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These highlights do not include all the information needed to use DOCETAXEL INJECTION safely and effectively. See full prescribing information for DOCETAXEL INJECTION. DOCETAXEL injection, for intravenous use Initial U.S. Approval: 1996 | Docetaxel [Actavis Pharma, Inc.] | BioPortfolio

12:30 EST 27th January 2019 | BioPortfolio

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The incidence of treatment-related mortality associated with Docetaxel Injection therapy 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 Injection as a single agent at a dose of 100 mg/m [see Warnings and Precautions (5.1)].

Docetaxel Injection should not be given to patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated elevations of transaminase >1.5 x ULN also had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic death. Bilirubin, AST or ALT, and alkaline phosphatase values should be obtained prior to each cycle of Docetaxel Injection therapy [see Warnings and Precautions (5.2)]. Docetaxel Injection therapy should not be given to patients with neutrophil counts of <1500 cells/mm. In order to monitor the occurrence of neutropenia, which may be severe and result in infection, frequent blood cell counts should be performed on all patients receiving Docetaxel Injection [see Warnings and Precautions (5.3)].

Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who received a 3-day dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the Docetaxel Injection infusion and administration of appropriate therapy [see Warnings and Precautions (5.5)]. Docetaxel Injection must not be given to patients who have a history of severe hypersensitivity reactions to Docetaxel Injection or to other drugs formulated with polysorbate 80 [see Contraindications (4)].

Severe fluid retention occurred in 6.5% (6/92) of patients despite use of a 3-day dexamethasone premedication regimen. 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)].

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.

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.

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

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.

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).

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).

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.

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)].

Breast Cancer

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

Combination therapy with Docetaxel Injection for chemotherapy-naive NSCLC

For patients who are dosed initially at Docetaxel Injection 75 mg/m in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm, 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/m. In patients who require a further dose reduction, a dose of 50 mg/m is recommended. For cisplatin dosage adjustments, see manufacturers’ prescribing information.

Prostate Cancer

Combination therapy with Docetaxel Injection for hormone-refractory metastatic prostate cancer

Docetaxel Injection should be administered when the neutrophil count is ≥1,500 cells/mm. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm 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/m to 60 mg/m. If subsequent episodes of complicated neutropenia occur the Docetaxel Injection dose should be reduced from 60 mg/m to 45 mg/m. In case of grade 4 thrombocytopenia the Docetaxel Injection dose should be reduced from 75 mg/m to 60 mg/m. Patients should not be retreated with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1,500 cells/mm and platelets recover to a level >100,000 cells/mm. 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.

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

In case of AST/ALT >5 x ULN and/or AP >5 x 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 NCIC-CTC grade:

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

Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 x 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.

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 co-administration of a strong CYP3A4 inhibitor [see Drug Interactions (7), Clinical Pharmacology (12.3)].

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%.
Table 2 – Dose Reductions for Evaluation of Creatinine Clearance
 Creatinine clearance result before next cycle  Cisplatin dose next cycle
  CrCl = Creatinine clearance 
 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. 

Docetaxel Injection is a cytotoxic 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. Please refer to [see How Supplied/Storage and Handling (16.3)].

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

One-vial Docetaxel Injection

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.

DO NOT use the two-vial formulation (Injection and diluent) with the one-vial formulation.

One-vial Docetaxel Injection

Docetaxel Injection (20 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.

Docetaxel Injection dilution for infusion is stable for 4 hours, if stored between 2°C and 25°C (36°F and 77°F).  Docetaxel Injection 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).

One-vial Docetaxel Injection

Docetaxel Injection USP is available as 20 mg/mL, 80 mg/4 mL, and 160 mg/8 mL. Each mL contains 20 mg docetaxel, citric acid anhydrous (6 mg), Povidone (kollidon 12 PF) (100 mg), polysorbate 80 (424 mg) and ethanol (400 mg).

Docetaxel Injection is contraindicated in patients with:

Breast Cancer

Docetaxel Injection administered at 100 mg/m 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/m, 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 Injection administered at a dose of 100 mg/m 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/m dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m dose level, 3 of 5 patients had an ECOG PS of 2 at study entry [see Dosage and Administration (2.2), Clinical Studies (14)].

Patients with combined abnormalities of transaminases and alkaline phosphatase should not be treated with Docetaxel Injection [see Boxed Warning, Use in Specific Populations (8.6), Clinical studies (14)].

Perform frequent peripheral blood cell counts on all patients receiving Docetaxel Injection. Patients should not be retreated with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1500 cells/mm and platelets recover to a level > 100,000 cells/mm.

A 25% reduction in the dose of Docetaxel Injection is recommended during subsequent cycles following severe neutropenia (<500 cells/mm) 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/mm) occurs in virtually all patients given 60 mg/m to 100 mg/m of Docetaxel Injection and grade 4 neutropenia (<500 cells/mm) occurs in 85% of patients given 100 mg/m and 75% of patients given 60 mg/m. 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/mm.

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

Enterocolitis and neutropenic colitis (typhlitis) have occurred in patients treated with Docetxel Injection alone and in combination with other chemotherapeutic agents, despite the co- administration 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)].

Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients pre-medicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the Docetaxel Injection infusion and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with Docetaxel Injection. 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 Injection 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)] .

Severe fluid retention has been reported following Docetaxel Injection 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/m. 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/m. Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of Docetaxel Injection to resolution (range: 0 to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).

Treatment-related acute myeloid leukemia (AML) or myelodysplasia 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 Injection, 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.

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 Injection due to skin toxicity.

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).

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.

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.

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/m delivers 2.0 g/mof ethanol. For a patient with a BSA of 2.0 m, this would deliver 4.0 grams of ethanol [see Description (11)]. Other docetaxel products may have a different amount of alcohol.

Docetaxel Injection can cause fetal harm when administered to a pregnant woman. Docetaxel caused embryofetal toxicities including intrauterine mortality when administered to pregnant rats and rabbits during the period of organogenesis. Embryofetal effects in animals occurred at doses as low as 1/50 and 1/300 the recommended human dose on a body surface area basis.

There are no adequate and well-controlled studies in pregnant women using Docetaxel Injection. If Docetaxel Injection is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Docetaxel Injection [see Use in Specific Populations (8.1)].

The most serious adverse reactions from Docetaxel Injection are:

The most common adverse reactions across all Docetaxel Injection 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.

Breast Cancer

Monotherapy with Docetaxel Injection for locally advanced or metastatic breast cancer after failure of prior chemotherapy

Docetaxel Injection 100 mg/m: Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received Docetaxel Injection administered at 100 mg/m 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 Injection. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving Docetaxel Injection for the treatment of breast cancer and in patients with other tumor types (See Table 3).

