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Date of Preparation: April 16, 2008 Control No. : 121190
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 14 DOSAGE AND ADMINISTRATION 15 OVERDOSAGE 17 ACTION AND CLINICAL PHARMACOLOGY 17 STORAGE AND STABILITY 19 SPECIAL HANDLING INSTRUCTIONS 20 DOSAGE FORMS, COMPOSITION AND PACKAGING 20
PHARMACEUTICAL INFORMATION 21 CLINICAL TRIALS 22 DETAILED PHARMACOLOGY 26 TOXICOLOGY 26 REFERENCES 29
for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel)
100 mg paclitaxel/vial
| Route of Administration | Dosage Form/Strength | Clinically Relevant Nonmedicinal Ingredients |
| Intravenous infusion | Lyophilized powder, 100 mg paclitaxel per single-use vial | Human albumin |
ABRAXANE(r) for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel) is indicated for: the treatment of metastatic breast cancer. ABRAXANE should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents and in the management of breast cancer. Appropriate management of therapy and complications is only possible when adequate diagnostic and treatment facilities are readily available. No premedication to prevent hypersensitivity reactions is required prior to administration of ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug's functional properties relative to those of drug in solution. Do not substitute with or for other paclitaxel formulations.
Geriatrics (> 65 years of age):
Evidence from clinical studies suggests that use in the geriatric population is not associated with notably more frequent toxicities among elderly patients who received ABRAXANE. A brief discussion can be found in the WARNINGS AND PRECAUTIONS section.
Pediatrics (<= 16 years of age):
The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.
Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing of ingredients, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section. ABRAXANE(r) for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel) should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.
ABRAXANE(r) for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. ABRAXANE therapy should not be administered to patients with metastatic breast cancer 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 Hematologic section below).
An albumin form of paclitaxel may substantially affect a drug's functional properties relative to those of drug in solution.
In the treatment of metastatic breast cancer, ABRAXANE has been evaluated as a single agent only.
General
Albumin (Human): ABRAXANE for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel) contains albumin (human), a derivative of human blood and is a nanoparticle albumin-bound (nab) form of paclitaxel. Based on effective donor screening and product manufacturing processes, it carries an extremely 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.
Carcinogenesis and Mutagenesis
The carcinogenic potential of ABRAXANE has not been studied. Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel injection was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay (see TOXICOLOGY).
Hematologic
Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity. ABRAXANE therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level > 1,500 cells/mm3 and platelets recover to a level > 100,000 cells/mm3. In the case of severe neutropenia (< 500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of therapy is recommended (see DOSAGE AND ADMINISTRATION).
Hepatic/Biliary/Pancreatic
The use of ABRAXANE has not been studied in patients with hepatic dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin > 1.5 mg/dL.
Neurologic
Sensory neuropathy occurs frequently with ABRAXANE. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE (see DOSAGE AND ADMINISTRATION).
Renal
The use of ABRAXANE has not been studied in patients with renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum creatinine > 2 mg/dL.
Sexual Function/Reproduction
Men should be advised to not father a child while receiving treatment with ABRAXANE. Administration of paclitaxel powder for injectable suspension to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a mg/m2 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. Dose levels of mg/m2 refer to mg of paclitaxel in ABRAXANE. 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 has also been observed in single-dose toxicology studies in rodents administered paclitaxel powder for injectable suspension at 54 mg/m2 and dogs administered 175 mg/m2.
Injection Site Reactions
Injection site reactions can occur with ABRAXANE. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.
Special Populations
Pregnant Women/Teratogenic Effects: ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel powder for injectable suspension to rats 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 embryo- and fetotoxicity, 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 was also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women using 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 treatment with ABRAXANE. There was no exposure in pregnancy in the clinical trials.
It is not known whether paclitaxel is excreted in human milk. In rats, following intravenous administration of carbon-14 labeled paclitaxel on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving ABRAXANE therapy.
