PACLitaxel

General

PACLitaxel

Pronunciation:
pak-li-tax-el


Trade Name(s)

  • Taxol

PACLitaxel protein-bound particles (albumin-bound)

Trade Name(s)

  • Abraxane

Ther. Class.
antineoplastics

Pharm. Class.
taxoids

Indications

  • Paclitaxel: Advanced ovarian cancer (with cisplatin).
  • Non-small cell lung cancer (NSCLC) when potentially curative surgery and/or radiation therapy is not an option.
  • Metastatic breast cancer unresponsive to other therapy.
  • Node-positive breast cancer when administered sequentially to standard combination chemotherapy that includes doxorubicin.
  • Treatment of AIDS-related Kaposi's sarcoma.
  • Paclitaxel (albumin-bound): Metastatic breast cancer after treatment failure or relapse where therapy included an anthracycline.
  • Locally advanced or metastatic NSCLC when potentially curative surgery or radiation therapy is not an option (with carboplatin).
  • Metastatic pancreatic adenocarcinoma (with gemcitabine)

Action

Interferes with the normal cellular microtubule function that is required for interphase and mitosis.

Therapeutic Effect(s):

Death of rapidly replicating cells, particularly malignant ones.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.

Distribution: Cross the placenta.

Protein Binding: 89–98%.

Metabolism and Excretion: Highly metabolized by the liver (primarily by CYP2C8 and CYP3A4), <10% excreted unchanged in urine.

Half-life: Paclitaxel– 13–52 hr;  Paclitaxel protein-bound particles (albumin-bound)– 27 hr.

TIME/ACTION PROFILE (effect on WBCs)

ROUTEONSETPEAKDURATION
IVunknown11 days3 wk

Contraindication/Precautions

Contraindicated in:

  • Hypersensitivity to paclitaxel, other taxanes, or castor oil (paclitaxel);
  • Severe hypersensitivity to paclitaxel protein-bound particles (paclitaxel protein-bound particles);
  • AST >10× ULN or total bilirubin >5× ULN (paclitaxel protein-bound particles);
  • Moderate or severe hepatic impairment (pancreatic adenocarcinoma only for paclitaxel protein-bound particles);
  • Known alcohol intolerance;
  • Neutrophil count ≤1500/mm3  (for patients with ovarian, lung, breast, or pancreatic cancer) or ≤1000/mm3  (for patients with AIDS-related Kaposi's sarcoma);
  • ANC ≤1000/mm3  in patients with AIDS-related Kaposi's sarcoma;
  • OB:  Pregnancy (may cause fetal harm)
  • Lactation: Lactation.

Use Cautiously in:

  • Moderate or severe hepatic impairment (↓ dose);
  • Active infection;
  • ↓ bone marrow reserve;
  • Rep:  Women of reproductive potential and men with female partners of reproductive potential;
  • Pedi:  Safety and effectiveness not established in children
  • Geri:  Older adults may have ↑ risk of adverse reactions.

Adverse Reactions/Side Effects

CV: ECG changes, edema, hypotension, bradycardia

Derm: STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, alopecia

GI: diarrhea, ↑ liver enzymes, mucositis, nausea, vomiting, pancreatitis

Hemat: NEUTROPENIA, anemia, thrombocytopenia

Local: injection site reactions

MS: arthralgia, myalgia

GU: renal failure

Neuro: peripheral neuropathy, dizziness, headache, seizures

Resp: PULMONARY EMBOLISM, PULMONARY FIBROSIS, cough, dyspnea, interstitial pneumonia

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS), SEPSIS

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

Route/Dosage

Many other regimens are used

Paclitaxel

Ovarian Cancer

IV (Adults): Previously untreated patients– 175 mg/m2  over 3 hr every 3 wk  or  135 mg/m2  over 24 hr every 3 wk, followed by cisplatin;  Previously treated patients– 135 mg/m2   or  175 mg/m2  over 3 hr every 3 wk.

Breast Cancer

IV (Adults): Adjuvant treatment of node-positive breast cancer– 175 mg/m2  over 3 hr every 3 wk for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy;  Failure of initial therapy for metastatic disease or relapse within 6 mo of adjuvant therapy– 175 mg/m2  over 3 hr every 3 wk.

NSCLC

IV (Adults): 135 mg/m2  over 24 hr every 3 wk, followed by cisplatin.

AIDS-Related Kaposi's Sarcoma

IV (Adults): 135 mg/m2  over 3 hr every 3 wk  or  100 mg/m2  over 3 hr every 2 wk (dose ↓/adjustment may be necessary in patients with advanced HIV infection).

Paclitaxel Protein-Bound Particles (albumin-bound)

Breast Cancer

IV (Adults): 260 mg/m2  over 30 min every 3 wk.