 

Hematologic Reactions

Reversible marrow suppression was the major dose-limiting toxicity of Docetaxel Injection [see Warnings and Precautions (5.3)]. The median time to nadir was 7 days, while the median duration of severe neutropenia (<500 cells/mm) 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/mm 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/mm) 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 Injection [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 Injection 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 to 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 occurred rarely. Seven of 86 (8.1%) of metastatic breast cancer patients receiving Docetaxel Injection 100 mg/m 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 Injection, 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 Injection at 100 mg/m 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 Injection at 60 mg/m who had normal LFTs (see Tables 4 and 5).

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

The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m, 75 mg/m, and 100 mg/m 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 Injection in the adjuvant treatment of breast cancer

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

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 736FAC 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

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 Injection for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapy

Docetaxel Injection 75 mg/m: 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.

.

Combination therapy with Docetaxel Injection in chemotherapy-naive 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.

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 Injection+carboplatin (which did not demonstrate a superior survival associated with Docetaxel Injection, [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 Injection+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 Injection in patients with prostate cancer

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

Gastric Cancer

Combination therapy with Docetaxel Injection in gastric adenocarcinoma

Data in the following table are based on the experience of 221 patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease, who were treated with Docetaxel Injection 75 mg/m in combination with cisplatin and fluorouracil (see Table 10).

Head and Neck Cancer

Combination therapy with Docetaxel Injection in head and neck cancer

Table 11 summarizes the safety data obtained from patients that received induction chemotherapy with Docetaxel Injection 75 mg/m in combination with cisplatin and fluorouracil followed by radiotherapy (TAX323; 174 patients) or chemoradiotherapy (TAX324; 251 patients). The treatment regimens are described in Section 14.6.

