Docetaxel (DOCETAXEL ANHYDROUS) injection, solution
Hospira, Inc.

Hospira, Inc.
Hospira Australia Pty Ltd
Zydus Hospira Oncology Private Limited
Docetaxel
DOCETAXEL ANHYDROUS
DOCETAXEL ANHYDROUS
DOCETAXEL ANHYDROUS
POLYSORBATE 80
CITRIC ACID MONOHYDRATE
ALCOHOL
POLYETHYLENE GLYCOL 300

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION

Treatment-related mortality associated with docetaxel is increased in patients with abnormal liver function, in patients receiving higher doses, and in patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who receive docetaxel as a single agent at a dose of 100 mg/m2 [see Warnings and Precautions (5.1) ].

Avoid the use of Docetaxel Injection in patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated elevations of transaminase >1.5 × ULN also had a higher rate of febrile neutropenia. Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of Docetaxel Injection [see Warnings and Precautions (5.2) ].

Do not administer Docetaxel Injection to patients with neutrophil counts of <1500 cells/mm3. Monitor blood counts frequently as neutropenia may be severe and result in infection [see Warnings and Precautions (5.3) ].

Do not administer Docetaxel Injection to patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80 [see Contraindications (4) ]. Severe hypersensitivity reactions have been reported in patients despite dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the Docetaxel Injection infusion and administration of appropriate therapy [see Warnings and Precautions (5.5) ].

Severe fluid retention occurred in 6.5% (6/92) of patients despite use of dexamethasone premedication. It was characterized by one or more of the following events: poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites) [see Warnings and Precautions (5.6) ].

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION

See full prescribing information for complete boxed warning.

  • Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1)
  • Avoid use of Docetaxel Injection if bilirubin > ULN, or if AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (5.2)
  • Do not administer Docetaxel Injection to patients with neutrophil counts <1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4, 5.3)
  • Severe hypersensitivity, including fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy (5.5)
  • Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4)
  • Severe fluid retention may occur despite dexamethasone (5.6)

1 INDICATIONS AND USAGE

Docetaxel Injection is a microtubule inhibitor indicated for:

  • Breast Cancer (BC): single agent for locally advanced or metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC (1.1)
  • Non-small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC (1.2)
  • Castration-Resistant Prostate Cancer (CRPC): with prednisone in metastatic castration-resistant prostate cancer (1.3)
  • Gastric Adenocarcinoma (GC): with cisplatin and fluorouracil for untreated, advanced GC, including the gastroesophageal junction (1.4)
  • Squamous Cell Carcinoma of the Head and Neck (SCCHN): with cisplatin and fluorouracil for induction treatment of locally advanced SCCHN (1.5)

1.1 Breast Cancer

Docetaxel Injection is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy.

Docetaxel Injection in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer.

1.2 Non-small Cell Lung Cancer

Docetaxel Injection as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy.

Docetaxel Injection in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition.

1.3 Prostate Cancer

Docetaxel Injection in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer.

1.4 Gastric Adenocarcinoma

Docetaxel Injection in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease.

1.5 Head and Neck Cancer

Docetaxel Injection in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

2 DOSAGE AND ADMINISTRATION

For all indications, toxicities may warrant dosage adjustments [see Dosage and Administration (2.7) ].

Administer in a facility equipped to manage possible complications (e.g., anaphylaxis).

Administer in a facility equipped to manage possible complications (e.g., anaphylaxis). Administer intravenously (IV) over 1 hour every 3 weeks. PVC equipment is not recommended. Use only a 21 gauge needle to withdraw Docetaxel Injection from the vial.

  • BC locally advanced or metastatic: 60 mg/m2 to 100 mg/m2 single agent (2.1)
  • BC adjuvant: 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 cycles (2.1)
  • NSCLC: after platinum therapy failure: 75 mg/m2 single agent (2.2)
  • NSCLC: chemotherapy-naïve: 75 mg/m2 followed by cisplatin 75 mg/m2 (2.2)
  • CRPC: 75 mg/m2 with 5 mg prednisone twice a day continuously (2.3)
  • GC: 75 mg/m2 followed by cisplatin 75 mg/m2 (both on day 1 only) followed by fluorouracil 750 mg/m2 per day as a 24-hour IV (days 1–5), starting at end of cisplatin infusion (2.4)
  • SCCHN: 75 mg/m2 followed by cisplatin 75 mg/m2 IV (day 1), followed by fluorouracil 750 mg/m2 per day as a 24-hour IV (days 1–5), starting at end of cisplatin infusion; for 4 cycles (2.5)
  • SCCHN: 75 mg/m2 followed by cisplatin 100 mg/m2 IV (day 1), followed by fluorouracil 1000 mg/m2 per day as a 24-hour IV (days 1–4); for 3 cycles (2.5)

For all patients:

  • Premedicate with oral corticosteroids (2.6)
  • Adjust dose as needed (2.7)

2.1 Breast Cancer

  • For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of Docetaxel Injection is 60 mg/m2 to 100 mg/m2 administered intravenously over 1 hour every 3 weeks.
  • For the adjuvant treatment of operable node-positive breast cancer, the recommended Docetaxel Injection dose is 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 courses. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities [see Dosage and Administration (2.7) ].

2.2 Non-small Cell Lung Cancer

  • For treatment after failure of prior platinum-based chemotherapy, docetaxel was evaluated as monotherapy, and the recommended dose is 75 mg/m2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m2 in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized controlled trials [see Boxed Warning, Dosage and Administration (2.7), Warnings and Precautions (5), Clinical Studies (14) ].
  • For chemotherapy-naïve patients, docetaxel was evaluated in combination with cisplatin. The recommended dose of Docetaxel Injection is 75 mg/m2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m2 over 30–60 minutes every 3 weeks [see Dosage and Administration (2.7) ].