Hepatic Impairment 
IV (Adults): Moderate hepatic impairment (AST levels <10 × ULN and bilirubin levels 1.51–3 × ULN)– 200 mg/m2  over 30 min every 3 wk; dose may be ↑ to 260 mg/m2  for the 3rd course based on individual tolerance;  Severe hepatic impairment (AST levels <10 × ULN and bilirubin levels 3.01–5× ULN)– 200 mg/m2  over 30 min every 3 wk; dose may be ↑ to 260 mg/m2  for the 3rd course based on individual tolerance;  Severe hepatic impairment (AST levels >10 × ULN or bilirubin levels >5 × ULN)– Avoid use.

NSCLC

IV (Adults): 100 mg/m2  over 30 min on Days 1, 8, and 15 of each 21-day cycle.

Hepatic Impairment 
IV (Adults): Moderate hepatic impairment (AST levels <10 × ULN and bilirubin levels 1.51–3 × ULN)– 80 mg/m2  over 30 min on Days 1, 8, and 15 of each 21–day cycle; dose may be ↑ to 100 mg/m2  for the 3rd course based on individual tolerance;  Severe hepatic impairment (AST levels <10 × ULN and bilirubin levels 3.01–5 × ULN)– 80 mg/m2  over 30 min on Days 1, 8, and 15 of each 21–day cycle; dose may be ↑ to 100 mg/m2  for the 3rd course based on individual tolerance;  Severe hepatic impairment (AST levels >10 × ULN or bilirubin levels >5 × ULN)– Avoid use.

Pancreatic Adenocarcinoma

IV (Adults): 125 mg/m2  over 30–40 min on Days 1, 8, and 15 of each 28–day cycle.

Hepatic Impairment 
IV (Adults): Moderate or severe hepatic impairment – Avoid use.

Availability

Paclitaxel

Solution for injection: 6 mg/mL

Paclitaxel Protein-Bound Particles (albumin-bound)

Lyophilized powder for injection: 100 mg/vial

Assessment

  • Monitor vital signs frequently, especially during first hr of the infusion.
  • Monitor cardiovascular status especially during first 3 hr of infusion. Hypotension and bradycardia are common but usually do not require treatment. Continuous ECG monitoring is recommended only for patients with serious underlying conduction abnormalities or those concurrently taking doxorubicin.
  • Monitor for bone marrow depression. Assess for bleeding (bleeding gums, bruising, petechiae, guaiac stools, urine, and emesis) and avoid IM injections and taking rectal temperatures if platelet count is low. Apply pressure to venipuncture sites for 10 min. Assess for signs of infection during neutropenia. Anemia may occur. Monitor for dyspnea and orthostatic hypotension. Granulocyte-colony stimulating factor (G-CSF) may be used if necessary.
  • Monitor intake and output, appetite, and nutritional intake. Paclitaxel causes nausea and vomiting in 50% of patients. Prophylactic antiemetics may be used. Adjust diet as tolerated to help maintain fluid and electrolyte balance and nutritional status.
  • Assess patient for arthralgia and myalgia, which usually begin 2–3 days after therapy and resolve within 5 days. Pain is usually relieved by nonopioid analgesics but may be severe enough to require treatment with opioid analgesics.
  • Assess for rash periodically during therapy. May cause Stevens-Johnson syndrome and toxic epidermal necrolysis. Discontinue therapy if severe or if accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.
  • Paclitaxel:

    Monitor for hypersensitivity reactions continuously during the first 30 min and frequently thereafter. These occur frequently (19%), usually during the first 10 min of paclitaxel infusion, after the 1st or 2nd dose. Pretreatment is recommended for all patients and should include dexamethasone 20 mg PO (10 mg for patients with advanced HIV disease) 12 and 6 hr prior to paclitaxel, diphenhydramine 50 mg IV 30–60 min prior to paclitaxel. Most common manifestations are dyspnea, flushing, tachycardia, rash, hypotension, and chest pain. If these occur, stop infusion and notify health care professional. Treatment may include bronchodilators, epinephrine, antihistamines, and corticosteroids. Keep these agents and resuscitative equipment close by in the event of an anaphylactic reaction. Other manifestations of hypersensitivity reactions include flushing and rash.

    • Assess for development of peripheral neuropathy. If severe symptoms occur, subsequent dose should be reduced by 20%.
    •  Paclitaxel protein-bound (albumin-bound): Consider premedication in patients who have had prior hypersensitivity reactions to paclitaxel protein-bound (albumin-bound). Do not re-challenge patients who experience a severe hypersensitivity reaction.
    • Sensory neuropathy is dose- and schedule-dependent.  If ≥Grade 3 sensory neuropathy occurs, withhold paclitaxel protein-bound (albumin-bound) 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 therapy.