Table 3 - Summary of Adverse Reactions in Patients Receiving Docetaxel Injection at 100 mg/m2
   All Tumor Types  All Tumor Types  Breast Cancer
   Normal LFTs*  Elevated LFTs**  Normal LFTs*
 Adverse Reaction  n=2045  n=61  n=965
   %  %  %
  *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 Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN
  ***Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization
 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 Neutropenia***  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
Table 4 - Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel Injection 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests
   Docetaxel Injection  Docetaxel Injection
   100 mg/m 2  60 mg/m 2
   Normal LFTs*  Elevated LFTs**  Normal LFTs*
 Adverse Reaction  n=730  n=18  n=174
   %  %  %
  *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 Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN 
  ***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.
  ****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 
 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***      
   Any  23  39  1
   Grade 3 and 4  7  33  0
 Febrile Neutropenia****      
   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 Injection 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests
   Docetaxel Injection  Docetaxel Injection
   100 mg/m 2  60 mg/m 2
   Normal LFTs*  Elevated LFTs**  Normal LFTs*
 Adverse Reaction  n=730  n=18  n=174
   %  %  %
  *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 Baseline Liver Function: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN
  ***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/m2 dose
  NA = not available
 Acute Hypersensitivity      
 Reaction Regardless of      
 Premedication      
    Any  13  6  1
   Severe  1  0  0
 Fluid Retention***      
   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
Table 6- Clinically Important Treatment Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving Docetaxel Injection in Combination with Doxorubicin and Cyclophosphamide (TAX316).
   Docetaxel Injection 75 mg/m 2 +  Fluorouracil 500 mg/m 2 +
   Doxorubicin 50 mg/m 2 +  Doxorubicin 50 mg/m 2 +
   Cyclophosphamide 500 mg/m 2 (TAC)  Cyclophosphamide 500 mg/m 2 (FAC)
   n=744 %  n=736 %
  * COSTART term and grading system for events related to treatment.
 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*  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
Table 7 - Treatment Emergent Adverse Reactions Regardless of Relationship to Treatment in Patients Receiving Docetaxel Injection as Monotherapy for Non-Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy*
   Docetaxel Injection    Vinorelbine/
   75 mg/m 2  Best Supportive Care  Ifosfamide
   n=176  n=49  n=119
 Adverse Reaction  %  %  %
  *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
  **Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization
  ***COSTART term and grading system
 Not Applicable; †† Not Done
 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**  6  NA  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  ND††  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
   Severe***  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
Table 8 - Adverse Reactions Regardless of Relationship to Treatment in Chemotherapy-Naive Advanced Non-Small Cell Lung Cancer Patients Receiving Docetaxel Injection in Combination with Cisplatin
   Docetaxel Injection 75 mg/m 2  
   + Cisplatin  Vinorelbine 25 mg/m 2 +
   75 mg/m 2  Cisplatin 100 mg/m 2
 Adverse Reaction  n=406  n=396
   %  %
  * Replaces NCI term “Allergy”
  ** COSTART term and grading system
 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*    
   Any  12  4
   Grade 3/4  3  < 1
 Fluid Retention**    
   Any  54  42
   All severe or life-threatening events  2  2
 Pleural effusion    
   Any  23  22
   All severe or life-threatening events  2  2
 Peripheral edema    
   Any   34  18
   All severe or life-threatening events  <1  <1
 Weight gain    
   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
Table 9 - Clinically Important Treatment Emergent Adverse Reactions (Regardless of Relationship) in Patients with Prostate Cancer who Received Docetaxel Injection in Combination with Prednisone (TAX327)
   Docetaxel Injection 75 mg/m 2  Mitoxantrone 12 mg/m 2
   every 3 weeks +  every 3 weeks +
   prednisone 5 mg twice daily  prednisone 5 mg twice daily
   n=332  n=335
   %  %
 Adverse Reaction  Any  Grade 3/4  Any  Grade 3/4
  *Related to treatment 
 Anemia  67  5  58  2
 Neutropenia  41  32  48  22
 Thrombocytopenia  3  1  8  1
 Febrile neutropenia  3  N/A  2  N/A
 Infection  32  6  20  4
 Epistaxis  6  0  2  0
 Allergic Reactions  8  1  1  0
 Fluid Retention*  24  1  5  0
 Weight Gain*  8  0  3  0
 Peripheral Edema*  18  0  2  0
 Neuropathy Sensory  30  2  7  0
 Neuropathy Motor  7  2  3  1
 Rash/Desquamation  6  0  3  1
 Alopecia  65  N/A  13  N/A
 Nail Changes  30  0  8  0
 Nausea  41  3  36  2
 Diarrhea  32  2  10  1
 Stomatitis/Pharyngitis  20  1  8  0
 Taste Disturbance  18  0  7  0
 Vomiting  17  2  14  2
 Anorexia  17  1  14  0
 Cough  12  0  8  0
 Dyspnea  15  3  9  1
 Cardiac left ventricular function  10  0  22  1
 Fatigue  53  5  35  5
 Myalgia  15  0  13  1
 Tearing  10  1  2  0
 Arthralgia  8  1  5  1
Table 10 - Clinically Important Treatment Emergent Adverse Reactions Regardless of Relationship to Treatment in the Gastric Cancer Study
   Docetaxel Injection 75 mg/m 2 +  
   cisplatin 75 mg/m 2 +  Cisplatin 100 mg/m 2 +
   fluorouracil 750 mg/m 2  fluorouracil 1000 mg/m 2
   n=221  n=224
 Adverse Reaction  Any  Grade 3/4  Any  Grade 3/4
  Clinically important treatment emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction.
  *Related to treatment
   %  %  %  %
 Anemia  97  18  93  26
 Neutropenia  96  82  83  57
 Fever in the absence of infection  36  2  23  1
 Thrombocytopenia  26  8  39  14
 Infection  29  16  23  10
 Febrile neutropenia  16  N/A  5  N/A
 Neutropenic infection  16  N/A  10  N/A
 Allergic reactions  10  2  6  0
 Fluid retention*  15  0  4  0
 Edema*  13  0  3  0
 Lethargy  63  21  58  18
 Neurosensory  38  8  25  3
 Neuromotor  9  3  8  3
 Dizziness  16  5  8  2
 Alopecia  67  5  41  1
 Rash/itch  12  1  9  0
 Nail changes  8  0  0  0
 Skin desquamation  2  0  0  0
 Nausea  73  16  76  19
 Vomiting  67  15  73  19
 Anorexia  51  13  54  12
 Stomatitis  59  21  61  27
 Diarrhea  78  20  50  8
 Constipation  25  2  34  3
 Esophagitis/dysphagia/odynophagia  16  2  14  5
 Gastrointestinal pain/cramping  11  2  7  3
 Cardiac dysrhythmias  5  2  2  1
 Myocardial ischemia  1  0  3  2
 Tearing  8  0  2  0
 Altered hearing  6  0  13  2
Table 11 – Clinically Important Treatment Emergent Adverse Reactions (Regardless of Relationship) in Patients with SCCHN Receiving Induction Chemotherapy with Docetaxel Injection in Combination with Cisplatin and Fluorouracil Followed by Radiotherapy (TAX323) or Chemoradiotherapy (TAX324)
   TAX323  TAX324
   (n=355)  (n=494)
   Docetaxel Injection  arm  Comparator arm  Docetaxel Injection arm  Comparator arm
   (n=174)  (n=181)  (n=251)  (n=243)
  Clinically important treatment emergent adverse reactions based upon frequency, severity, and clinical impact.
  *Febrile neutropenia: grade ≥2 fever concomitant with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization.
  **Related to treatment.
  *** Includes superficial and deep vein thrombosis and pulmonary embolism
   Any  Grade  Any  Grade  Any  Grade  Any  Grade
 Adverse Reaction  %  3/4  %  3/4  %  3/4  %  3/4
 (by Body System)    %    %    %    %
 Neutropenia  93  76  87  53  95  84  84  56
 Anemia  89  9  88  14  90  12  86  10
 Thrombocytopenia  24  5  47  18  28  4  31  11
 Infection  27  9  26  8  23  6  28  5
 Febrile neutropenia*  5  N/A  2  N/A  12  N/A  7  N/A
 Neutropenic infection  14  N/A  8  N/A  12  N/A  8  N/A
 Cancer pain  21  5  16  3  17  9  20  11
 Lethargy  41  3  38  3  61  5  56  10
 Fever in the absence of infection  32  1  37  0  30  4  28  3
 Myalgia  10  1  7  0  7  0  7  2
 Weight loss  21  1  27  1  14  2  14  2
 Allergy  6  0  3  0  2  0  0  0
 Fluid retention**  20  0  14  1  13  1  7  2
 Edema only  13  0  7  0  12  1  6  1
 Weight gain only  6  0  6  0  0  0  1  0
 Dizziness  2  0  5  1  16  4  15  2
 Neurosensory  18  1  11  1  14  1  14  0
 Altered hearing  6  0  10  3  13  1  19  3
 Neuromotor  2  1  4  1  9  0  10  2
 Alopecia  81  11  43  0  68  4  44  1
 Rash/itch  12  0  6  0  20  0  16  1
 Dry skin  6  0  2  0  5  0  3  0
 Desquamation  4  1  6  0  2  0  5  0
 Nausea  47  1  51  7  77  14  80  14
 Stomatitis  43  4  47  11  66  21  68  27
 Vomiting  26  1  39  5  56  8  63  10
 Diarrhea  33  3  24  4  48  7  40  3
 Constipation  17  1  16  1  27  1  38  1
 Anorexia  16  1  25  3  40  12  34  12
 Esophagitis/dysphagia/ Odynophagia  13  1  18  3  25  13  26  10
 Taste, sense of smell altered  10  0  5  0  20  0  17  1
 Gastrointestinal pain/cramping  8  1  9  1  15  5  10  2
 Heartburn  6  0  6  0  13  2  13  1
 Gastrointestinal bleeding  4  2  0  0  5  1  2  1
 Cardiac dysrhythmia  2  2  2  1  6  3  5  3
 Venous***  3  2  6  2  4  2  5  4
 Ischemia myocardial  2  2  1  0  2  1  1  1
 Tearing  2  0  1  0  2  0  2  0
 Conjunctivitis  1  0  1  0  1  0  0.4  0

The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.

Body as a whole: diffuse pain, chest pain, radiation recall phenomenon, injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) at the site of previous extravasation.

Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction. Ventricular arrhythmia including ventricular tachycardia has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide, and may be associated with fatal outcome.

Cutaneous: very rare cases of cutaneous lupus erythematosus and rare cases of bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Scleroderma-like changes usually preceded by peripheral lymphedema. In some cases multiple factors may have contributed to the development of these effects. Severe hand and foot syndrome has been reported. Cases of permanent alopecia have been reported.

Gastrointestinal: enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, has been reported with a potential fatal outcome. Abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, intestinal obstruction, ileus, and dehydration as a consequence to gastrointestinal events have been reported.  

Hematologic: bleeding episodes. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported. Cases of acute myeloid leukemia and myelodysplasic syndrome have been reported in association with Docetaxel Injection when used in combination with other chemotherapy agents and/or radiotherapy.

Hypersensitivity: rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication. Hypersensitivity reactions with potential fatal outcome have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.