The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.
Of the 229 patients in the randomized study who received ABRAXANE, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among elderly patients who received ABRAXANE.
Monitoring and Laboratory Tests
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. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level > 1,500 cells/mm3 and platelets recover to a level > 100,000 cells/mm3. In the case of severe neutropenia (< 500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of therapy is recommended (see DOSAGE AND ADMINISTRATION).
Adverse Drug Reaction Overview
In the phase III study, the adverse events which were very common were those expected for paclitaxel and included alopecia (90%), neutropenia (80%), leukopenia (72%), sensory neuropathy (71%), asthenia (47%), arthralgia/myalgia (44%), AST (SGPT) elevations (39%), alkaline phosphatase elevations (36%), abnormal ECG [all patients (60%) and patients with normal baseline (35%)], anemia in patients with normal baseline (20%), nausea (30%), vomiting (18%), infections (24%), diarrhea (27%), dyspnea (12%), and fluid retention/edema (10%). In the phase III study, twenty-seven percent of patients receiving ABRAXANE(r) for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel) on a 3 weekly regimen experienced serious adverse events (SAEs). The events occurring in greater than 10 patients were grade 4 neutropenia (9%), infection (3%), and increased GGT (3%).
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The following table shows the frequency of common important adverse events for the patients who received single-agent ABRAXANE for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel) or Paclitaxel Injection for the treatment of metastatic breast cancer in the randomized comparative phase III trial.
Randomized Study
| ABRAXANE (r) for Injectable Suspension b 260 mg/m 2 /30 minutes n = 229 (%) | Paclitaxel Injection b 175 mg/m 2 /3 hours n = 225 (%) | |
| Bone Marrow | ||
| Neutropenia | 80 | 82 |
| < 2.0 x 10 9 /L | ||
| < 0.5 x 10 9 /L | 9 | 22 |
| Leukopenia | 72 | 79 |
| < 4.0 x 10 9 /L | ||
| < 1.0 x 10 9 /L | 0 | 1 |
| Thrombocytopenia | 2 | 3 |
| < 100 x 10 9 /L | ||
| < 50 x 10 9 /L | < 1 | < 1 |
| Anemia (normal at baseline) | 33 | 25 |
| < 11 g/dL | ||
| < 8 g/dL | 1 | < 1 |
| Infections | 24 | 20 |
| Febrile Neutropenia | 2 | 1 |
| Bleeding | 2 | 2 |
| Hypersensitivity Reaction c | ||
| All | 4 | 12 |
| Severe d | 0 | 2 |
| Cardiovascular | ||
| Vital Sign Changes e | ||
| Bradycardia | < 1 | < 1 |
| Hypotension | 5 | 5 |
| Severe Cardiovascular Events d | 3 | 4 |
| Abnormal ECG | ||
| All patients | 60 | 52 |
| Patients with Normal Baseline | 35 | 30 |
| Respiratory | ||
| Cough | 7 | 6 |
| Dyspnea | 12 | 9 |
Based on worst grade.
Paclitaxel injection patients received premedication.
Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing.
Severe events are defined as at least grade 3 toxicity.
During study drug dosing. Bradycardia defined as pulse < 50 bpm and hypotension defined as diastolic blood pressure < 40 mmHg or decrease in systolic blood pressure of >= 30 mmHg.