2.3 Prostate Cancer

  • For metastatic castration-resistant prostate cancer, the recommended dose of Docetaxel Injection is 75 mg/m2 every 3 weeks as a 1 hour intravenous infusion. Prednisone 5 mg orally twice daily is administered continuously [see Dosage and Administration (2.7) ].

2.4 Gastric Adenocarcinoma

  • For gastric adenocarcinoma, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m2 per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration (2.7) ].

2.5 Head and Neck Cancer

Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the Docetaxel Injection containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.

Induction Chemotherapy Followed by Radiotherapy (TAX323)

For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion followed by cisplatin 75 mg/m2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy [see Dosage and Administration (2.7) ].

Induction Chemotherapy Followed by Chemoradiotherapy (TAX324)

For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy [see Dosage and Administration (2.7) ].

2.6 Premedication Regimen

All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to Docetaxel Injection administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.5) ].

For metastatic castration-resistant prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg at 12 hours, 3 hours, and 1 hour before the Docetaxel Injection infusion [see Warnings and Precautions (5.5) ].

2.7 Dosage Adjustments during Treatment

Breast Cancer

Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, or severe or cumulative cutaneous reactions during Docetaxel Injection therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during Docetaxel Injection therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection treatment discontinued entirely.

Combination Therapy with Docetaxel Injection in the Adjuvant Treatment of Breast Cancer

Docetaxel Injection in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1500 cells/mm3. Patients who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their Docetaxel Injection dose reduced to 60 mg/m2. Patients who experience grade 3 or 4 stomatitis should have their Docetaxel Injection dose decreased to 60 mg/m2. Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection therapy should have their dosage of Docetaxel Injection reduced from 75 mg/m2 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, treatment should be discontinued.

Non-small Cell Lung Cancer

Monotherapy with Docetaxel Injection for NSCLC Treatment after Failure of Prior Platinum-Based Chemotherapy

Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during Docetaxel Injection treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection treatment discontinued entirely.

Combination Therapy with Docetaxel Injection for Chemotherapy-Naïve NSCLC

For patients who are dosed initially at Docetaxel Injection 75 mg/m2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the Docetaxel Injection dosage in subsequent cycles should be reduced to 65 mg/m2. In patients who require a further dose reduction, a dose of 50 mg/m2 is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information.

Prostate Cancer

Combination Therapy with Docetaxel Injection for Metastatic Castration-Resistant Prostate Cancer

Docetaxel Injection should be administered when the neutrophil count is ≥1500 cells/mm3. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection therapy should have the dosage of Docetaxel Injection reduced from 75 mg/m2 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, the treatment should be discontinued.

Gastric or Head and Neck Cancer

Docetaxel Injection in Combination with Cisplatin and Fluorouracil in Gastric Cancer or Head and Neck Cancer

Patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines. In both studies, G-CSF was recommended during the second and/or subsequent cycles in case of febrile neutropenia, or 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 use, the Docetaxel Injection dose should be reduced from 75 mg/m2 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur the Docetaxel Injection dose should be reduced from 60 mg/m2 to 45 mg/m2. In case of grade 4 thrombocytopenia the Docetaxel Injection dose should be reduced from 75 mg/m2 to 60 mg/m2. Do not retreat patients with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1500 cells/mm3 [see Contraindications (4) ]. Avoid retreating patients until platelets recover to a level >100,000 cells/mm3. Discontinue treatment if these toxicities persist [see Warnings and Precautions (5.3) ].

Recommended dose modifications for toxicities in patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil are shown in Table 1.

Table 1: Recommended Dose Modifications for Toxicities in Patients Treated with Docetaxel Injection in Combination with Cisplatin and Fluorouracil

Toxicity

Dosage Adjustment

Diarrhea grade 3

First episode: reduce fluorouracil dose by 20%.
Second episode: then reduce Docetaxel Injection dose by 20%.

Diarrhea grade 4

First episode: reduce Docetaxel Injection and fluorouracil doses by 20%.
Second episode: discontinue treatment.

Stomatitis/mucositis grade 3

First episode: reduce fluorouracil dose by 20%.
Second episode: stop fluorouracil only, at all subsequent cycles.
Third episode: reduce Docetaxel Injection dose by 20%.

Stomatitis/mucositis grade 4

First episode: stop fluorouracil only, at all subsequent cycles.
Second episode: reduce Docetaxel Injection dose by 20%.

Liver dysfunction: In case of AST/ALT >2.5 to ≤5 × ULN and AP ≤2.5 × ULN, or AST/ALT >1.5 to ≤5 × ULN and AP >2.5 to ≤5 × ULN, Docetaxel Injection should be reduced by 20%.

In case of AST/ALT >5 × ULN and/or AP >5 × ULN Docetaxel Injection should be stopped.

The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below.

Cisplatin Dose Modifications and Delays

Peripheral Neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCI-CTCAE grade:

  • Grade 2: Reduce cisplatin dose by 20%.
  • Grade 3: Discontinue treatment.

Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.

Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 × normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2).

For other cisplatin dosage adjustments, also refer to the manufacturers' prescribing information.

Table 2: Dose Reductions for Evaluation of Creatinine Clearance
CrCl = Creatinine clearance

Creatinine Clearance Result Before Next Cycle

Cisplatin Dose Next Cycle

CrCl ≥60 mL/min

Full dose of cisplatin was given. CrCl was to be repeated before each treatment cycle.

CrCl between 40 and 59 mL/min

Dose of cisplatin was reduced by 50% at subsequent cycle. If CrCl was >60 mL/min at end of cycle, full cisplatin dose was reinstituted at the next cycle.