Hepatic: rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.

Neurologic: confusion, rare cases of seizures or transient loss of consciousness have been observed, sometimes appearing during the infusion of the drug.

Ophthalmologic: conjunctivitis, lacrimation or lacrimation with or without conjunctivitis. Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion. Cases of cystoid macular edema (CME) have been reported in patients treated with Docetaxel Injection.

Hearing: rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs.

Respiratory: dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis have rarely been reported and may be associated with fatal outcome. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

Renal: renal insufficiency and renal failure have been reported, the majority of these cases were associated with concomitant nephrotoxic drugs.

Metabolism and nutrition disorders: electrolyte imbalance, including cases of hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia has been reported.

Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4.

In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of Docetaxel Injection and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In patients receiving treatment with Docetaxel Injection, close monitoring for toxicity and a Docetaxel Injection dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)].

Pregnancy Category D [see Warnings and Precautions (5.13)]

Based on its mechanism of action and findings in animals, Docetaxel Injection can cause fetal harm when administered to a pregnant woman. If Docetaxel Injection is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Docetaxel Injection [see Warnings and Precautions (5.13)].

Docetaxel Injection can cause fetal harm when administered to a pregnant woman. Studies in both rats and rabbits at doses ≥0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on a mg/m basis), administered during the period of organogenesis, have shown that Docetaxel Injection is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight, and fetal ossification delay). The doses indicated above also caused maternal toxicity [see Warnings and Precautions (5.13)].

It is not known whether docetaxel is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Docetaxel Injection, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The efficacy of docetaxel in pediatric patients as monotherapy or in combination has not been established. The overall safety profile of docetaxel in pediatric patients receiving monotherapy or TCF was consistent with the known safety profile in adults.

Docetaxel has been studied in a total of 289 pediatric patients: 239 in 2 trials with monotherapy and 50 in combination treatment with cisplatin and 5-fluoruracil (TCF).

Docetaxel Monotherapy

Docetaxel monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12.5 years, range 1 to 22 years) with a variety of refractory solid tumors. The recommended dose was 125 mg/m as a 1-hour intravenous infusion every 21 days. The primary dose limiting toxicity was neutropenia.

The recommended dose for docetaxel monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1 to 26 years) with a variety of recurrent/refractory solid tumors. Efficacy was not established with tumor response rates ranging from one complete response (CR) (0.6%) in a patient with undifferentiated sarcoma to four partial responses (2.2%) seen in one patient each with Ewing Sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma.

Docetaxel in Combination

Docetaxel was studied in combination with cisplatin and 5-fluorouracil (TCF) versus cisplatin and 5-fluorouracil (CF) for the induction treatment of nasopharyngeal carcinoma (NPC) in pediatric patients prior to chemoradiation consolidation. Seventy-five patients (median age 16 years, range 9 to 21 years) were randomized (2:1) to docetaxel (75 mg/m) in combination with cisplatin (75 mg/m) and 5-fluorouracil (750 mg/m) (TCF) or to cisplatin (80 mg/m) and 5-fluorouracil (1000 mg/m/day) (CF). The primary endpoint was the CR rate following induction treatment of NPC. One patient out of 50 in the TCF group (2%) had a complete response while none of the 25 patients in the CF group had a complete response.

Pharmacokinetics

Pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials. Following docetaxel administration at 55 mg/m to 235 mg/m in a 1-hour intravenous infusion every 3 weeks in 25 patients aged 1 to 20 years (median 11 years), docetaxel clearance was 17.3±10.9 L/h/m.

Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF), at dose levels of 75 mg/m in a 1-hour intravenous infusion day 1 in 28 patients aged 10 to 21 years (median 16 years, 17 patients were older than 16). Docetaxel clearance was 17.9±8.75 L/h/m, corresponding to an AUC of 4.20±2.57 µg.h/mL.

In summary, the body surface area adjusted clearance of docetaxel monotherapy and TCF combination in children were comparable to those in adults [see Clinical Pharmacology (12.3)].

 

The alcohol content of Docetaxel Injection should be taken into account when given to pediatric patients [see Warnings and Precautions (5.12)] .

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients.

Non-Small Cell Lung Cancer

In a study conducted in chemotherapy-naive patients with NSCLC (TAX326), 148 patients (36%) in the Docetaxel Injection+cisplatin group were 65 years of age or greater. There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In the Docetaxel Injection+cisplatin group, patients less than 65 years of age had a median survival of 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% CI: 9.3 months, 14 months). In patients 65 years of age or greater treated with Docetaxel Injection+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). Patients treated with Docetaxel Injection+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively).

When Docetaxel Injection was combined with carboplatin for the treatment of chemotherapy-naive, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with Docetaxel Injection+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin.

Prostate Cancer

Of the 333 patients treated with Docetaxel Injection every three weeks plus prednisone in the prostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with Docetaxel Injection every three weeks, the following treatment emergent adverse reactions occurred at rates ≥10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs. 59%), infection (37% vs. 24%), nail changes (34% vs. 23%), anorexia (21% vs. 10%), weight loss (15% vs. 5%) respectively.

Breast Cancer

In the adjuvant breast cancer trial (TAX316), Docetaxel Injection in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. The number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients.

Gastric Cancer

Among the 221 patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years. In this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. However, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients. The incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored.

Head and Neck Cancer

Among the 174 and 251 patients who received the induction treatment with Docetaxel Injection in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively.

These clinical studies of Docetaxel Injection in combination with cisplatin and fluorouracil in patients with SCCHN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients.

Patients with bilirubin >ULN should not receive Docetaxel Injection. Also, patients with AST and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN should not receive Docetaxel Injection [see Boxed Warning , Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

The alcohol content of Docetaxel Injection should be taken into account when given to patients with hepatic impairment [see Warnings and Precautions (5.12)].

There is no known antidote for Docetaxel Injection overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.

In two reports of overdose, one patient received 150 mg/m and the other received 200 mg/m as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident.

In mice, lethality was observed following single intravenous doses that were ≥154 mg/kg (about 4.5 times the human dose of 100 mg/m on a mg/m basis); neurotoxicity associated with paralysis, non-extension of hind limbs, and myelin degeneration was observed in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m basis). In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m on a mg/m basis) and was associated with abnormal mitosis and necrosis of multiple organs.

Docetaxel, USP is an antineoplastic agent belonging to the taxoid family. It is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel, USP is (2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, anhydrous. Docetaxel, USP has the following structural formula:

Docetaxel, USP is a white to almost-white powder with an empirical formula of CHNO, and a molecular weight of 807.88. It is highly lipophilic and practically insoluble in water.