Randomized Study (continued)
| ABRAXANE (r) for Injectable Suspension b 260 mg/m 2 /30 minutes n = 229 (%) | Paclitaxel Injection b 175 mg/m 2 /3 hours n = 225 (%) | |
| Sensory Neuropathy | ||
| Any Symptoms | 71 | 56 |
| Severe Symptoms d | 10 | 2 |
| Myalgia/Arthralgia | ||
| Any Symptoms | 44 | 49 |
| Severe Symptoms d | 8 | 4 |
| Fluid Retention/Edema | ||
| Any Symptoms | 10 | 8 |
| Severe Symptoms d | 0 | < 1 |
| Gastrointestinal | ||
| Nausea - Any Symptoms | 30 | 22 |
| Vomiting - Any Symptoms | 18 | 10 |
| Diarrhea - Any Symptoms | 27 | 15 |
| Mucositis - Any Symptoms | 7 | 6 |
| Alopecia | 90 | 94 |
| Asthenia | ||
| Any Symptoms | 47 | 39 |
| Severe Symptoms d | 8 | 3 |
| Hepatic (Patients with Normal Baseline) | ||
| Bilirubin Elevations | 7 | 7 |
| Alkaline Phosphatase Elevations | 36 | 31 |
| AST Elevations | 39 | 32 |
| Injection Site Reaction | < 1 | 1 |
| Skin/Dermatology | ||
| Nail changes | 1 | 0 |
Based on worst grade.
Paclitaxel injection patients received premedication.
Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing.
Severe events are defined as at least grade 3 toxicity.
During study drug dosing. Bradycardia defined as pulse < 50 bpm and hypotension defined as diastolic blood pressure < 40 mmHg or decrease in systolic blood pressure of >= 30 mmHg.
Adverse Event Experiences by Body System: Less Common Clinical Trial Adverse Drug Reactions
Unless otherwise noted, the following discussion refers to the primary safety database of 229 patients with metastatic breast cancer treated with single-agent ABRAXANE in the randomized controlled trial. The frequency and severity of important clinically relevant adverse events for the study are presented above in tabular form. In some instances, rare severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Refer to the following section,
for the adverse events that occurred at a rate of less than 1%.
Hematologic: Neutropenia, the most important hematologic toxicity, was dose-dependent and generally rapidly 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 ABRAXANE at a dose of 260 mg/m2 compared to 22% in patients receiving Cremophor(r)- based paclitaxel injection at a dose of 175 mg/m2. In the randomized metastatic breast cancer study, infectious episodes were reported in 24% of the patients treated with a dose of 260 mg/m2 given as a 30-minute infusion. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Febrile neutropenia was reported in 2% of patients in the ABRAXANE arm and 1% of patients in the paclitaxel injection arm. Fever occurring at any time during the treatment course was reported in 14% of patients in the ABRAXANE arm. Thrombocytopenia was almost never severe (< 50 x 109/L). Two percent of patients treated with ABRAXANE in the randomized trial experienced a decrease in their platelet count below 100 x 109/L at least once while on treatment. In the randomized metastatic breast cancer study, bleeding episodes were reported in 2% of the patients in each treatment arm. Anemia (Hb < 11 g/dL) in patients with normal baseline was observed in 20% of patients treated with ABRAXANE in the randomized trial and was severe (Hb < 8 g/dL) in 1% of the patients with normal baseline hemoglobin. Red cell transfusions were required in 2% of patients in the phase III study, and in 1% of those with normal baseline hemoglobin levels.
Hypersensitivity Reactions (HSRs):
Hypersensitivity reactions to ABRAXANE were observed in 4% of all patients. None of these reactions were severe. In the phase III study, the minor hypersensitivity reactions (i.e., those related to hypersensitivity and occurring on the day of dosing) 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. During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.
Cardiovascular:
Hypotension, during the 30-minute infusion, occurred in 5% of patients treated with ABRAXANE in the randomized metastatic breast cancer trial. This vital sign change 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 in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. 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 treated with ABRAXANE in the metastatic breast cancer randomized trial. Among patients with a normal ECG prior to study entry, 35% of patients treated with ABRAXANE developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia.
Respiratory:
Dyspnea (12%) and cough (7%) were reported after treatment with ABRAXANE in the randomized trial.
Neurologic:
The frequency and severity of neurologic manifestations were influenced by prior and/or concomitant therapy with neurotoxic agents.
