Dosing and uses of Abraxane (paclitaxel protein bound)
Adult dosage forms and strengths
injection, lyophilized powder for reconstitution
- 100mg/vial
Pancreatic Cancer
Indicated for metastatic adenocarcinoma of the pancreas as first-line treatment in combination with gemcitabine
125 mg/m² IV infused over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle
Administer gemcitabine 1000 mg/m² IV infused over 30-40 minutes immediately after paclitaxel protein bound on Days 1, 8 and 15 of each 28-day cycle
Dosage modifications (pancreatic cancer)
- 1st dose reduction: 100 mg/m² (paclitaxel); 800 mg/m² (gemcitabine)
- 2nd dose reduction: 75 mg/m² (paclitaxel); 600 mg/m² (gemcitabine)
- Discontinue if additional dose reduction required
Dosage modifications (pancreatic cancer – hematologic toxicities)
- Cycle Day 1: ANC <1500/mm³ or platelets <100,000/mm³ - Delay doses until recovery
- Cycle Day 8: ANC 500 to <1000/mm³ or platelets 50,000 to <75,000/mm³ - Reduce 1 dose level
- Cycle Day 8: ANC <500/mm³ or platelets <50,000/mm³ - Withhold doses
- Cycle Day 15: ANC 500 to <1000/mm³ or platelets 50,000 to <75,000/mm³ - Reduce 1 dose level from Day 8
- Cycle Day 15: ANC <500/mm³ or platelets <50,000/mm³ - Withhold doses
- Cycle Day 15 (if Day 8 doses withheld): ANC >1000/mm³ or platelets ≥75,000/mm³ - Reduce 1 dose level from Day 1
- Cycle Day 15 (if Day 8 doses withheld): ANC 500 to <1000/mm³ or platelets 50,000 to <75,000/mm³ - Reduce 2 dose levels from Day 1
- Cycle Day 15 (if Day 8 doses withheld): ANC <500/mm³ or platelets <50,000 /mm³ - Withhold doses
Dosage modifications (pancreatic cancer – other toxicities)
- Febrile neutropenia (grade 3 or 4): Withhold until fever resolves and ANC ≥1500/mm³ - Resume at next lower dose level
- Peripheral neuropathy (Grade 3 or 4): Withhold paclitaxel until improves to ≤ Grade 1, then resume at next lower dose (no need to reduce gemcitabine)
- 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
Breast Cancer
Microtubule inhibitor 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 contraindicated
260 mg/m² IV infused over 30 minutes q3weeks
Dosage modfications (breast cancer)
- Severe neutropenia (<500 cells/mm³) or severe sensory neuropathy: Decrease dose to 220 mg/m²
- Recurrence of severe neutropenia or severe sensory neuropathy: Decrease dose to 180 mg/m²
- Grade 3 sensory neuropathy: Hold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses
Non-Small Cell Lung Cancer
Indicated for locally advanced or metastatic non-small cell lung cancer (NSCLC), as first-line treatment in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy
100 mg/m² IV infused over 30 minutes on Days 1, 8, and 15 of each 21-day cycle, PLUs
Carboplatin AUC 6 mg•min/mL IV on Day 1 of each 21 day cycle immediately after paclitaxel protein bound infusion
Dosage modifications (NSCLS)
- Do not administer on Day 1 of a cycle until ANC is at least 1500 cells/mm³ and platelet count is at least 100,000 cells/mm³
- Severe neutropenia or thrombocytopenia: Withhold treatment until counts recover to an ANC of 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
- Grade 3-4 peripheral neuropathy: Withhold dose; resume paclitaxel protein bound and carboplatin at reduced doses when peripheral neuropathy improves to Grade 1 or completely resolves
Permanent dose reductions (NSCLC)
- Neutropenic fever (ANC <500/mm³ and fever >38°C) or next cycle delayed by >7 days for ANC <1500/mm³ or ANC <500/mm³ for >7 days or severe sensory neuropathy (grade 3 or 4):
- -First occurrence: reduce dose to 75 mg/m² (and decrease carboplatin dose to 4.5 AUC mg•min/mL)
- -Second occurrence: reduce dose to 50 mg/m² (and decrease carboplatin dose to 3 AUC mg•min/mL)
- -Third occurrence: Discontinue treatment