If no recovery was observed, then cisplatin was omitted from the next treatment cycle.

CrCl <40 mL/min

Dose of cisplatin was omitted in that treatment cycle only.

If CrCl was still <40 mL/min at the end of cycle, cisplatin was discontinued.

If CrCl was >40 and <60 mL/min at end of cycle, a 50% cisplatin dose was given at the next cycle.

If CrCl was >60 mL/min at end of cycle, full cisplatin dose was given at next cycle.

Fluorouracil Dose Modifications and Treatment Delays

For diarrhea and stomatitis, see Table 1.

In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%.

For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade ≤1 and then recommenced, if medically appropriate.

For other fluorouracil dosage adjustments, also refer to the manufacturers' prescribing information.

Combination Therapy with Strong CYP3A4 Inhibitors

Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require coadministration of a strong CYP3A4 inhibitor [see Drug Interactions (7), Clinical Pharmacology (12.3) ].

2.8 Administration Precautions

Docetaxel Injection is a hazardous anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Docetaxel Injection solutions. The use of gloves is recommended [see How Supplied/Storage and Handling (16.3) ].

If Docetaxel Injection or final dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Docetaxel Injection or final dilution for infusion should come into contact with mucosa, immediately and thoroughly wash with water.

Contact of the Docetaxel Injection with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final Docetaxel Injection dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

Docetaxel Injection requires NO prior dilution with a diluent and is ready to add to the infusion solution.

Please follow the preparation instructions provided below.

2.9 Preparation and Administration

Docetaxel Injection (10 mg/mL) requires NO prior dilution with a diluent and is ready to add to the infusion solution. Use only a 21 gauge needle to withdraw Docetaxel Injection from the vial because larger bore needles (e.g., 18 and 19 gauge) may result in stopper coring and rubber particulates.

Dilution for Infusion

  • 1.Docetaxel Injection unopened vials should be stored between 20°C and 25°C (68°F and 77°F). After first use and following multiple needle entries and product withdrawals, Docetaxel Injection multiple-dose vials should be stored between 2°C and 8°C (36°F and 46°F). If the vials are stored under refrigeration, allow the appropriate number of vials of Docetaxel Injection vials to stand at room temperature for approximately 5 minutes before use.
  • 2.Using only a 21 gauge needle, aseptically withdraw the required amount of Docetaxel Injection (10 mg docetaxel/mL) with a calibrated syringe and inject via a single injection (one shot) into a 250 mL infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 mg/mL to 0.74 mg/mL.
    If a dose greater than 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL docetaxel is not exceeded.
  • 3.Thoroughly mix the infusion by gentle manual rotation.
  • 4.As with all parenteral products, Docetaxel Injection should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the Docetaxel Injection dilution for intravenous infusion is not clear or appears to have precipitation, it should be discarded.
  • 5.Docetaxel Injection infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded.

The Docetaxel Injection dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25°C) and lighting conditions.

2.10 Stability

Docetaxel Injection final dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F), is stable for 4 hours. Docetaxel Injection final dilution for infusion (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 1 hour intravenous administration).

3 DOSAGE FORMS AND STRENGTHS

Docetaxel Injection, USP is a colorless to pale yellow solution available as:

  • 20 mg/2 mL (10 mg/mL) single-dose vial
  • 80 mg/8 mL (10 mg/mL) multiple-dose vial
  • 160 mg/16 mL (10 mg/mL) multiple-dose vial
  • 20 mg/2 mL (10 mg/mL) single-dose vial (3)
  • 80 mg/8 mL (10 mg/mL) multiple-dose vial (3)
  • 160 mg/16 mL (10 mg/mL) multiple-dose vial (3)

4 CONTRAINDICATIONS

Docetaxel Injection is contraindicated in patients with:

  • Hypersensitivity to docetaxel or polysorbate 80 (4)
  • Neutrophil counts of <1500 cells/mm3 (4)

5 WARNINGS AND PRECAUTIONS

  • Second primary malignancies: In patients treated with Docetaxel Injection-containing regimens, monitor for delayed AML, MDS, NHL, and renal cancer. (5.7)
  • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe cutaneous adverse reactions have been reported. Severe skin toxicity may require dose adjustment or permanent treatment discontinuation. (5.8)
  • Neurologic reactions: Reactions including paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.9)
  • Eye disorders: Cystoid macular edema (CME) has been reported and requires treatment discontinuation. (5.10)
  • Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.11)
  • Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (5.12, 8.1, 8.3)
  • Alcohol content: The alcohol content in a dose of Docetaxel Injection may affect the central nervous system. This may include impairment of a patient's ability to drive or use machines immediately after infusion. (5.13)
  • Tumor lysis syndrome: Tumor lysis syndrome has been reported. Patients at risk should be well hydrated and closely monitored during treatment. (5.14)

5.1 Toxic Deaths

Breast Cancer

Docetaxel administered at 100 mg/m2 was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients dosed at 60 mg/m2, mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function. Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths.

Non-small Cell Lung Cancer

Docetaxel administered at a dose of 100 mg/m2 in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies). There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m2 dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m2 dose level, 3 of 5 patients had an ECOG PS of 2 at study entry [see Dosage and Administration (2.2), Clinical Studies (14) ].

5.2 Hepatic Impairment

Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death.

Avoid Docetaxel Injection in patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN [see Warnings and Precautions (5.1) ].

For patients with isolated elevations of transaminase >1.5 × ULN, consider Docetaxel Injection dose modifications [see Dosage and Administration (2.7) ].

Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of Docetaxel Injection therapy.

5.3 Hematologic Effects

Perform frequent peripheral blood cell counts on all patients receiving Docetaxel Injection. Do not retreat patients with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1500 cells/mm3 [see Contraindications (4) ]. Avoid retreating patients until platelets recover to a level >100,000 cells/mm3.