In general, the frequency and severity of neurologic manifestations were dose-dependent in patients receiving single-agent ABRAXANE. In the randomized trial, sensory neuropathy was observed in 71% of patients (10% severe) in the ABRAXANE arm and in 56% of patients (2% severe) in the paclitaxel injection arm. The frequency of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of discontinuation in 7/229 (3%) patients receiving ABRAXANE in the randomized trial. Severe sensory symptoms have typically improved in a median of 22 days after interrupting ABRAXANE therapy. No incidences of grade 4 sensory neuropathies were reported in the clinical trials. Reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the continuing surveillance of paclitaxel injection safety. Cranial nerve palsies have been reported during postmarketing surveillance of ABRAXANE. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. Only one incident of motor neuropathy (grade 2) was observed in either arm of the controlled trial. Ocular/visual disturbances: Thirteen percent (13%) of all patients (n = 366) treated with ABRAXANE in single-arm and randomized trials reported ocular/visual disturbances, and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients in a single- arm study who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. However, rare reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection have suggested persistent optic nerve damage.
Arthralgia/Myalgia:
Forty-four percent (44%) of patients treated with ABRAXANE in the randomized trial experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. There was no consistent relationship between dose of ABRAXANE and the frequency of arthralgia/myalgia.
Hepatic:
Among patients with normal baseline liver function treated with ABRAXANE in the randomized trial, 7%, 36%, 39%, 36%, and 50% had elevations in bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT) and GGT respectively. 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. Prolonged exposure to ABRAXANE was not associated with cumulative hepatic toxicity.
Renal:
Eleven percent (11%) of patients treated with ABRAXANE in the randomized trial experienced creatinine elevation, < 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities.
Gastrointestinal (GI):
Nausea, vomiting, diarrhea, and mucositis were reported by 30%, 18%, 27%, and 7% of patients treated with ABRAXANE in the randomized trial. These manifestations were usually mild to moderate. The frequency and severity of GI adverse events were not obviously dose-related. Infrequent reports of esophagitis were reported in the clinical trials. Dehydration was reported commonly in clinical trials. Constipation and anorexia were considered very common.
Injection Site Reactions:
Injection site reactions were reported in 1% of patients treated with ABRAXANE and included reactions secondary to extravasation, which were usually mild and included erythema.
Asthenia:
Asthenia was reported in 47% of patients (8% severe) treated with ABRAXANE in the randomized trial. Asthenia included reports of asthenia, fatigue, weakness, lethargy and malaise.
Alopecia:
Alopecia was observed in almost all of the patients.
Skin:
Nail changes (changes in pigmentation or discolouration of nail bed) occurred in 1% of patients treated with ABRAXANE in the randomized trial. Transient skin changes (rash 9%; flushing 2%; pruritus 6%) were observed in the randomized trial. No other skin adverse events were significantly associated with ABRAXANE administration.
Less Common Clinical Trial Adverse Drug Reactions (< 1%)
Cardiovascular:
Bradycardia during the 30-minute infusion, occurred in < 1% of patients in the phase III study. Cases of cardiac ischemia/infarction and thrombosis/embolism possibly related to ABRAXANE treatment were uncommon. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks were uncommon.
Gastrointestinal:
Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of neutropenic enterocolitis (typhlitis), despite the co-administration of G-CSF, were observed in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.
Hepatic:
Rare 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.
Hypersensitivity Reactions:
Flushing, hypotension, chest pain, and arrhythmia occurring on the day of dosing were all reported at < 1%.
Injection Site Reactions:
Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been received 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 rarely.
Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.
Neurologic:
Uncommon serious neurologic events following ABRAXANE administration have included ischemic stroke, metabolic encephalopathy, confusion, dizziness/light-headedness, and mood alteration/depression.
