcitabine / gemcitabine, ITT = intent-to-treat population. a Stratified Cox proportional hazard model. b Stratified log-rank test stratified by geographic region (North America versus Others), Karnofsky performance score (70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no). c Based on Independent Radiological Reviewer Assessment. d Chi-square test. |
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In exploratory analyses conducted in clinically relevant subgroups with a sufficient number of subjects, the treatment effects on overall survival were similar to that observed in the overall study population.
Figure 1: Kaplan-Meier Curve of Overall Survival
(Intent-to-treat Population)
 |
ABRAXANE®
(ah-BRAKS-ane)
(paclitaxel) Protein-bound Particles for Injectable Suspension
Read this Patient Information before you start receiving ABRAXANE and before each infusion. This information does not take the place of talking with your doctor about your medical condition or your treatment.
What is ABRAXANE?
ABRAXANE is a prescription medicine used to treat:
It is not known if ABRAXANE is safe or effective in children.
Who should not receive ABRAXANE?
Do not receive ABRAXANE if:
What should I tell my doctor before receiving ABRAXANE?
Before you receive ABRAXANE, tell your doctor if you:
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list to show your doctor and pharmacist when you get a new medicine.
How will I receive ABRAXANE?
What are the possible side effects of ABRAXANE?
ABRAXANE may cause serious side effects, including:
The most common side effects of ABRAXANE include:
These are not all the possible side effects of ABRAXANE. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of ABRAXANE.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.
This Patient Information leaflet summarizes the important information about ABRAXANE. If you would like more information, talk to your doctor. You can ask your doctor or pharmacist for information about ABRAXANE that is written for health professionals.
For more information, call 1-888-423-5436.
What are the ingredients in ABRAXANE?
Active ingredient: paclitaxel (bound to human albumin).
Other ingredient: human albumin (containing sodium caprylate and sodium acetyltryptophanate).