    Lab Test Considerations:

    • Verify negative pregnancy test before starting therapy.
    • Paclitaxel:

      Monitor CBC and differential prior to and periodically during therapy. The nadir of leukopenia occurs in 11 days, with recovery by days 15–21.  If neutrophil counts less than 500/mm3  for ≥1 wk,  reduce dose by 20% for subsequent courses.

      •  Paclitaxel Protein-Bound Particles (albumin-bound): Monitor CBC and differential frequently, including before starting therapy and prior to dosing on Day 1 (for breast cancer), 8, and 15 (for NSCLC and pancreatic cancer). For NSCLC: If neutropenic fever (ANC <500/mm3  with fever >38°C) OR delay of next cycle by more than 7 days for ANC <1500/mm3  OR ANC <500/mm3  for >7 days,  reduce dose on 1st occurrence to 75 mg/m2  and on 2nd occurrence, reduce dose to 50 mg/m2 . For 3rd occurrence, discontinue therapy. Do not administer if neutrophil count is <1500/mm3 . If severe neutropenia (neutrophils <500 cells/mm3  for seven days or more), reduce dose in subsequent courses.  If platelet count <50,000/mm3 , for 1st occurrence, reduce dose to 75 mg/m2 . Discontinue therapy at 2nd occurrence. For Pancreatic Cancer:  On Day 1, if ANC <1500 cells/mm3 OR platelet count <100,000 cells/mm3 ,  hold next dose until recovery.  On Day 8, if ANC 500 to <1000 cells/mm3  OR platelet count 50,000 to <75,000 cells/mm3 , reduce dose one level;  On Day 8, if ANC <500 cells/mm3  OR <50,000 cells/mm3 ,  hold dose.  On Day 15, if Day 8 doses were reduced or given without modification, and ANC 500 to <1000 cells/mm3  OR platelet count 50,000 to <75,000 cells/mm3 ,  reduce dose 1 level from Day 8.  On Day 15, if Day 8 doses were reduced or given without modification, and ANC <500 cells/mm3 OR platelet count <50,000 cells/mm3 , hold doses.  On Day 15, if Day 8 doses were held and ANC ≥1000 cells/mm3 OR platelet count ≥75,000 cells/mm3 ,  reduce dose 1 level from Day 1.  On Day 15, if Day 8 doses were held and ANC 500 to <1000 cells/mm3 OR platelet count 50,000 to <75,000 cells/mm3 ,  reduce dose 2 levels from Day 1. On Day 15, if Day 8 doses were held and ANC <500 cells/mm3 OR platelet count <50,000 cells/mm3 , hold doses.
      • Monitor liver function studies (AST, ALT, LDH, bilirubin) prior to and periodically during therapy to detect hepatotoxicity.

    Implementation

    • Do not confuse paclitaxel with docetaxel or paclitaxel protein-bound particles.

    Paclitaxel

    •  Dose Reduction for Pancreatic Cancer: Full dose – 125 mm/m2 . 1st dose reduction – 100 mm/m2 . 2nd dose reduction – 75 mm/m2 . If additional dose reduction required – discontinue therapy.

    IV Administration

    • Continuous Infusion:  Paclitaxel must be diluted prior to injection. Diluent:  Dilute contents of 5-mL (30-mg) vials with the following diluents: 0.9% NaCl, D5W, D5/0.9% NaCl, or dextrose in Ringer's solution. Concentration: 0.3–1.2 mg/mL. Although haziness in solution is normal, inspect for particulate matter or discoloration before use. Use an in-line filter of not >0.22-micron pore size. Solutions are stable for 27 hr at room temperature and lighting. Do not use PVC containers or administration sets.
    • Rate: Dose for  breast cancer, ovarian cancer, or AIDS-related Kaposi's sarcoma  is administered over 3 hr. Dose for   ovarian cancer  can also be administered as a 24-hr infusion.
    • Y-Site Compatibility:
      • acyclovir
      • alemtuzumab
      • alfentanil
      • MORE...
        • allopurinol
        • amifostine
        • amikacin
        • aminophylline
        • amphotericin B lipid complex
        • ampicillin
        • ampicillin/sulbactam
        • anidulafungin
        • argatroban
        • azithromycin
        • aztreonam
        • bivalirudin
        • bleomycin
        • bumetanide
        • buprenorphine
        • busulfan
        • butorphanol
        • calcium chloride
        • calcium gluconate
        • carboplatin
        • carmustine
        • caspofungin
        • cefazolin
        • cefepime
        • cefotaxime
        • cefotetan
        • cefoxitin
        • ceftazidime
        • ceftriaxone
        • cefuroxime
        • chloramphenicol
        • ciprofloxacin
        • cisatracurium
        • cisplatin
        • cladribine
        • clindamycin
        • cyclophosphamide
        • cyclosporine
        • cytarabine
        • dacarbazine
        • dactinomycin
        • dantrolene
        • daptomycin
        • daunorubicin hydrochloride
        • dexamethasone
        • dexmedetomidine
        • dexrazoxane
        • diltiazem
        • diphenhydramine
        • dobutamine
        • dopamine
        • doxorubicin hydrochloride
        • doxycycline
        • droperidol
        • enalaprilat
        • ephedrine
        • epinephrine
        • epirubicin
        • ertapenem
        • erythromycin
        • esmolol
        • etoposide
        • etoposide phosphate
        • famotidine
        • fenoldopam
        • fentanyl
        • floxuridine
        • fluconazole
        • fludarabine
        • fluorouracil
        • foscarnet
        • fosphenytoin
        • furosemide
        • ganciclovir
        • gemcitabine
        • gentamicin
        • glycopyrrolate
        • granisetron
        • haloperidol
        • heparin
        • hetastarch
        • hydralazine
        • hydrocortisone
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        • insulin, regular
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        • magnesium sulfate
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        • nitroglycerin
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        • oxaliplatin
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        • pamidronate
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        • pentamidine
        • pentobarbital
        • pentostatin
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        • phentolamine
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        • potassium acetate
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        • procainamide
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        • sodium acetate
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        • verapamil
        • vinblastine
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        • vinorelbine
        • voriconazole
        • zidovudine
        • zoledronic acid
    • Y-Site Incompatibility:
      • amiodarone
      • amphotericin B deoxycholate
      • amphotericin B liposome
      • MORE...
        • chlorpromazine
        • diazepam
        • digoxin
        • doxorubicin liposomal
        • gemtuzumab ozogamicin
        • hydroxyzine
        • idarubicin
        • indomethacin
        • labetalol
        • methylprednisolone
        • mitoxantrone
        • phenytoin
        • propranolol