Respiratory:
Reports (< 1%) of pneumothorax were uncommon after treatment with ABRAXANE in the randomized trial. Rare reports of interstitial pneumonia, lung fibrosis, and pulmonary embolism have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of radiation pneumonitis have been received in paclitaxel injection patients receiving concurrent radiotherapy. There is no experience with the use of ABRAXANE with concurrent radiotherapy.
Postmarket Adverse Drug Reactions
The following rare adverse events have been reported as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment: skin abnormalities related to radiation recall as well as reports of Stevens-Johnson syndrome, toxic epidermal necrolysis, conjunctivitis, and increased lacrimation. As part of the continuing surveillance of ABRAXANE, skin reactions including generalized or maculo-papular rash, erythema, and pruritis have been observed. Additionally, there have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodyaesthesiae. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. Cranial nerve palsies have been reported during postmarketing surveillance of ABRAXANE. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. Only one incident of motor neuropathy (grade 2) was observed in either arm of the controlled trial.
Overview
No drug interaction studies have been conducted with ABRAXANE(r) for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel). The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with known substrates or inhibitors of CYP2C8 and CYP3A4 (see ACTIONS AND CLINICAL PHARMACOLOGY). Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (such as ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials.
Drug-Drug Interactions
Interactions with other drugs have not been established.
Drug-Food Interactions
Interactions with food have not been established.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.
Dosing Considerations
No premedication to prevent hypersensitivity reactions is required prior to administration of ABRAXANE(r) for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel).
Recommended Dose and Dosage Adjustment
For the treatment of metastatic breast cancer, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. Dose levels of mg/m2 refer to mg of paclitaxel in ABRAXANE. Dose Reduction: Patients who experience severe neutropenia (neutrophil < 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, an 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.
The appropriate dose of ABRAXANE for patients with bilirubin greater than 1.5 mg/dL is not known.
Missed Dose
ABRAXANE is administered every three weeks. In the event that the next scheduled dose is missed, dosing should occur as soon as possible, consistent with good medical practice, after the missed dose.
Administration
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 WARNINGS AND PRECAUTIONS, Injection Site Reactions). Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel. Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient: Dosing volume (mL) = Total dose (mg)/5 (mg/mL). Inject the appropriate amount of reconstituted ABRAXANE into an empty, sterile, intravenous infusion bag (plasticized polyvinyl chloride (PVC), PVC or non-PVC type i.v. bag). No further dilution is required. The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer ABRAXANE infusions. The use of an in-line filter is not recommended. Do not mix any other drugs with the ABRAXANE infusion.
Reconstitution
ABRAXANE is supplied as a sterile lyophilized powder for reconstitution before use. AVOID
.
| Vial Size | Volume of Diluent to be Added to Vial | Approximate Available Volume | Nominal Concentration per mL |
| 50 mL | 20 mL 0.9% Sodium Chloride Injection, USP | 20 mL | 5 mg/mL |
Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP.
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.
DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized cake as this will result in foaming.
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.
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.
If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides.
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. Neither freezing nor refrigeration adversely affects the stability of the product.
Stability of Reconstituted Suspension in the Vial
ABRAXANE reconstituted in the vial should be used immediately, but may be refrigerated between 2 and 8degC for a maximum of 8 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. Some settling of the reconstituted suspension may occur. 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. Inject the appropriate amount of reconstituted ABRAXANE into an empty, sterile, i.v. bag (plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type i.v. bag). No further dilution is required. The use of specialized DEHP-free solution containers or administration sets may also be used but are not required to prepare or administer ABRAXANE infusions. The use of an in-line filter is not recommended.
Stability of Reconstituted Suspension in the Infusion Bag
The suspension for infusion prepared as recommended in an infusion bag should be used immediately, but may be stored at ambient temperature (approximately 20 to 25degC) and ambient lighting conditions for up to 8 hours. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit. ABRAXANE is a cytotoxic anticancer 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.
There is no known antidote for ABRAXANE(r) for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel) overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.