- Platelets <50,000/mm³:
- -First occurrence: reduce dose to 75 mg/m² (and decrease carboplatin dose to 4.5 AUC mg•min/mL)
- -Second occurrence: Discontinue treatment
Hepatic Impairment
Breast cancer
- Mild (AST <10 x ULN; bilirubin >ULN to 1.25 X ULN): No dose adjustment required
- Moderate (AST <10 x ULN; bilirubin 1.26-2 x ULN): Reduce starting dose to 200 mg/m²
- Severe: (AST <10 x ULN; bilirubin 2.01-5 x ULN): Reduce starting dose to 130 mg/m²; may increase up to 200 mg/m² in subsequent cycles based on individual tolerance
- AST >10 x ULN or bilirubin >5 X ULN: Do not administer paclitaxel protein bound
NSCLC
- Mild (AST <10 x ULN; bilirubin >ULN to 1.25 X ULN): No dose adjustment required
- Moderate (AST <10 x ULN; bilirubin 1.26-2 x ULN): Reduce starting dose to 75 mg/m²
- Severe: (AST <10 x ULN; bilirubin 2.01-5 x ULN): Reduce starting dose to 50 mg/m²; may increase up to 75 mg/m2 in subsequent cycles based on individual tolerance
- AST >10 x ULN or bilirubin >5 X ULN: Do not administer paclitaxel protein bound
Pancreatic cancer
- Mild (AST <10 x ULN; bilirubin >ULN to 1.25 X ULN): No dose adjustment required
- Moderate-to-severe (AST <10 x ULN; bilirubin 1.26-5 x ULN): Not recommended
- AST >10 x ULN or bilirubin >5 X ULN: Do not administer paclitaxel protein bound
Administration
Use cytotoxic handling precautions
Monitor for extravasation during infusion
Premedication for hypersensitivity reaction is NOT required
Melanoma (Orphan)
Orphan designation for treatment of stage IIb to IV melanoma
Orphan sponsor
- Abraxis BioScience, LLC; 11755 Wilshire Blvd; Los Angeles, CA 90025
Gastric Cancer (Orphan)
Orphan designation for gastric cancer
Sponsor
- Insys Therapeutics, Inc.; 1333 South Spectrum Boulevard, Suite 100; Chandler, AZ 85286
Ovarian Cancer (Orphan)
Liposomal encapsulated paclitaxeL
Sponsor
- Insys Therapeutics, Inc; 1333 South Spectrum Boulevard, Suite 100; Chandler, AZ 85286
Breast Cancer with Brain Metastases (Orphan)
Peptide-paclitaxel conjugate
Orphan designation for treatment of patients with breast cancer with brain metastases
Sponsor
- Angiochem, Inc; 201 President Kennedy; Montreal, Quebec H2X 3Y7; Canada
Pediatric dosage forms and strengths
Safety and efficacy not established
Abraxane (paclitaxel protein bound) adverse (side) effects
>10%
Alopecia (90%)
Neutropenia (<2 x 10^9/L) (80%)
Sensory neuropathy, any (71%)
Abnormal EKG, all patients (60%)
Asthenia (47%)
Myalgia/arthralgia (44%)
AST increased (39%)
Alkaline phosphatase increased (36%)
Abnormal EKG, patients normal at baseline (35%)
Anemia (<11 g/dL) (33%)
Nausea (30%)
Diarrhea (27%)
Infections (24%)
Vomiting (18%)
Dyspnea (12%)
Neutropenia (grade 3-4)
- NSCLC (47%)
- Pancreatic cancer (38%)
- Metastatic breast cancer (34%)
1-10%
Sensory neuropathy, severe (10%)
Edema (10%)
Neutropenia (<0.5 x 10^9/L) (9%)
Cough (7%)
Mucositis (7%)
Bilirubin increased (7%)
Hypotension, during infusion (5%)
Hypersensitivity reactions (4%)
Thrombocytopenia (2%)
Febrile neutropenia (2%)
Bleeding (2%)
Anemia (<8 g/dL) (1%)
Postmarketing Reports
Hypersensitivity: Severe hypersensitivity reactions
Cardiovascular: Congestive heart failure, left ventricular dysfunction, and atrioventricular block; most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history
Respiratory: Interstitial pneumonia, pulmonary embolism, lung fibrosis
Neurologic: Cranial nerve palsies, vocal cord paresis, autonomic neuropathy resulting in paralytic ileu
Vision Disorders: Persistent optic nerve damage; reduced visual acuity due to cystoid macular edema
Hepatic: Hepatic necrosis and hepatic encephalopathy leading to death
Gastrointestinal: Intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis, neutropenic enterocolitis (typhlitis)