    Paclitaxel Protein-Bound Particles (albumin-bound)

    IV Administration

    • Intermittent Infusion:   Reconstitution: Reconstitute by slowly adding 20 mL to each vial over at least 1 min for a concentration of 5 mg/mL. Direct solution to inside wall of vial to prevent foaming. Allow vial to sit for at least 5 min to ensure proper wetting of cake/powder. Gently swirl or invert vial for at least 2 min until powder is completely dissolved; avoid foaming. If foaming or clumping occurs, allow vial to stand for 15 min until foaming dissolves. Solution should be milky and homogenous without visible particles. If particles or settling are visible, gently invert vial to resuspend. Inject appropriate amount into sterile PVC IV bag. Do not use an in-line filter during administration. Do not administer solutions that are discolored or contain particulate matter. Reconstituted solution should be administered immediately but is stable for 8 hr if refrigerated. Discard unused portion.
    • Rate: Administer over 30 min. Monitor infusion site closely for infiltration.
    • Y-Site Compatibility:
      • carboplatin
      • dexamethasone
      • gemcitabine
      • MORE...
        • granisetron
        • palonosetron

    Patient/Family Teaching

    • Explain purpose of paclitaxel to patient. Advise patient to read  Patient Information  before starting therapy and periodically during therapy in case of changes.
    • Advise patient to notify health care professional immediately of rash, difficulty breathing, or symptoms of hypersensitivity reaction occurs.
    • Instruct patient to notify health care professional promptly if fever; chills; cough; hoarseness; sore throat; signs of infection; lower back or side pain; painful or difficult urination; bleeding gums; bruising; petechiae; blood in stools, urine, or emesis; dyspnea; or orthostatic hypotension occurs. Caution patient to avoid crowds and persons with known infections. Instruct patient to use soft toothbrush and electric razor and to avoid falls. Caution patient not to drink alcoholic beverages or to take medication containing aspirin or NSAIDs; may precipitate gastric bleeding.
    • May cause dizziness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
    • Instruct patient to notify health care professional if abdominal pain, yellow skin, weakness, paresthesia, gait disturbances, or joint or muscle aches occur.
    • Instruct patient to inspect oral mucosa for redness and ulceration. If mouth sores occur, advise patient to use sponge brush and rinse mouth with water after eating and drinking. Stomatitis usually resolves in 5–7 days.
    • Discuss with patient the possibility of hair loss. Complete hair loss usually occurs between days 14 and 21 and is reversible after discontinuation of therapy. Explore coping strategies.
    • Instruct patient not to receive any vaccinations without advice of health care professional.
    • Rep:  Advise females of reproductive potential to use a nonhormonal method of contraception during and for at least 6 mo after last dose of therapy and to avoid breast feeding during and for 2 wk after last dose. Advise male patients with female partners of reproductive potential to use effective contraception during and for at least 3 mo after last dose. May impair fertility in females and males.
    • Emphasize the need for periodic lab tests to monitor for side effects.

    Evaluation/Desired Outcomes

    Decrease in size or spread of malignancy.

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