A 25% reduction in the dose of Docetaxel Injection is recommended during subsequent cycles following severe neutropenia (<500 cells/mm3) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a Docetaxel Injection cycle [see Dosage and Administration (2.7) ].

Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 mg/m2 to 100 mg/m2 of docetaxel and grade 4 neutropenia (<500 cells/mm3) occurs in 85% of patients given 100 mg/m2 and 75% of patients given 60 mg/m2. Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. Docetaxel Injection should not be administered to patients with neutrophils <1500 cells/mm3.

Febrile neutropenia occurred in about 12% of patients given 100 mg/m2 but was very uncommon in patients given 60 mg/m2.

Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related [see Adverse Reactions (6.1), Clinical Studies (14) ].

Three breast cancer patients with severe liver impairment (bilirubin >1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia. In gastric cancer patients treated with docetaxel in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not. Patients receiving TCF should be closely monitored during the first and subsequent cycles for febrile neutropenia and neutropenic infection [see Dosage and Administration (2.7), Adverse Reactions (6) ].

5.4 Enterocolitis and Neutropenic Colitis

Enterocolitis and neutropenic colitis (typhlitis) have occurred in patients treated with Docetaxel Injection alone and in combination with other chemotherapeutic agents, despite the coadministration of G-CSF. Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications. Enterocolitis and neutropenic enterocolitis may develop at any time, and could lead to death as early as the first day of symptom onset.

Monitor patients closely from onset of any symptoms of gastrointestinal toxicity. Inform patients to contact their healthcare provider with new, or worsening symptoms of gastrointestinal toxicity [see Dosage and Administration (2), Warnings and Precautions (5.3), Adverse Reactions (6.2) ].

5.5 Hypersensitivity Reactions

Monitor patients closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the Docetaxel Injection infusion and aggressive therapy. Do not rechallenge patients with a history of severe hypersensitivity reactions with Docetaxel Injection [see Contraindications (4) ].

Patients who have previously experienced a hypersensitivity reaction to paclitaxel may develop a hypersensitivity reaction to docetaxel that may include severe or fatal reactions such as anaphylaxis. Monitor patients with a previous history of hypersensitivity to paclitaxel closely during initiation of docetaxel therapy. Hypersensitivity reactions may occur within a few minutes following initiation of a Docetaxel Injection infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of Docetaxel Injection [see Dosage and Administration (2.6) ].

5.6 Fluid Retention

Severe fluid retention has been reported following docetaxel therapy. Patients should be premedicated with oral corticosteroids prior to each Docetaxel Injection administration to reduce the incidence and severity of fluid retention [see Dosage and Administration (2.6) ]. Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions.

When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg.

Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m2. Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention. The median cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m2. Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of docetaxel to resolution (range: 0 to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).

5.7 Second Primary Malignancies

Second primary malignancies, notably acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), Non-Hodgkin's Lymphoma (NHL), and renal cancer, have been reported in patients treated with docetaxel-containing regimens. These adverse reactions may occur several months or years after docetaxel-containing therapy.

Treatment-related AML or MDS has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. In the adjuvant breast cancer trial (TAX316) AML occurred in 3 of 744 patients who received docetaxel, doxorubicin, and cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, doxorubicin, and cyclophosphamide [see Clinical Studies (14.2) ]. In TAC-treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up. Monitor patients for second primary malignancies [see Adverse Reactions (6.1) ].

5.8 Cutaneous Reactions

Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended [see Dosage and Administration (2.7) ]. The discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued docetaxel due to skin toxicity.

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with docetaxel treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and monitored closely. Permanent treatment discontinuation should be considered in patients who experience SCARs.

5.9 Neurologic Reactions

Severe neurosensory symptoms (e.g., paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued [see Dosage and Administration (2.7) ]. Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks). Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965).

5.10 Eye Disorders

Cystoid macular edema (CME) has been reported in patients treated with Docetaxel Injection. Patients with impaired vision should undergo a prompt and comprehensive ophthalmologic examination. If CME is diagnosed, Docetaxel Injection treatment should be discontinued and appropriate treatment initiated. Alternative non-taxane cancer treatment should be considered.

5.11 Asthenia

Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease.

5.12 Embryo-Fetal Toxicity

Based on findings from animal reproduction studies and its mechanism of action, Docetaxel Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ]. Available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify pregnancy status in females of reproductive potential prior to initiating Docetaxel Injection. Advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of Docetaxel Injection. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of Docetaxel Injection [see Use in Specific Populations (8.1, 8.3) ].

5.13 Alcohol Content

Cases of intoxication have been reported with some formulations of docetaxel due to the alcohol content. The alcohol content in a dose of Docetaxel Injection may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in Docetaxel Injection on the ability to drive or use machines immediately after the infusion. Each administration of Docetaxel Injection at 100 mg/m2 delivers 1.8 g/m2 of ethanol. For a patient with a BSA of 2.0 m2, this would deliver 3.6 grams of ethanol [see Description (11) ]. Other docetaxel products may have a different amount of alcohol.

5.14 Tumor Lysis Syndrome

Tumor lysis syndrome has been reported with docetaxel [see Adverse Reactions (6.2) ]. Patients at risk of tumor lysis syndrome (e.g., with renal impairment, hyperuricemia, bulky tumor) should be closely monitored prior to initiating Docetaxel Injection and periodically during treatment. Correction of dehydration and treatment of high uric acid levels are recommended prior to initiation of treatment.

6 ADVERSE REACTIONS

The most serious adverse reactions from docetaxel are:

The most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the indication.