Injection Site Reaction: Extravasation, severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis (may be delayed by 7-10 ten days)
Warnings
Black box warnings
Should not be administered if baseline neutrophil counts <1,500 cells/mm³; frequent monitoring of peripheral blood cell counts for all patients recommended to avoid bone marrow suppression
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
Contraindications
Neutrophils <1500 cells/mm³
Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions reported; do not rechallenge in patients who experience severe hypersensitivity
Cautions
Causes myelosuppression; monitor CBC and withhold and/or reduce the dose as needed (see Dosage modifications)
Sensory neuropathy occurs frequently and may require dose reduction or treatment interruption (see Dosage modifications)
Sepsis occurred in 5% of patients with or without neutropenia; biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis
Pneumonitis, including fatalities, occurred in 4% of patients
Exposure and toxicity increased with hepatic impairment; particularly from myelosuppression; closely monitor for development of profound myelosuppression; monitor AST and bilirubin and adjust dose if needed (see Dosage modifications)
Contains albumin derived from human blood which has a theoretical risk of viral transmission
Fetal harm may occur when administered to a pregnant woman; women of childbearing potential should avoid becoming pregnant
Men should not father a child while taking paclitaxeL
CYP3A4 and CYP2C8 substrate; inducers or inhibitors of these isoenzymes may alter metabolism; if coadministered, monitor closely
Pregnancy and lactation
Pregnancy category: d
Lactation: Unknown whether distributed in breast milk; 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
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Abraxane (paclitaxel protein bound)
Mechanism of action
Microtubular inhibitor (albumin-conjugated formulation); natural taxane, prevents depolymerization of cellular microtubules, which results in DNA, RNA, and protein synthesis inhibition
Absorption
Peak Plasma Time: Immediately after completing infusion
Peak Plasma Concentration: 18,741 ng/mL
Distribution
Protein Bound: 89-98%
Vd: 632 L/m²
Metabolism
Metabolized primarily to 6- alpha hydroxypaclitaxel by CYP2C8; and to 2 minor metabolites, 3’-p-hydroxypaclitaxel and 6-alpha, 3’-p-dihydroxypaclitaxel, by CYP3A4
Elimination
Half-life: 27 hr
Total body clearance: 15 L/hr/m²
Excretion: 20% feces, 4% urine (unchanged)
Administration
IV Preparation
Aseptically reconstitute vial by slowly injecting 20 mL 0.9% NaCl over 1 min by allowing fluid to fall down inside wall of tube (this will avoid foaming)
Swirl or invert to mix (do not shake)
Resulting reconstituted suspension should be milky and homogenous without visible particulates
Resulting solution is 5 mg/mL
If foaming occurs stand solution for at least 15 min until foaming subsides
Inject the appropriate amount of reconstituted suspension into an empty, sterile IV bag (PVC containers, PVC or non-PVC type IV bag)
The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer paclitaxel protein bound infusions
The use of an in-line filter is not recommended
IV Administration
Infuse IV over 30 min
Do not use in-line filter
Storage
Unopened vials: Store between 20-25ºC (68-77ºF) in the original package; neither freezing nor refrigeration adversely affects the stability of the product
Reconstituted suspension in vial: Preferably should be used immediately, but can be refrigerated at 2-8°C (36-46°F) for up to 8 hr if needed
Reconstituted suspension in infusion bag: Should be used immediately but may be stored at ambient temperature (approximately 25ºC) and lighting conditions for up to 4 hr; discard any unused portion
