Docetaxel

Pronunciation

Pronunciation: DOE-se-TAX-el
Class: Taxoid

Trade Names

Taxotere
- Injection 20 mg per 0.5 mL
- Injection 80 mg per 2 mL

Pharmacology

Inhibits mitosis by disrupting microtubular network essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly.

Slideshow: 2014 Update: First Time Brand-to-Generic Switches

Pharmacokinetics

Distribution

Approximately 94% to 97% protein bound. Steady-state Vd is 113 L.

Metabolism

Metabolized by CYP3A4 to 1 major and 3 minor metabolites.

Elimination

The t ½ is 4 min (alpha phase), 36 min (beta phase), and 11.1 h (gamma phase). Cl is 21 L/h/m 2 . Approximately 6% excreted in urine; approximately 75% excreted in feces (less than 8% as unchanged drug).

Special Populations

Hepatic Function Impairment

Total body Cl reduced by average of 27% and AUC increased 38% in patients with mild to moderate hepatic function impairment (ALT and/or AST more than 1.5 × ULN concomitant with alkaline phosphatase more than 2.5 × ULN).

Indications and Usage

For locally advanced or metastatic breast cancer after failure of prior chemotherapy; in combination with doxorubicin and cyclophosphamide for adjuvant treatment in operable node-positive breast cancer; in combination with cisplatin and fluorouracil for the treatment of advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, in patients who have not received prior chemotherapy for advanced disease; in combination with cisplatin and fluorouracil for induction treatment of inoperable, locally advanced, squamous cell carcinoma of the head and neck; as single agent for locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy; in combination with cisplatin for unresectable, locally advanced, or metastatic NSCLC for those who have not previously received chemotherapy; in combination with prednisone for androgen-independent metastatic prostate cancer.

Unlabeled Uses

Ovarian cancer; urothelial cancer; small cell lung cancer; esophageal cancer.

Contraindications

History of severe hypersensitivity reactions to docetaxel or other drugs formulated with polysorbate 80; neutrophil counts of less than 1,500 cells/mm 3 .

Dosage and Administration

Premedication Regimen

Premedicate patients with prostate cancer with dexamethasone 8 mg at 12, 3, and 1 h before docetaxel infusion. Premedicate all other patients with dexamethasone 8 mg twice daily for 3 days starting 1 day before docetaxel infusion.

Locally Advanced or Metastatic Breast Cancer After Failure of Prior Chemotherapy
Adults

IV 60 to 100 mg/m 2 IV as a 1-h infusion every 3 wk.

Dosage Adjustment

Discontinue docetaxel treatment entirely in patients who develop grade 3 or higher peripheral neuropathy.

Initial dose 60 mg/m 2

Patients who do not experience these symptoms may tolerate higher doses.

Initial dose 100 mg/m 2

Adjust dose to 75 mg/m 2 in patients who experience febrile neutropenia, neutrophils less than 500 cells/mm 3 for longer than 1 wk, or severe or cumulative cutaneous reactions. If reactions continue, reduce dose to 55 mg/m 2 or discontinue treatment.

Operable Node-Positive Breast Cancer, Adjuvant Treatment
Adults

IV 75 mg/m 2 as a 1-h infusion administered 1 h after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 every 3 wk for 6 cycles. Prophylactic granulocyte colony-stimulating factor (G-CSF) may be used to mitigate the risk of hematological toxicities.

Dosage Adjustment Neutropenia

Administer docetaxel in combination with doxorubicin and cyclophosphamide when neutrophil count is at least 1,500 cells/mm 3 . Patients who experience febrile neutropenia should receive G-CSF in all subsequent cycles without dose reduction. Patients who continue to experience febrile neutropenia should have docetaxel dose reduced to 60 mg/m 2 with continuation of G-CSF.

Other reactions

Patients who experience severe or cumulative cutaneous reactions, moderate neurosensory signs and/or symptoms, or grade 3/4 stomatitis should have docetaxel dose reduced to 60 mg/m 2 . Discontinue treatment if reactions continue at reduced dose.