One-vial Docetaxel Injection

Docetaxel Injection, USP is a sterile, non-pyrogenic, clear, viscous, colorless to pale yellow solution, without macroscopic particles in solution at 20 mg/mL docetaxel concentration.

Each mL contains 20 mg docetaxel, USP, citric acid anhydrous (6 mg), kollidon 12 PF (povidone P12) (100 mg), polysorbate 80 (424 mg) and ethanol (400 mg).

Docetaxel Injection, USP is available in single use vials containing 20 mg (1 mL), 80 mg (4 mL), 140 mg (7 mL) or 160 mg (8 mL) docetaxel.

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

Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel’s binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use.

Absorption

The pharmacokinetics of docetaxel has been evaluated in cancer patients after administration of 20 mg/m to 115 mg/m in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m to 115 mg/m with infusion times of 1 to 2 hours. Docetaxel’s pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with half-lives for the α, β, and γ phases of 4 min, 36 min, and 11.1 hr, respectively. Mean total body clearance was 21 L/h/m.

Distribution

The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Mean steady state volume of distribution was 113 L. In vitro studies showed that docetaxel is about 94% protein bound, mainly to α-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding of docetaxel.

Metabolism

In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4 [see Drug Interactions (7)].

Elimination

A study of C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as 1 major and 3 minor metabolites with very small amounts (less than 8%) of unchanged drug.

Specific Populations

Effect of Age: A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m. Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of docetaxel was not influenced by age.

Effect of Gender: The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel.

Hepatic Impairment: The population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment (AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN), total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients. Patients with combined abnormalities of transaminase and alkaline phosphatase should not be treated with Docetaxel Injection. Patients with severe hepatic impairment have not been studied [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].

Effect of Race: Mean total body clearance for Japanese patients dosed at the range of 10 mg/m to 90 mg/m was similar to that of European/American populations dosed at 100 mg/m, suggesting no significant difference in the elimination of docetaxel in the two populations.

Drug Interaction Studies

Effect of Ketoconazole: The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients were randomized to receive either docetaxel (100 mg/m² intravenous) alone or docetaxel (10 mg/m² intravenous) in combination with ketoconazole (200 mg orally once daily for 3 days) in a crossover design with a 3-week washout period. The results of this study indicated that the mean dose-normalized AUC of docetaxel was increased 2.2-fold and its clearance was reduced by 49% when docetaxel was co-administered with ketoconazole [see Dosage and Administration (2.7) and Drug Interactions (7)].

Effect of Combination Therapies:

Carcinogenicity studies with docetaxel have not been performed.

Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60 to 1/15 the recommended human dose on a mg/m basis). Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays.

Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50 the recommended human dose on a mg/m basis), but decreased testicular weights were reported. This correlates with findings of a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3 and 1/15 the recommended human dose on a mg/m basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.  

The efficacy and safety of Docetaxel Injection have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens).

Randomized Trials

In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with Docetaxel Injection (100 mg/m every 3 weeks) or the combination of mitomycin (12 mg/m every 6 weeks) and vinblastine (6 mg/m every 3 weeks). Two hundred three patients were randomized to Docetaxel Injection and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the Docetaxel Injection arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The following table summarizes the study results (See Table 12).

In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with Docetaxel Injection (100 mg/m) or doxorubicin (75 mg/m) every 3 weeks. One hundred sixty-one patients were randomized to Docetaxel Injection and 165 patients to doxorubicin. Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The study results are summarized below (See Table 13).

In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive Docetaxel Injection monotherapy 60 mg/m (n=151), 75 mg/m (n=188) or 100 mg/m (n=188). In this trial, 94% of patients had metastatic disease and 79% had received prior anthracycline therapy. Response rate was the primary endpoint.

Response rates increased with Docetaxel Injection dose: 19.9% for the 60 mg/m group compared to 22.3% for the 75 mg/m and 29.8% for the 100 mg/m group; pair-wise comparison between the 60 mg/m and 100 mg/m groups was statistically significant (p=0.037).

Single Arm Studies

Docetaxel Injection at a dose of 100 mg/m was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% CI: 31.0 to 44.8) and the complete response rate was 2.1%.

Docetaxel Injection was also studied in three single arm Japanese studies at a dose of 60 mg/m, in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% CI: 17.2 to 55.7), similar to the response rate in single arm studies of 100 mg/m.

Table 12 - Efficacy of Docetaxel Injection in the Treatment of Breast Cancer Patients Previously Treated with an Anthracycline-Containing Regimen (Intent-to-Treat Analysis)
 Efficacy Parameter  Docetaxel  Mitomycin/  p-value
     Vinblastine  
   (n=203)  (n=189)  
  *For the risk ratio, a value less than 1.00 favors docetaxel. 
 Median Survival  11.4 months  8.7 months  
 Risk Ratio*, Mortality    
 (Docetaxel: Control)  0.73  
     p=0.01
     Log Rank
 95% CI (Risk Ratio)  0.58 to 0.93  
 Median Time to Progression  4.3 months  2.5 months  
 Risk Ratio*, Progression    p=0.01
 (Docetaxel: Control)  0.75  Log Rank
     
     
 95% CI (Risk Ratio)  0.61 to 0.94  
 Overall Response Rate  28.1%  9.5%  p<0.0001
 Complete Response Rate  3.4%  1.6%  Chi Square
Table 13 - Efficacy of Docetaxel Injection in the Treatment of Breast Cancer Patients Previously Treated with an Alkylating-Containing Regimen (Intent-to-Treat Analysis)
 Efficacy Parameter  Docetaxel  Doxorubicin  p-value
   (n=161)  (n=165)  
  *For the risk ratio, a value less than 1.00 favors docetaxel.
 Median Survival  14.7 months  14.3 months  
 Risk Ratio*, Mortality    
 (Docetaxel: Control)  0.89  
     p=0.39
     Log Rank
 95% CI (Risk Ratio)  0.68 to 1.16  
 Median Time to Progression  6.5 months  5.3 months  
 Risk Ratio*, Progression    
 (Docetaxel: Control)  0.93  p=0.45
     Log Rank
     
 95% CI (Risk Ratio)  0.71 to 1.16  
 Overall Response Rate  45.3%  29.7%  p=0.004
 Complete Response Rate  6.8%  4.2%  Chi Square

A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of Docetaxel Injection for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease. After stratification according to the number of positive lymph nodes (1 to 3, 4+), 1491 patients were randomized to receive either Docetaxel Injection 75 mg/m administered 1-hour after doxorubicin 50 mg/m and cyclophosphamide 500 mg/m (TAC arm), or doxorubicin 50 mg/m followed by fluorouracil 500 mg/m and cyclosphosphamide 500 mg/m (FAC arm). Both regimens were administered every 3 weeks for 6 cycles. Docetaxel Injection was administered as a 1-hour infusion; all other drugs were given as intravenous bolus on day 1. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC.  