Mechanism of Action
Paclitaxel, the active pharmaceutical ingredient in ABRAXANE(r) for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel), is an antimicrotubule agent 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.
Pharmacodynamics
In preclinical models, ABRAXANE resulted in higher intra-tumour concentrations of paclitaxel compared to paclitaxel injection. Albumin is known to mediate endothelial transcytosis of plasma constituents and, based on in vitro data, it is hypothesized that albumin-bound paclitaxel facilitates the transport of paclitaxel across the endothelial cell via an albumin-receptor (gp60) mediated pathway.
Pharmacokinetics
| C max (ng/mL) | T 1/2 (h) | AUC 0 -[?] (h *ng/mL) | Clearance (L/h/m 2 ) | Volume of Distribution (L/m 2 ) | |
| Single Dose Mean | 18,741 | 27.4 | 17,940 | 15.2 | 632 |
The pharmacokinetics of total paclitaxel following 30- and 180-minute infusions of paclitaxel powder for injectable suspension at dose levels of
80 - 375 mg/m2 were determined in clinical studies. Following intravenous administration of paclitaxel powder for injectable suspension, 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 terminal half-life was about 27 hours. The drug exposure (AUCs) was dose proportional over 80 to 300 mg/m2 and the pharmacokinetics of paclitaxel for paclitaxel powder for injectable suspension were independent of the duration of administration. At the recommended clinical dose, 260 mg/m2, the mean maximum concentration of paclitaxel, which occurred at the end of the infusion, was 18,741 ng/mL. The mean total clearance was 15 L/h/m2. The mean volume of distribution was 632 L/m2; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel. The pharmacokinetic data of 260 mg/m2 paclitaxel powder for injectable suspension administered over 30 minutes was compared to the pharmacokinetics of 175 mg/m2 paclitaxel injection over 3 hours. The volume of distribution and clearance of paclitaxel powder for injectable suspension were greater (by 53% and 43% respectively) than for paclitaxel injection. Differences in Cmax and Cmax corrected for dose, reflected differences in total dose and rate of infusion. There were no differences in terminal half-lives (approximately 21 hours for each).
In vitro
studies of binding to human serum proteins, using paclitaxel concentrations ranging from
0.1 to 50 ug/mL, indicate that between 89% and 98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel. Metabolism: In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6a-hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3'-p-hydroxypaclitaxel and 6a, 3'-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6a-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, 17a-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6a-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). The effect of renal or hepatic dysfunction on the disposition of paclitaxel powder for injectable suspension has not been investigated. Excretion: After a 30-minute infusion of 260 mg/m2 doses of paclitaxel powder for injectable suspension, 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 6a-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel. Fecal excretion was approximately 20% of the total dose administered. Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.
Store the vials of ABRAXANE(r) for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel) in original cartons between 20 and 25degC. Retain in the original package to protect from bright light. Neither freezing nor refrigeration adversely affects the stability of the product. ABRAXANE reconstituted in the original vial should be used immediately, but may be refrigerated between 2 and 8degC for a maximum of 8 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. Some settling of the reconstituted suspension may occur. Ensure complete resuspension by mild agitation before use. Discard the reconstituted suspension if precipitates are observed. The suspension for infusion prepared as recommended in an infusion bag should be used immediately, but may be stored at ambient temperature (approximately 20 to 25degC) and ambient lighting conditions for up to 8 hours.
ABRAXANE(r) for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel) is a cytotoxic anticancer drug and, as with other potentially toxic paclitaxel compounds, caution should be exercised in handling ABRAXANE. The use of gloves is recommended. Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate (see REFERENCES).
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. 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.
ABRAXANE(r) for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound [nab] paclitaxel) is supplied as a white to yellow, sterile, lyophilized cake 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 and approximately 900 mg of human albumin. Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel. ABRAXANE is free of solvents. ABRAXANE is available in a single-use glass vial with a latex free stopper, individually packaged in a carton.