For doxorubicin and cyclophosphamide dose modifications, see manufacturer's prescribing information.

Gastric Adenocarcinoma
Adults

IV 75 mg/m 2 as a 1-h infusion, followed by cisplatin 75 mg/m 2 as a 1- to 3-h infusion (both on day 1), followed by fluorouracil 750 mg/m 2 daily as a 24-h continuous infusion for 5 days starting at the end of the cisplatin infusion. Repeat treatment every 3 wk. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration.

Dosage Adjustment

G-CSF is recommended during the second and/or subsequent cycles in case of febrile neutropenia, documented infection with neutropenia, or neutropenia lasting more than 7 days. If an episode of febrile neutropenia, prolonged neutropenia, or neutropenic infection occurs despite G-CSF administration, reduce docetaxel dose to 60 mg/m 2 . If subsequent episodes of complicated neutropenia occur, reduce docetaxel dose to 45 mg/m 2 . In case of grade 4 thrombocytopenia, reduce docetaxel to 60 mg/m 2 . Patients should not be retreated with subsequent cycles of docetaxel until neutrophils return to a level of more than 1,500 cells/mm 3 and platelets recover to more than 100,000 cells/mm 3 . Discontinue treatment if toxicities persist.

For cisplatin and fluorouracil dose modifications, see manufacturer's prescribing information.

Head and Neck Cancer
Adults

IV 75 mg/m 2 as a 1-h infusion, followed by cisplatin 75 mg/m 2 IV over 1 h on day 1, followed by fluorouracil as a continuous infusion at 750 mg/m 2 daily for 5 days. Repeat this regimen every 3 wk for 4 cycles. Following chemotherapy, patients should receive radiotherapy. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration.

Dosage Adjustment

G-CSF is recommended during the second and/or subsequent cycles in case of febrile neutropenia, documented infection with neutropenia, or neutropenia lasting more than 7 days. If an episode of febrile neutropenia, prolonged neutropenia, or neutropenic infection occurs despite G-CSF administration, reduce docetaxel dose to 60 mg/m 2 . If subsequent episodes of complicated neutropenia occur, reduce docetaxel dose to 45 mg/m 2 . In case of grade 4 thrombocytopenia, reduce docetaxel to 60 mg/m 2 . Patients should not be retreated with subsequent cycles of docetaxel until neutrophils return to a level of more than 1,500 cells/mm 3 and platelets recover to more than 100,000 cells/mm 3 . Discontinue treatment if toxicities persist.

For cisplatin and fluorouracil dose modifications, see manufacturer's prescribing information.

Locally Advanced or Metastatic NSCLC After Failure of Prior Platinum-Based Chemotherapy
Adults

IV 75 mg/m 2 as a 1-h infusion every 3 wk.

Dosage Adjustment

For patients who experience either febrile neutropenia, neutrophils less than 500 cells/mm 3 for longer than 1 wk, severe or cumulative cutaneous reactions, or other grade 3/4 nonhematologic toxicities, withhold docetaxel until resolution of toxicity and then resume therapy at 55 mg/m 2 . Discontinue docetaxel entirely in patients who develop grade 3 or higher peripheral neuropathy.

Locally Advanced or Metastatic NSCLC (Chemotherapy Naive)
Adults

IV 75 mg/m 2 as a 1-h infusion immediately followed by cisplatin 75 mg/m 2 over 30 to 60 min every 3 wk.

Dosage Adjustment

For patients whose nadir of platelet count is less than 25,000 cells/mm 3 during previous course of therapy, those who experience febrile neutropenia, or those with serious nonhematologic toxicities, reduce docetaxel dose to 65 mg/m 2 in subsequent cycles. In patients who require a further dose reduction, a dose of 50 mg/m 2 is recommended. For cisplatin dosage adjustments, see manufacturer's prescribing information.

Prostate Cancer
Adults

IV 75 mg/m 2 as a 1-h infusion every 3 wk. Prednisone 5 mg PO twice daily is administered continuously.