Results from a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio=0.74; 2-sided 95% CI=0.60, 0.92, stratified log rank p=0.0047). The primary endpoint, disease-free survival, included local and distant recurrences, contralateral breast cancer and deaths from any cause. The overall reduction in risk of relapse was 25.7% for TAC-treated patients. (See Figure 1).

At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio=0.69, 2-sided 95% CI=0.53, 0.90). (See Figure 2). There will be further analysis at the time survival data mature.

The following table describes the results of subgroup analyses for DFS and OS (See Table 14).

Table 14 - Subset Analyses-Adjuvant Breast Cancer Study
     Disease Free Survival  Overall Survival
 Patient subset  Number of  Hazard  95% CI  Hazard  95% CI
   patients  ratio*    ratio*  
  *a hazard ratio of less than 1 indicates that TAC is associated with a longer disease free survival or overall survival compared to FAC.
 No. of positive nodes          
 Overall  744  0.74  (0.60, 0.92)  0.69  (0.53, 0.90)
 1 to 3  467  0.64  (0.47, 0.87)  0.45  (0.29, 0.70)
 4+  277  0.84  (0.63, 1.12)  0.93  (0.66, 1.32)
 Receptor status          
 Positive  566  0.76  (0.59, 0.98)  0.69  (0.48, 0.99)
 Negative  178  0.68  (0.48, 0.97)  0.66  (0.44, 0.98)

The efficacy and safety of Docetaxel Injection has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy-naive.

Monotherapy with Docetaxel Injection for NSCLC Previously Treated with Platinum-Based Chemotherapy

Two randomized, controlled trials established that a Docetaxel Injection dose of 75 mg/m was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel Injection at a dose of 100 mg/m, however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used [see Boxed Warning , Dosage and Administration (2.7), Warnings and Precautions (5.3)].

One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status ≤2 to Docetaxel Injection or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to Docetaxel Injection 100 mg/m or best supportive care, but early toxic deaths at this dose led to a dose reduction to Docetaxel Injection 75 mg/m. A total of 104 patients were randomized in this amended study to either Docetaxel Injection 75 mg/m or best supportive care.

In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status ≤2 were randomized to Docetaxel Injection 75 mg/m, Docetaxel Injection 100 mg/m and a treatment in which the investigator chose either vinorelbine 30 mg/m days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m days 1 to 3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was survival in both trials. The efficacy data for the Docetaxel Injection 75 mg/m arm and the comparator arms are summarized in Table 15 and Figures 3 and 4 showing the survival curves for the two studies.

Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored Docetaxel Injection 75 mg/m.

Patients treated with Docetaxel Injection at a dose of 75 mg/m experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.

Combination Therapy with Docetaxel Injection for Chemotherapy-Naive NSCLC

In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: Docetaxel Injection 75 mg/m as a 1 hour infusion immediately followed by cisplatin 75 mg/m over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m administered over 6 to 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m administered on day 1 of cycles repeated every 4 weeks; or a combination of Docetaxel Injection and carboplatin.

The primary efficacy endpoint was overall survival. Treatment with Docetaxel Injection+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin (see table below). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of Docetaxel Injection to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The efficacy data for the Docetaxel Injection+cisplatin arm and the comparator arm are summarized in Table 16.

The second comparison in the same three-arm study, vinorelbine+cisplatin versus Docetaxel Injection+carboplatin, did not demonstrate superior survival associated with the Docetaxel Injection arm (Kaplan-Meier estimate of median survival was 9.1 months for Docetaxel Injection+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the Docetaxel Injection+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between Docetaxel Injection+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 17).

Table 15 - Efficacy of Docetaxel Injection in the Treatment of Non-Small Cell Lung Cancer Patients Previously Treated with a Platinum-Based Chemotherapy Regimen (Intent-to-Treat Analysis)
   TAX317  TAX320
   Docetaxel  Best  Docetaxel  Control
   75 mg/m 2  Supportive  75 mg/m 2  (V/I*)
   n=55  Care  n=125  n=123
     n=49    
  * Vinorelbine/Ifosfamide
  ** p≤0.05
  uncorrected for multiple comparisons
 †† a value less than 1.00 favors docetaxel
 Overall Survival    
 Log-rank Test  p=0.01  p=0.13
 Risk Ratio††, Mortality    
 (Docetaxel: Control)  0.56  0.82
 95% CI (Risk Ratio)  (0.35, 0.88)  (0.63, 1.06)
 Median Survival  7.5 months**  4.6 months  5.7 months  5.6 months
 95% CI  (5.5, 12.8)  (3.7, 6.1)  (5.1, 7.1)  (4.4, 7.9)
 % 1-year Survival  37%**  12%  30%**  20%
 95% CI  (24, 50)  (2, 23)  (22, 39)  (13, 27)
 Time to Progression  12.3 weeks**  7.0 weeks  8.3 weeks  7.6 weeks
 95% CI  (9.0, 18.3)  (6.0, 9.3)  (7.0, 11.7)  (6.7, 10.1)
 Response Rate  5.5%    5.7%  0.8%
     Not    
 95% CI  (1.1, 15.1)  Applicable  (2.3, 11.3)  (0.0, 4.5)
Table 16 - Survival Analysis of Docetaxel Injection in Combination Therapy for Chemotherapy-Naive NSCLC
  Comparison   Docetaxel Injection +Cisplatin   Vinorelbine+Cisplatin
    n=408   n=405
 a From the superiority test (stratified log rank) comparing Docetaxel Injection+cisplatin to vinorelbine+cisplatin 
 bHazard ratio of Docetaxel Injection+cisplatin vs. vinorelbine+cisplatin. A hazard ratio of less than 1 indicates that Docetaxel Injection+cisplatin is associated with a longer survival.
 cAdjusted for interim analysis and multiple comparisons.
 Kaplan-Meier Estimate of Median Survival  10.9 months  10.0 months
 p-valuea  0.122
 Estimated Hazard Ratiob  0.88
 Adjusted 95% CIc  (0.74, 1.06)
Table 17 - Response and TTP Analysis of Docetaxel Injection in Combination Therapy for Chemotherapy-Naive NSCLC
  Endpoint   Docetaxel Injection+Cisplatin   Vinorelbine+Cisplatin   p-value
 aAdjusted for multiple comparisons.
 bKaplan-Meier estimates.
 Objective Response Rate  31.6%  24.4%  Not Significant
 (95% CI)a  (26.5%, 36.8%)  (19.8%, 29.2%)  
 Median Time to      
 Progressionb  21.4 weeks  22.1 weeks  Not Significant
 (95% CI)a  (19.3, 24.6)  (18.1, 25.6)  

The safety and efficacy of Docetaxel Injection in combination with prednisone in patients with metastatic castration-resistant prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) ≥60 were randomized to the following treatment groups:

All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously.

