Pronunciation (PAK li taks el PROE teen bownd)

U.S. Brand Names AbraxaneTM

Synonyms BI-007; NAB-Paclitaxel; Protein-Bound Paclitaxel

Therapeutic Category
Antineoplastic Agent, Antimicrotubular
Antineoplastic Agent, Natural Source (Plant) Derivative
Use Treatment of breast cancer (second-line)

Pregnancy Risk Factor D

Pregnancy Implications Teratogenic effects have been observed in animal studies; women of childbearing potential should be advised to avoid becoming pregnant. Additionally, testicular atrophy/degeneration was observed in animal studies; males should be advised to not father a child during therapy.

Contraindications Hypersensitivity to paclitaxel or any component of the formulation; baseline neutrophil count <1,500 cells/mm3

Warnings/Precautions The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered.
Paclitaxel (protein-bound) is not interchangeable with Cremophor-based paclitaxel. Use caution in neutropenia or thrombocytopenia, dosage adjustment recommended if severe drug-induced neutropenia lasts for 1 week; severe sensory neuropathy may occur; modified dosage recommended for subsequent courses of therapy. Use caution in hepatic and renal dysfunction. When administered as sequential infusions, taxane derivatives (docetaxel, paclitaxel) should be administered before platinum derivatives (carboplatin, cisplatin) to limit myelosuppression.

Adverse Reactions

>10: Cardiovascular: EKG abnormal (60%)
Dermatologic: Alopecia (90%)
Gastrointestinal: Nausea (30%; severe 3%), diarrhea (26%; severe <1%), vomiting (18%; severe 4%)
Hematologic: Neutropenia (80%; grade 4 - 9%), anemia (33%; severe 1%)
Hepatic: AST increased (39%), alkaline phosphatase increased (36%)
Neuromuscular & skeletal: Sensory neuropathy (71%; severe 10%), asthenia (47%; severe 8%), myalgia/arthralgia (44%; severe 8%)
Ocular: Vision disturbance (13%; severe 1%)
Respiratory: Dyspnea (12%)
Miscellaneous: Infections (24%; primarily included oral candidiasis, respiratory tract infections, and pneumonia)

1% to 10%: Cardiovascular: Edema (10%; severe 0%), hypotension (5%), Grade 3 cardiovascular events (3%; included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension)
Central nervous system: Febrile neutropenia (2%)
Gastrointestinal: Mucositis (7%; severe < 1%)
Hematologic: Thrombocytopenia (2%), bleeding (2%)
Hepatic: Bilirubin increased (7%)
Local: Injection site reaction (1%)
Renal: Creatinine increased (11%; severe 1%)
Respiratory: Cough (6%)
Miscellaneous: Hypersensitivity reaction (4%)

<1%: Bradycardia, cerebral vascular attacks, conjunctivitis, hepatic necrosis, hepatic encephalopathy, interstitial pneumonia, intestinal obstruction, intestinal perforation, ischemic colitis, lacrimation increased, lung fibrosis, maculopapular rash, neutropenic enterocolitis, pancreatitis, pneumothorax, radiation pneumonitis with concurrent radiation therapy, Stevens-Johnson syndrome, toxic epidermal necrolysis, transient ischemic attacks

Overdose/Toxicology Overdose would likely result in severe bone marrow suppression, sensory neuropathy, and mucositis. Treatment should be supportive.

Drug Interactions Substrate (major) of CYP2C8/9, 3A4; Induces CYP3A4 (weak)

Carboplatin, cisplatin (platinum derivatives): When administered as sequential infusions, taxane derivatives should be administered before platinum derivatives to limit myelosuppression and to enhance efficacy.

CYP2C8/9 inducers: May decrease the levels/effects of paclitaxel. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.

CYP2C8/9 inhibitors: May increase the levels/effects of paclitaxel. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, pioglitazone, and sulfonamides.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of paclitaxel. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of paclitaxel. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Doxorubicin: Paclitaxel may increase doxorubicin levels/toxicity.

Food Interactions

Herb/Nutraceutical: Avoid black cohosh, dong quai in estrogen-dependent tumors. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Mechanism of Action Paclitaxel promotes microtubule assembly by enhancing the action of tubulin dimers, stabilizing existing microtubules, and inhibiting their disassembly, interfering with the late G2 mitotic phase, and inhibiting cell replication. In addition, the drug can distort mitotic spindles, resulting in the breakage of chromosomes. Paclitaxel may also suppress cell proliferation and modulate immune response.

Pharmacodynamics/Kinetics

Distribution: Vd: 632 L/m2

Protein binding: 89% to 98%

Metabolism: Hepatic via CYP3A4 and 2C8

Half-life elimination: Terminal: 27 hours

Excretion: Urine (4% as unchanged drug, 1% as metabolites); feces (20%) Clearance 15 L/hour/m2

Usual Dosage I.V.: Adults: Breast cancer: 260 mg/m2 every 3 weeks

Dosage adjustment for toxicity:Severe neutropenia (<500 cells/mm3) 1 week: Reduce dose to 220 mg/m2 for subsequent courses
Recurrent severe neutropenia: Reduce dose to 180 mg/m2
Severe sensory neuropathy: Reduce dose to 180 mg/m2
Sensory neuropathy grade 3 or 4: Hold treatment until resolved to grade 1 or 2, then resume with reduced dose

Dosage adjustment in renal impairment: Safety not established for serum creatinine >2 mg/dL; use with caution

Dosage adjustment in hepatic impairment: Effects of hepatic dysfunction (serum bilirubin >1.5 mg/dL) unknown; dosage adjustment recommendations are not available

Administration I.V.: Administer over 30 minutes; use of DEHP-free containers or administration sets is not necessary; do not use an in-line filter

Monitoring Parameters CBC, BP (during infusion), baseline ECG, infusion site

Patient Information Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This drug can only be given by infusion. Report immediately any redness, swelling, burning, pain at infusion site or signs of allergic reaction (eg, respiratory difficulty or swallowing, chest tightness, rash, hives, swelling of lips or mouth). Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake, and nutrition. You will be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause loss of hair (will grow back after therapy); experience nausea or vomiting (consult prescriber for approved antiemetic); feel weak or lethargic (use caution when driving or engaging in tasks that require alertness until response to drug is known); or mouth sores (use good oral care, bush with soft toothbrush and use waxed dental floss). Report numbness or tingling in fingers or toes (use care to prevent injury); signs of opportunistic infection (fever, chills, sore throat, burning urination, fatigue); unusual bleeding (tarry stools, easy bruising, or blood in stool, urine, or mouth); unresolved mouth sores; nausea or vomiting; or skin rash or itching. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication. Consult prescriber for appropriate barrier contraceptive measures. Do not breast-feed. Men should not father a child during therapy.

Dosage Forms Injection, powder for reconstitution: 100 mg [contains human albumin 900 mg]