Adverse reactions are described according to indication. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Responding patients may not experience an improvement in performance status on therapy and may experience worsening. The relationship between changes in performance status, response to therapy, and treatment-related side effects has not been established.

Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience

Breast Cancer

Monotherapy with Docetaxel for Locally Advanced or Metastatic Breast Cancer after Failure of Prior Chemotherapy

Docetaxel 100 mg/m2: Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received docetaxel administered at 100 mg/m2 as a 1-hour infusion every 3 weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to docetaxel. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving docetaxel for the treatment of breast cancer and in patients with other tumor types (see Table 3).

Table 3: Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m2

Adverse Reaction

All Tumor Types
Normal LFTs Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
n=2045
%

All Tumor Types
Elevated LFTs Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN
n=61
%

Breast Cancer
Normal LFTs


n=965
%

Hematologic

Neutropenia

  <2000 cells/mm3

96

96

99

  <500 cells/mm3

75

88

86

Leukopenia

  <4000 cells/mm3

96

98

99

  <1000 cells/mm3

32

47

44

Thrombocytopenia

  <100,000 cells/mm3

8

25

9

Anemia

  <11 g/dL

90

92

94

  <8 g/dL

9

31

8

Febrile NeutropeniaFebrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization

11

26

12

Septic Death

2

5

1

Non-Septic Death

1

7

1

Infections

  Any

22

33

22

  Severe

6

16

6

Fever in Absence of Infection

  Any

31

41

35

  Severe

2

8

2

Hypersensitivity Reactions

Regardless of Premedication

  Any

21

20

18

  Severe

4

10

3

With 3-day Premedication

n=92

n=3

n=92

  Any

15

33

15

  Severe

2

0

2

Fluid Retention

Regardless of Premedication

  Any

47

39

60

  Severe

7

8

9

With 3-day Premedication

n=92

n=3

n=92

  Any

64

67

64

  Severe

7

33

7

Neurosensory

  Any

49

34

58

  Severe

4

0

6

Cutaneous

  Any

48

54

47

  Severe

5

10

5

Nail Changes

  Any

31

23

41

  Severe

3

5

4

Gastrointestinal

Nausea

39

38

42

Vomiting

22

23

23

Diarrhea

39

33

43

  Severe

5

5

6

Stomatitis

  Any

42

49

52

  Severe

6

13

7

Alopecia

76

62

74

Asthenia

  Any

62

53

66

  Severe

13

25

15

Myalgia

  Any

19

16

21

  Severe

2

2

2

Arthralgia

9

7

8

Infusion Site Reactions

4

3

4

Hematologic Reactions

Reversible marrow suppression was the major dose-limiting toxicity of docetaxel [see Warnings and Precautions (5.3) ]. The median time to nadir was 7 days, while the median duration of severe neutropenia (<500 cells/mm3) was 7 days. Among 2045 patients with solid tumors and normal baseline LFTs, severe neutropenia occurred in 75.4% and lasted for more than 7 days in 2.9% of cycles.

Febrile neutropenia (<500 cells/mm3 with fever >38°C with intravenous antibiotics and/or hospitalization) occurred in 11% of patients with solid tumors, in 12.3% of patients with metastatic breast cancer, and in 9.8% of 92 breast cancer patients premedicated with 3-day corticosteroids.

Severe infectious episodes occurred in 6.1% of patients with solid tumors, in 6.4% of patients with metastatic breast cancer, and in 5.4% of 92 breast cancer patients premedicated with 3-day corticosteroids.

Thrombocytopenia (<100,000 cells/mm3) associated with fatal gastrointestinal hemorrhage has been reported.

Hypersensitivity Reactions

Severe hypersensitivity reactions have been reported [see Boxed Warning, Warnings and Precautions (5.5) ]. Minor events, including flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever, or chills, have been reported and resolved after discontinuing the infusion and instituting appropriate therapy.

Fluid Retention

Fluid retention can occur with the use of docetaxel [see Boxed Warning, Dosage and Administration (2.6), Warnings and Precautions (5.6) ].

Cutaneous Reactions

Severe skin toxicity is discussed elsewhere in the label [see Warnings and Precautions (5.8) ]. Reversible cutaneous reactions characterized by a rash including localized eruptions, mainly on the feet and/or hands, but also on the arms, face, or thorax, usually associated with pruritus, have been observed. Eruptions generally occurred within 1 week after docetaxel infusion, recovered before the next infusion, and were not disabling.

Severe nail disorders were characterized by hypo- or hyperpigmentation, and occasionally by onycholysis (in 0.8% of patients with solid tumors) and pain.

Neurologic Reactions

Neurologic reactions are discussed elsewhere in the label [see Warnings and Precautions (5.9) ].

Gastrointestinal Reactions

Nausea, vomiting, and diarrhea were generally mild to moderate. Severe reactions occurred in 3%–5% of patients with solid tumors and to a similar extent among metastatic breast cancer patients. The incidence of severe reactions was 1% or less for the 92 breast cancer patients premedicated with 3-day corticosteroids.

Severe stomatitis occurred in 5.5% of patients with solid tumors, in 7.4% of patients with metastatic breast cancer, and in 1.1% of the 92 breast cancer patients premedicated with 3-day corticosteroids.

Cardiovascular Reactions

Hypotension occurred in 2.8% of patients with solid tumors; 1.2% required treatment. Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension have occurred. Seven of 86 (8.1%) of metastatic breast cancer patients receiving docetaxel 100 mg/m2 in a randomized trial and who had serial left ventricular ejection fractions assessed developed deterioration of LVEF by ≥10% associated with a drop below the institutional lower limit of normal.

Infusion Site Reactions

Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein.