In the Docetaxel Injection every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the Docetaxel Injection weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the Docetaxel Injection every 3 week arm versus the control arm are summarized in Table 18 and Figure 5.

Table 18 - Efficacy of Docetaxel Injection in the Treatment of Patients with  Metastatic Castration-Resistant Prostate Cancer (Intent-to-Treat Analysis)
   Docetaxel Injection + Prednisone  Mitoxantrone+ Prednisone
   every 3 weeks  every 3 weeks
  *Stratified log rank test. Threshold for statistical significance = 0.0175 because of 3 arms.
 Number of patients  335  337
 Median survival (months)  18.9  16.5
 95% CI  (17.0 to 21.2)  (14.4 to 18.6)
 Hazard ratio  0.761  --
 95% CI  (0.619 to 0.936)  --
 p-value*  0.0094  --

A multicenter, open-label, randomized trial was conducted to evaluate the safety and efficacy of Docetaxel Injection for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for advanced disease. A total of 445 patients with KPS >70 were treated with either Docetaxel Injection (T) (75 mg/m on day 1) in combination with cisplatin (C) (75 mg/m on day 1) and fluorouracil (F) (750 mg/m per day for 5 days) or cisplatin (100 mg/m on day 1) and fluorouracil (1000 mg/m per day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF arm. The demographic characteristics were balanced between the two treatment arms. The median age was 55 years, 71% were male, 71% were Caucasian, 24% were 65 years of age or older, 19% had a prior curative surgery and 12% had palliative surgery. The median number of cycles administered per patient was 6 (with a range of 1 to 16) for the TCF arm compared to 4 (with a range of 1 to 12) for the CF arm. Time to progression (TTP) was the primary endpoint and was defined as time from randomization to disease progression or death from any cause within 12 weeks of the last evaluable tumor assessment or within 12 weeks of the first infusion of study drugs for patients with no evaluable tumor assessment after randomization. The hazard ratio (HR) for TTP was 1.47 (CF/TCF, 95% CI: 1.19 to 1.83) with a significantly longer TTP (p=0.0004) in the TCF arm. Approximately 75% of patients had died at the time of this analysis. Overall survival was significantly longer (p=0.0201) in the TCF arm with a HR of 1.29 (95% CI: 1.04 to 1.61). Efficacy results are summarized in Table 19 and Figures 6 and 7.

Subgroup analyses were consistent with the overall results across age, gender and race.

Table 19 - Efficacy of Docetaxel Injection  in the treatment of patients with Gastric Adenocarcinoma
 Endpoint  TCF  CF
   n=221  n=224
  *Unstratified log-rank test
 For the hazard ratio (TCF/CF), values less than 1.00 favor the Docetaxel Injection arm.
 Median TTP (months)  5.6  3.7
 (95%CI)  (4.86 to 5.91)  (3.45 to 4.47)
 Hazard ratio  0.68
 (95%CI)  (0.55 to 0.84)
 *p-value  0.0004
 Median survival (months)  9.2  8.6
 (95%CI)  (8.38 to 10.58)  (7.16 to 9.46)
 Hazard ratio  0.77
 (95%CI)  (0.62 to 0.96)
 *p-value  0.0201
 Overall Response Rate (CR+PR) (%)  36.7  25.4
 p-value  0.0106

Induction chemotherapy followed by radiotherapy (TAX323)

The safety and efficacy of Docetaxel Injection in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, were randomized to one of two treatment arms. Patients on the Docetaxel Injection arm received Docetaxel Injection (T) 75 mg/m followed by cisplatin (P) 75 mg/m on Day 1, followed by fluorouracil (F) 750 mg/m per day as a continuous infusion on Days 1 to 5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m on Day 1, followed by fluorouracil (F) 1000 mg/m/day as a continuous infusion on Days 1 to 5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with a conventional fraction regimen (1.8 Gy to 2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week, for a total dose of 70 to 74 Gy, respectively). Surgical resection was allowed following chemotherapy, before or after radiotherapy.

The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p=0.0077 (median PFS: 11.4 vs. 8.3 months respectively) with an overall median follow up time of 33.7 months. Median overall survival with a median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.2 months respectively). Efficacy results are presented in Table 20 and Figures 8 and 9.

Induction chemotherapy followed by chemoradiotherapy (TAX324)

The safety and efficacy of Docetaxel Injection in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms. Patients on the Docetaxel Injection arm received Docetaxel Injection (T) 75 mg/m² by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m² administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m²/day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on the comparator arm received cisplatin (P) 100 mg/m² as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m²/day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles.

All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70 to 72 Gy). Surgery on the primary site of disease and/or neck could be considered at anytime following completion of CRT.

The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p=0.0058) with the Docetaxel Injection-containing regimen compared to PF [median OS: 70.6 versus 30.1 months respectively, hazard ratio (HR)=0.70, 95% confidence interval (CI)= 0.54 – 0.90]. Overall survival results are presented in Table 21 and Figure 10.