Dosage Adjustment

Administer docetaxel when neutrophil count is 1,500 cells/mm 3 or higher. Adjust dose to 60 mg/m 2 in patients who experience febrile neutropenia, neutrophils less than 500 cells/mm 3 for longer than 1 wk, severe or cumulative cutaneous reactions, or moderate neurosensory signs and/or symptoms. If reactions continue at 60 mg/m 2 , discontinue docetaxel.

Dosage Modifications for GI Toxicities in Patients Treated With Docetaxel in Combination With Cisplatin and Fluorouracil
Diarrhea grade 3

For first episode, reduce fluorouracil dose 20%; for second episode, reduce docetaxel dose 20%.

Diarrhea grade 4

For first episode, reduce docetaxel and fluorouracil doses 20%; for second episode, discontinue treatment.

Stomatitis/Mucositis grade 3

For first episode, reduce fluorouracil dose 20%; for second episode, stop fluorouracil only, at all subsequent cycles; for third episode, reduce docetaxel dose 20%.

Stomatitis/Mucositis grade 4

For first episode, stop fluorouracil only, at all subsequent cycles; for second episode, reduce docetaxel dose 20%.

Dosage Adjustment in Hepatic Function Impairment

Reduce docetaxel dose 20% for AST/ALT more than 2.5 to 5 × ULN and alkaline phosphatase 2.5 × ULN or less, or AST/ALT more than 1.5 to 5 × ULN and alkaline phosphatase more than 2.5 to 5 × ULN. Discontinue docetaxel for AST/ALT more than 5 × ULN and/or alkaline phosphatase more than 5 × ULN (see Warnings and Precautions).

Dosage Adjustment for Neutropenia

Reduce docetaxel dose 25% in subsequent cycles following severe neutropenia (less than 500 cell/mm 3 ) lasting at least 7 days, febrile neutropenia, or a grade 4 infection in a docetaxel cycle.

General Advice

  • Premedicate all patients with oral corticosteroids to reduce incidence and severity of fluid retention and hypersensitivity reactions.
  • For IV infusion only. Not for intradermal, subcutaneous, IM, IV bolus, or intraarterial administration.
  • Concentrate must be diluted before administration.
  • Diluted solutions may leach diethylhexyl phthalate from polyvinyl chloride infusion sets or plastic bags. Use glass, polypropylene, or polyolefin containers, and polyethylene-lined administration sets.
  • Follow institutional and National Institutes of Health procedures for handling, administration, and disposal of cancer drugs. Wear appropriate protective equipment when preparing and administering docetaxel.
  • If docetaxel injection concentrate, initial diluted solution, or final dilution for infusion comes in contact with skin, wash skin immediately with soap and water. If contact with a mucous membrane occurs, flush thoroughly with water.
  • Allow refrigerated vials to stand at room temperature for approximately 5 min before performing initial dilution.
  • Withdraw entire contents of appropriate supplied diluent (approximately 1.8 mL for 20 mg vial; approximately 7.1 mL for 80 mg vial) and transfer to appropriate vial of docetaxel injection concentrate to produce a final concentration of docetaxel 10 mg/mL. Mix initial diluted solution by repeated inversion for at least 45 sec. Do not shake.
  • Diluted solution should be clear yellow to brownish-yellow. Some foaming at top of solution is normal; allow solution to stand for a few minutes to allow foam to dissipate.
  • Prepare final dilution for infusion by withdrawing required amount of initial diluted docetaxel and injecting it into 250 mL infusion bag or bottle of either sodium chloride 0.9% solution or dextrose 5% injection to produce a final concentration of docetaxel 0.3 to 0.74 mg/mL. If required docetaxel dose is more than 200 mg, use a larger volume of infusion vehicle so concentration does not exceed 0.74 mg/mL. Thoroughly mix infusion by manual rotation.
  • Do not use initial diluted solution or final dilution for infusion if solution is discolored, cloudy, or contains particulate matter.
  • Administer final diluted infusion solution IV over 1 h.