Hepatic Reactions

In patients with normal LFTs at baseline, bilirubin values greater than the ULN occurred in 8.9% of patients. Increases in AST or ALT >1.5 times the ULN, or alkaline phosphatase >2.5 times ULN, were observed in 18.9% and 7.3% of patients, respectively. While on docetaxel, increases in AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN occurred in 4.3% of patients with normal LFTs at baseline. Whether these changes were related to the drug or underlying disease has not been established.

Hematologic and Other Toxicity: Relation to Dose and Baseline Liver Chemistry Abnormalities

Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given docetaxel at 100 mg/m2 in the randomized and single arm studies of metastatic breast cancer after failure of previous chemotherapy; 18 patients in these studies who had abnormal baseline LFTs (defined as AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN); and 174 patients in Japanese studies given docetaxel at 60 mg/m2 who had normal LFTs (see Tables 4 and 5).

Table 4: Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests

Adverse Reaction

Docetaxel
100 mg/m2

Docetaxel
60 mg/m2

Normal LFTs Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN
n=730
%

Elevated LFTs Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN
n=18
%

Normal LFTs


n=174
%

Neutropenia

  Any <2000 cells/mm3

98

100

95

  Grade 4 <500 cells/mm3

84

94

75

Thrombocytopenia

  Any <100,000 cells/mm3

11

44

14

  Grade 4 <20,000 cells/mm3

1

17

1

Anemia <11 g/dL

95

94

65

Infection Incidence of infection requiring hospitalization and/or intravenous antibiotics was 8.5% (n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46 patients had grade 4 neutropenia.

  Any

23

39

1

  Grade 3 and 4

7

33

0

Febrile Neutropenia Febrile Neutropenia: For 100 mg/m2, ANC grade 4 and fever >38°C with intravenous antibiotics and/or hospitalization; for 60 mg/m2, ANC grade 3/4 and fever >38.1°C

  By Patient

12

33

0

  By Course

2

9

0

Septic Death

2

6

1

Non-Septic Death

1

11

0

Table 5: Non-Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests
NA = not available

Docetaxel
100 mg/m2

Docetaxel
60 mg/m2

Adverse Reaction

Normal LFTs Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN

Elevated LFTs Elevated Baseline Liver Function: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN

Normal LFTs

n=730

n=18

n=174

%

%

%

Acute Hypersensitivity Reaction

Regardless of Premedication

  Any

13

6

1

  Severe

1

0

0

Fluid Retention Fluid Retention includes (by COSTART): edema (peripheral, localized, generalized, lymphedema, pulmonary edema, and edema otherwise not specified) and effusion (pleural, pericardial, and ascites); no premedication given with the 60 mg/m 2 dose

Regardless of Premedication

  Any

56

61

13

  Severe

8

17

0

Neurosensory

  Any

57

50

20

  Severe

6

0

0

Myalgia

23

33

3

Cutaneous

  Any

45

61

31

  Severe

5

17

0

Asthenia

  Any

65

44

66

  Severe

17

22

0

Diarrhea

  Any

42

28

NA

  Severe

6

11

Stomatitis

  Any

53

67

19

  Severe

8

39

1

In the three-arm monotherapy trial, TAX313, which compared docetaxel 60 mg/m2, 75 mg/m2 and 100 mg/m2 in advanced breast cancer, grade 3/4 or severe adverse reactions occurred in 49.0% of patients treated with docetaxel 60 mg/m2 compared to 55.3% and 65.9% treated with 75 mg/m2 and 100 mg/m2, respectively. Discontinuation due to adverse reactions was reported in 5.3% of patients treated with 60 mg/m2 versus 6.9% and 16.5% for patients treated at 75 mg/m2 and 100 mg/m2, respectively. Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m2 compared to 5.3% and 1.6% for patients treated at 75 mg/m2 and 100 mg/m2, respectively.

The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m2, 75 mg/m2, and 100 mg/m2, respectively), thrombocytopenia (7%, 11% and 12%, respectively), neutropenia (92%, 94%, and 97%, respectively), febrile neutropenia (5%, 7%, and 14%, respectively), treatment-related grade 3/4 infection (2%, 3%, and 7%, respectively) and anemia (87%, 94%, and 97%, respectively).

Combination Therapy with Docetaxel in the Adjuvant Treatment of Breast Cancer

The following table presents treatment-emergent adverse reactions observed in 744 patients, who were treated with docetaxel 75 mg/m2 every 3 weeks in combination with doxorubicin and cyclophosphamide (see Table 6).

Table 6: Clinically Important Treatment-Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving Docetaxel in Combination with Doxorubicin and Cyclophosphamide (TAX316)

Docetaxel 75
mg/m2 + Doxorubicin 50 mg/m2 + Cyclophosphamide 500 mg/m2 (TAC)
n=744
%

Fluorouracil 500 mg/m2 + Doxorubicin 50 mg/m2 + Cyclophosphamide 500 mg/m2 (FAC)
n=736
%

Adverse Reaction

Any

Grade 3/4

Any

Grade 3/4

Anemia

92

4

72

2

Neutropenia

71

66

82

49

Fever in absence of infection

47

1

17

0

Infection

39

4

36

2

Thrombocytopenia

39

2

28

1

Febrile neutropenia

25

N/A

3

N/A

Neutropenic infection

12

N/A

6

N/A

Hypersensitivity reactions

13

1

4

0

Lymphedema

4

0

1

0

Fluid Retention COSTART term and grading system for events related to treatment.