Storage/Stability

Store vials between 36° and 77°F in original package to protect from bright light. Freezing does not adversely affect docetaxel injection concentrate. Use initial diluted solution immediately or store for up to 8 h in refrigerator or at room temperature. Final diluted infusion solution is stable for 4 h if stored between 36° and 77°F. Use final diluted infusion solution within 4 h, including the 1-h IV administration.

Drug Interactions

CYP-450

Docetaxel is metabolized by CYP-450 3A. Potential exists for significant drug interactions between docetaxel and agents that inhibit or induce CYP-450 enzymes (eg, cyclosporine, erythromycin, ketoconazole, phenobarbital, rifampin).

Laboratory Test Interactions

None well documented.

Adverse Reactions

The incidences stated for the following adverse reactions were reported with docetaxel 75 or 100 mg/m 2 monotherapy.

Cardiovascular

Hypotension (3%); atrial fibrillation, deep vein thrombosis, ECG abnormalities, MI, pulmonary embolism, syncope, tachycardia, thrombophlebitis (postmarketing).

CNS

Asthenia (65%); neurosensory (57%); neuromotor (16%); confusion, seizures, transient loss of consciousness (postmarketing).

Dermatologic

Alopecia (76%); cutaneous reactions (48%); nail changes (31%); rare cases of bullous eruptions such as erythema multiforme or Stevens-Johnson syndrome (postmarketing).

EENT

Conjunctivitis, lacrimation, transient visual disturbances including flashes, flashing lights, and scotomata (postmarketing).

GI

Stomatitis (53%; severe, 8%); diarrhea (42%); nausea (39%); vomiting (22%); taste perversion (6%); abdominal pain, anorexia, colitis, constipation, dehydration associated with GI reactions, duodenal ulcer, esophagitis, GI hemorrhage, GI perforation, ileus, intestinal obstruction, ischemic colitis, neutropenic enterocolitis (postmarketing).

Genitourinary

Renal insufficiency (postmarketing).

Hematologic-Lymphatic

Neutropenia (98%; severe, 84%), leukopenia (96%); anemia (95%); febrile neutropenia (12%); thrombocytopenia (11%); bleeding episodes (postmarketing).

Hepatic

Increased ALT or AST (19%); elevated bilirubin (9%); increased alkaline phosphatase (7%); hepatitis (postmarketing).

Hypersensitivity

Hypersensitivity reactions (21%; severe, 47%).

Local

Infusion-site reactions including extravasation, hyperpigmentation, inflammation, phlebitis, redness or dryness of skin, and swelling of vein (4%).

Metabolic-Nutritional

Fluid retention (64%; severe, 7%).

Musculoskeletal

Myalgia (23%); arthralgia (9%).

Respiratory

Acute pulmonary edema, acute respiratory distress syndrome, dyspnea, interstitial pneumonia, pulmonary fibrosis (postmarketing).

Miscellaneous

Infection (34%; severe, 10%); fever in absence of infection (31%); septic death (2%); nonseptic death (1%); chest pain, diffuse pain, radiation recall phenomenon (postmarketing).

Precautions

Warnings

Fluid retention

Severe fluid retention, characterized by poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, and/or pronounced abdominal distention caused by ascites, has occurred despite corticosteroid pretreatment.

Hepatic function impairment

In general, do not give docetaxel to patients with bilirubin higher than ULN or to patients with AST and/or ALT more than 1.5 × ULN concomitant with alkaline phosphatase more than 2.5 × ULN. These patients are at increased risk for development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death.

Hypersensitivity

Severe hypersensitivity reactions, characterized by hypotension and/or bronchospasm, generalized rash/erythema, or, rarely, fatal anaphylaxis, may occur within a few min following initiation of infusion and despite corticosteroid pretreatment. Hypersensitivity reactions require immediate discontinuation of docetaxel and administration of appropriate therapy. Severe reactions should not receive rechallenge. Do not administer to patients with prior severe hypersensitivity reactions to docetaxel or other drugs formulated with polysorbate 80.

Increased mortality

Treatment-related mortality is increased in patients with liver dysfunction, those receiving higher doses, and those with NSCLC and history of platinum therapy who receive docetaxel 100 mg/m 2 .

Neutropenia

Neutropenia (less than 2,000 neutrophils/mm 3 ) occurs in virtually all patients given docetaxel 60 to 100 mg/m 2 , and grade 4 neutropenia (less than 500 cells/mm 3 ) occurs in 85% of patients given 100 mg/m 2 and 75% of patients given 60 mg/m 2 . Do not administer docetaxel to patients with neutrophil counts less than 1,500 cells/mm 3 .


Monitor

Frequently monitor CBC, including differential and platelet counts. Evaluate bilirubin, ALT or AST, and alkaline phosphatase prior to each cycle of docetaxel.


Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Patients 65 yr of age and older appear to experience adverse reactions more frequently than younger patients treated with the same regimen. Make dose selection with caution, reflecting the greater frequency of decreased hepatic and renal function, and comorbidity.

Acute myeloid leukemia (AML)

AML has occurred in patients receiving anthracyclines or cyclophosphamide, including use in adjuvant therapy for breast cancer.

Asthenia

Severe asthenia has been reported in 14.9% of metastatic breast cancer patients.

Dermatologic

Reversible cutaneous reactions characterized by a rash, including localized eruptions, mainly on the feet or hands, but also on the arms, face, or thorax, usually associated with pruritus, have been observed. Localized erythema of the extremities with edema followed by desquamation has been observed. Severe nail disorders also have been reported.

Neuropathy

Severe sensory neuropathy (eg, dysesthesia, pain, paresthesia) has been reported in 5.5% of metastatic breast cancer patients. Adjust dose if symptoms occur; discontinue treatment if symptoms persist. Severe peripheral motor neuropathy, mainly manifested by distal extremity weakness, also can occur.

Neutropenia/Thrombocytopenia

Reversible bone marrow suppression is the major dose-limiting toxicity. The median time to nadir is 7 days and the median duration of severe neutropenia is 7 days. Thrombocytopenia associated with fatal GI hemorrhage has been reported. Do not retreat with subsequent cycles until neutrophils recover to more than 1,500 cells/mm 3 and platelets recover to more than 100,000 cells/mm 3 .

Overdosage

Symptoms

Bone marrow suppression, mucositis, peripheral neurotoxicity.

Patient Information

  • Advise patient or caregiver to read patient information leaflet before starting therapy.
  • Explain name, action, potential benefits, and potential adverse reactions of drug, including risk of fluid retention, hypersensitivity reactions, and infections. Review the treatment regimen, including dosing schedule, duration of treatment, and monitoring that will be required.
  • Advise patient or caregiver that medication will be prepared and administered by health care provider in a health care setting.
  • Advise patients of importance of pretreatment with a corticosteroid (eg, dexamethasone) and instruct patient to take corticosteroid exactly on the schedule set by health care provider. Instruct patients to notify health care provider before receiving docetaxel if they did not take the corticosteroid or did not take it on schedule.
  • Instruct patient to immediately notify health care provider if any of the following occur: bleeding; chest tightness; difficulty breathing or unexplained shortness of breath; fever, chills, or other signs of infection; muscle or joint pain; numbness, tingling, or burning sensation in hands or feet; rapid, unexplained weight gain; rash, hives, or any other sign of allergic reaction; severe or persistent diarrhea or vomiting; sores in mouth; swelling in feet and/or legs; unusual bruising.
  • Advise patient or caregiver that hair loss is a common adverse reaction of therapy, but is usually reversible after therapy has been completed.
  • Advise patient that color changes to fingernails or toenails may occur and, in extreme cases, the nails may fall off, but the nails will usually grow back after therapy has been completed.
  • Caution women of childbearing potential to avoid becoming pregnant during therapy.

Copyright © 2009 Wolters Kluwer Health.

Hide
(web2)