35

1

15

0

Peripheral edema

27

0

7

0

Weight gain

13

0

9

0

Neuropathy sensory

26

0

10

0

Neuro-cortical

5

1

6

1

Neuropathy motor

4

0

2

0

Neuro-cerebellar

2

0

2

0

Syncope

2

1

1

0

Alopecia

98

N/A

97

N/A

Skin toxicity

27

1

18

0

Nail disorders

19

0

14

0

Nausea

81

5

88

10

Stomatitis

69

7

53

2

Vomiting

45

4

59

7

Diarrhea

35

4

28

2

Constipation

34

1

32

1

Taste perversion

28

1

15

0

Anorexia

22

2

18

1

Abdominal Pain

11

1

5

0

Amenorrhea

62

N/A

52

N/A

Cough

14

0

10

0

Cardiac dysrhythmias

8

0

6

0

Vasodilatation

27

1

21

1

Hypotension

2

0

1

0

Phlebitis

1

0

1

0

Asthenia

81

11

71

6

Myalgia

27

1

10

0

Arthralgia

19

1

9

0

Lacrimation disorder

11

0

7

0

Conjunctivitis

5

0

7

0

Of the 744 patients treated with TAC, 36.3% experienced severe treatment-emergent adverse reactions compared to 26.6% of the 736 patients treated with FAC. Dose reductions due to hematologic toxicity occurred in 1% of cycles in the TAC arm versus 0.1% of cycles in the FAC arm. Six percent of patients treated with TAC discontinued treatment due to adverse reactions, compared to 1.1% treated with FAC; fever in the absence of infection and allergy being the most common reasons for withdrawal among TAC-treated patients. Two patients died in each arm within 30 days of their last study treatment; 1 death per arm was attributed to study drugs.

Fever and Infection

During the treatment period, fever in the absence of infection was seen in 46.5% of TAC-treated patients and in 17.1% of FAC-treated patients. Grade 3/4 fever in the absence of infection was seen in 1.3% and 0% of TAC- and FAC-treated patients, respectively. Infection was seen in 39.4% of TAC-treated patients compared to 36.3% of FAC-treated patients. Grade 3/4 infection was seen in 3.9% and 2.2% of TAC-treated and FAC-treated patients, respectively. There were no septic deaths in either treatment arm during the treatment period.

Gastrointestinal Reactions

In addition to gastrointestinal reactions reflected in the table above, 7 patients in the TAC arm were reported to have colitis/enteritis/large intestine perforation versus one patient in the FAC arm. Five of the 7 TAC-treated patients required treatment discontinuation; no deaths due to these events occurred during the treatment period.

Cardiovascular Reactions

More cardiovascular reactions were reported in the TAC arm versus the FAC arm during the treatment period: arrhythmias, all grades (6.2% vs. 4.9%), and hypotension, all grades (1.9% vs. 0.8%). Twenty-six (26) patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm developed CHF during the study period. All except one patient in each arm were diagnosed with CHF during the follow-up period. Two (2) patients in TAC arm and 4 patients in FAC arm died due to CHF. The risk of CHF was higher in the TAC arm in the first year, and then was similar in both treatment arms.

Adverse Reactions during the Follow-Up Period (Median Follow-Up Time of 8 Years)

In study TAX316, the most common adverse reactions that started during the treatment period and persisted into the follow-up period in TAC and FAC patients are described below (median follow-up time of 8 years).

Nervous System Disorders: In study TAX316, peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2%) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm.

Skin and Subcutaneous Tissue Disorders: In study TAX316, alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients (92.3%) and 645 of 736 FAC patients (87.6%). At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

Reproductive System and Breast Disorders: In study TAX316, amenorrhea that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 202 of 744 TAC patients (27.2%) and 125 of 736 FAC patients (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%).

General Disorders and Administration Site Conditions: In study TAX316, peripheral edema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16.0%) and 23 of 736 FAC patients (3.1%). At the end of the follow-up period (actual median follow-up time of 8 years), peripheral edema was ongoing in 19 TAC patients (2.6%) and 4 FAC patients (0.5%).

In study TAX316, lymphedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1.5%) and 1 of 736 FAC patients (0.1%). At the end of the follow-up period (actual median follow-up time of 8 years), lymphedema was observed to be ongoing in 6 TAC patients (0.8%) and 1 FAC patient (0.1%).

In study TAX316, asthenia that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 236 of 744 TAC patients (31.7%) and 180 of 736 FAC patients (24.5%). At the end of the follow-up period (actual median follow-up time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

Acute Myeloid Leukemia (AML)/Myelodysplastic Syndrome (MDS): AML occurred in the adjuvant breast cancer trial (TAX316). The cumulative risk of developing treatment-related AML at median follow-up time of 8 years in TAX316 was 0.4% for TAC-treated patients and 0.1% for FAC-treated patients. One TAC patient (0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of 8 years).

Myelodysplastic syndrome occurred in 2 of 744 (0.3%) patients who received TAC and in 1 of 736 (0.1%) patients who received FAC. AML occurs at a higher frequency when these agents are given in combination with radiation therapy.

Lung Cancer

Monotherapy with Docetaxel for Unresectable, Locally Advanced or Metastatic NSCLC Previously Treated with Platinum-Based Chemotherapy

Docetaxel 75 mg/m2: Treatment-emergent adverse drug reactions are shown in Table 7. Included in this table are safety data for a total of 176 patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who were treated in two randomized, controlled trials. These reactions were described using NCI Common Toxicity Criteria regardless of relationship to study treatment, except for the hematologic toxicities or where otherwise noted.

Table 7: Treatment-Emergent Adverse Reactions Regardless of Relationship to Treatment in Patients Receiving Docetaxel as Monotherapy for Non-small Cell Lung Cancer Previously Treated with Platinum-Based ChemotherapyNormal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN

Adverse Reaction

Docetaxel 75 mg/m2
n=176
%

Best Supportive Care
n=49
%

Vinorelbine/Ifosfamide
n=119
%

Neutropenia

  Any

84

14

83

  Grade 3/4

65

12

57

Leukopenia

  Any

84

6

89

  Grade 3/4

49

0

43

Thrombocytopenia

  Any

8

0

8

  Grade 3/4

3

0

2

Anemia

  Any

91

55

91

  Grade 3/4

9

12

14

Febrile Neutropenia Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization

6

NANot Applicable

1

Infection

  Any

34

29

30

  Grade 3/4

10

6

9

Treatment Related Mortality

3

NA

3

Hypersensitivity Reactions

  Any

6

0

1

  Grade 3/4

3

0

0

Fluid Retention

  Any

34

NDNot Done

23

  Severe

3

3

Neurosensory

  Any

23

14

29

  Grade 3/4

2

6

5

Neuromotor

  Any

16

8

10

  Grade 3/4

5

6

3

Skin

   Any

20

6

17

  Grade 3/4

1

2

1

Gastrointestinal

Nausea

  Any

34

31

31

  Grade 3/4

5

4

8

Vomiting

  Any

22

27

22

  Grade 3/4

3

2

6

Diarrhea

  Any

23

6

12

  Grade 3/4

3

0

4

Alopecia

56

35

50

Asthenia

  Any

53

57

54

  SevereCOSTART term and grading system

18

39

23

Stomatitis

  Any

26

6

8

  Grade 3/4

2

0

1

Pulmonary

  Any

41

49

45

  Grade 3/4

21

29

19

Nail Disorder

  Any

11

0

2

  Severe

1

0

0

Myalgia

  Any

6

0

3

  Severe

0

0

0

Arthralgia

  Any

3

2

2

  Severe

0

0

1

Taste Perversion

  Any

6

0

0

  Severe

1

0

0

Combination Therapy with Docetaxel in Chemotherapy-Naïve Advanced Unresectable or Metastatic NSCLC

Table 8 presents safety data from two arms of an open label, randomized controlled trial (TAX326) that enrolled patients with unresectable stage IIIB or IV non-small cell lung cancer and no history of prior chemotherapy. Adverse reactions were described using the NCI Common Toxicity Criteria except where otherwise noted.

Table 8: Adverse Reactions Regardless of Relationship to Treatment in Chemotherapy-Naïve Advanced Non-small Cell Lung Cancer Patients Receiving Docetaxel in Combination with Cisplatin

Adverse Reaction

Docetaxel 75 mg/m2 + Cisplatin 75 mg/m2
n=406
%

Vinorelbine 25 mg/m2 + Cisplatin 100 mg/m2
n=396
%

Neutropenia

  Any

91

90

  Grade 3/4

74

78

Febrile Neutropenia

5

5

Thrombocytopenia

  Any

15

15

  Grade 3/4

3

4

Anemia

  Any

89

94

  Grade 3/4

7

25

Infection

  Any

35

37

  Grade 3/4

8

8

Fever in absence of infection

  Any

33

29

  Grade 3/4

<1

1

Hypersensitivity Reaction Replaces NCI term "Allergy"

  Any

12

4

  Grade 3/4

3

<1

Fluid Retention COSTART term and grading system

  Any

54

42

  All severe or life-threatening events
Pleural effusion

2

2

  Any

23

22

  All severe or life-threatening events
Peripheral edema

2

2

  Any

34

18

  All severe or life-threatening events
Weight gain

<1

<1

  Any

15

9

  All severe or life-threatening events

<1

<1

Neurosensory

  Any

47

42

  Grade 3/4

4

4

Neuromotor

  Any

19

17

  Grade 3/4

3

6

Skin

  Any

16

14

  Grade 3/4

<1

1

Nausea

  Any

72

76

  Grade 3/4

10

17

Vomiting

  Any

55

61

  Grade 3/4

8

16

Diarrhea

  Any

47

25

  Grade 3/4

7

3

Anorexia

  Any

42

40

  All severe or life-threatening events

5

5

Stomatitis

  Any

24

21

  Grade 3/4

2

1

Alopecia

  Any

75

42

  Grade 3

<1

0

Asthenia

  Any

74

75

  All severe or life-threatening events

12

14

Nail Disorder

  Any

14

<1

  All severe events

<1

0

Myalgia

  Any

18

12

  All severe events

<1

<1

Deaths within 30 days of last study treatment occurred in 31 patients (7.6%) in the docetaxel+cisplatin arm and 37 patients (9.3%) in the vinorelbine+cisplatin arm. Deaths within 30 days of last study treatment attributed to study drug occurred in 9 patients (2.2%) in the docetaxel+cisplatin arm and 8 patients (2.0%) in the vinorelbine+cisplatin arm.

The second comparison in the study, vinorelbine+cisplatin versus docetaxel+carboplatin (which did not demonstrate a superior survival associated with docetaxel, [see Clinical Studies (14.3) ]) demonstrated a higher incidence of thrombocytopenia, diarrhea, fluid retention, hypersensitivity reactions, skin toxicity, alopecia and nail changes on the docetaxel+carboplatin arm, while a higher incidence of anemia, neurosensory toxicity, nausea, vomiting, anorexia and asthenia was observed on the vinorelbine+cisplatin arm.

Prostate Cancer

Combination Therapy with Docetaxel in Patients with Prostate Cancer

The following data are based on the experience of 332 patients, who were treated with docetaxel 75 mg/m2 every 3 weeks in combination with prednisone 5 mg orally twice daily (see Table 9).

Table 9: Clinically Important Treatment-Emergent Adverse Reactions (Regardless of Relationship) in Patients with Prostate Cancer who Received Docetaxel in Combination with Prednisone (TAX327)

Docetaxel 75 mg/m2 every 3 weeks + prednisone 5 mg twice daily
n=332
%

Mitoxantrone 12 mg/m2 every 3 weeks + prednisone 5 mg twice daily
n=335
%