Table 20 - Efficacy of Docetaxel Injection in the Induction Treatment of Patients with Inoperable Locally Advanced SCCHN (Intent-to-Treat Analysis)
 Endpoint  Docetaxel Injection +  
   Cisplatin+  Cisplatin+
   Fluorouracil  Fluorouracil
   n=177  n=181
  A Hazard ratio of less than 1 favors Docetaxel Injection+Cisplatin+Fluorouracil
  * Stratified log-rank test based on primary tumor site
  ** Stratified log-rank test, not adjusted for multiple comparisons
  *** Chi square test, not adjusted for multiple comparisons
 Median progression free survival (months)  11.4  8.3
 (95%CI)  (10.1 to 14.0)  (7.4 to 9.1)
 Adjusted Hazard ratio  0.71
 (95%CI)  (0.56 to 0.91)
 *p-value  0.0077
 Median survival (months)  18.6  14.2
 (95%CI)  (15.7 to 24.0)  (11.5 to 18.7)
 Hazard ratio  0.71
 (95%CI)  (0.56 to 0.90)
 **p-value  0.0055
 Best overall response (CR + PR) to    
 chemotherapy (%)  67.8  53.6
 (95%CI)  (60.4 to 74.6)  (46.0 to 61.0)
 ***p-value  0.006
 Best overall response (CR + PR) to study    
 treatment [chemotherapy +/- radiotherapy] (%)  72.3  58.6
 (95%CI)  (65.1 to 78.8)  (51.0 to 65.8)
 ***p-value  0.006
Table 21 - Efficacy of Docetaxel Injection in the Induction Treatment of Patients with Locally Advanced SCCHN (Intent-to-Treat Analysis)
   Docetaxel Injection +  Cisplatin+
   Cisplatin+ Fluorouracil  Fluorouracil
 Endpoint  n=255  n=246
  A Hazard ratio of less than 1 favors Docetaxel  Injection+cisplatin+fluorouracil
  * un-adjusted log-rank test 
  NE - not estimable
 Median overall survival (months)  70.6  30.1
 (95% CI)  (49.0 to NE)  (20.9 to 51.5)
 Hazard ratio:  0.70
 (95% CI)  (0.54 to 0.90)
 *p-value  0.0058

One-vial Docetaxel Injection

Docetaxel Injection, USP is supplied as a sterile, pyrogen-free, non-aqueous solution in single-use, flip-top glass vials, as a clear, viscous, colorless to pale yellow solution, without macroscopic particles in solution at 20 mg/mL concentration in the following package strengths:

Docetaxel Injection, USP 20 mg/mL                                   NDC 45963-734-54

Docetaxel Injection, USP 80 mg/4 mL (20 mg/mL)            NDC 45963-765-52

Docetaxel Injection, USP 160 mg/8 mL (20 mg/mL)          NDC 45963-790-56

The vial stopper is not made with natural rubber latex.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Retain in the original package to protect from light.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)].

A dvise the patient to read the FDA-approved Patient Labeling (Patient Information).

Bone Marrow Suppression

Explain the significance of routine blood cell counts. Thus, it is important that periodic assessment of their blood count be performed to detect the development of neutropenia, thrombocytopenia and/ or anemia [see Contraindications (4) and Warnings and Precautions (5.3)]. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever.

Gastrointestinal Events, Eye Disorders

Explain to patients that side effects such as nausea, vomiting, diarrhea, constipation, excessive tearing and/or vision disturbances are associated with docetaxel administration [see Adverse Reactions (6)]. Tell patients to immediately report abdominal pain or tenderness, and/or diarrhea, with or without fever [see Warnings and Precautions (5.4)], any vision changes [see Warnings and Precautions (5.10)].

Hypersensitivity Reactions

Obtain detailed allergy information from the patient prior to Docetaxel Injection administration. Instruct patients to immediately report signs of a hypersensitivity reaction. Ask patients whether they have previously received paclitaxel therapy, and if they have experienced a hypersensitivity reaction to paclitaxel [see Contraindications (4) and Warnings and Precautions (5.5)].

Fluid Retention

Tell patients to watch for signs of fluid retention such as peripheral edema in the lower extremities, weight gain and dyspnea and instruct patients to immediately report them [see Warnings and Precautions (5.6)].

Myalgia, Cutaneous Reactions, Neurologic Reactions, Local Site Reactions, Fatigue, Alopecia

Instruct patients to report myalgia [see Adverse Reactions (6)], cutaneous reactions [see Warnings and Precautions (5.8)], neurologic reactions [see Warnings and Precautions (5.9)], or infusion site reactions [see Adverse Reactions (6)]. Explain to patients that side effects such as fatigue and hair loss (cases of permanent hair loss have been reported) are associated with docetaxel administration [see Adverse Reactions (6)].

Cardiac disorders

Tell patients to report any irregular and/or rapid heartbeat, severe shortness of breath, dizziness, and/or fainting [see Adverse Reactions (6)].

Importance of Corticosteroids

Explain the significance of oral corticosteroids such as dexamethasone administration to the patient to help facilitate compliance. Instruct patients to report if they were not compliant with oral corticosteroid regimen [see Dosage and Administration (2.6)].

Alcohol Content in Docetaxel Injection

Explain to patients the possible effects of the alcohol content in Docetaxel Injection, including possible effects on the central nervous system [see Warnings and Precautions (5.12)].

Ability to Drive or Operate Machines

Explain to patients that Docetaxel Injection may impair their ability to drive or operate machines due to its side effects [see Adverse Reactions (6)] or due to the alcohol content of Docetaxel Injection [see Warnings and Precautions (5.12)]. Advise them not to drive or use machines if they experience these side effects during treatment.

Drug Interactions

Inform patients about the risk of drug interactions and the importance of providing a list of prescription and non-prescription drugs to their healthcare provider [see Drug Interactions (7)].

Embryo-Fetal Toxicity

Docetaxel Injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Advise female patients of childbearing potential to use effective contraceptives during treatment [see Warnings and Precautions (5.13) and Use in Specific Populations (8.1)].

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Rev. A 11/2018

Docetaxel (doe-se-TAKS-el) Injection

for Intravenous Use

Read this Patient Information before you receive your first treatment with Docetaxel Injection and each time before you are treated. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about Docetaxel Injection? 

Docetaxel Injection can cause serious side effects, including death.

What is Docetaxel Injection?

Docetaxel Injection is a prescription anti-cancer medicine used to treat certain people with:

It is not known if Docetaxel Injection is effective in children.

Do not receive Docetaxel Injection if you:

See “What is the most important information I should know about Docetaxel Injection?” for the signs and symptoms of a severe allergic reaction.

See the end of this Patient Information for a complete list of the ingredients in Docetaxel Injection.

Before you receive Docetaxel Injection, tell your healthcare provider about all of your medical conditions, including if you:

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Docetaxel Injection may affect the way other medicines work, and other medicines may affect the way Docetaxel Injection works.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How will I receive Docetaxel Injection?

What are the possible side effects of Docetaxel Injection?

Docetaxel Injection may cause serious side effects including death. 

The most common side effects of Docetaxel Injection include:

Tell your healthcare provider if you have a fast or irregular heartbeat, severe shortness of breath, dizziness or fainting during your infusion. If any of these events occurs after your infusion, get medical help right away.

These are not all the possible side effects of Docetaxel Injection. For more information ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of Docetaxel Injection

Medicines are sometimes prescribed for purposes other than those listed in this Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about Docetaxel Injection that is written for health professionals.

What are the ingredients in Docetaxel Injection?

Active ingredient: docetaxel

Inactive ingredients: citric acid anhydrous, kollidon 12 PF (povidone P12), polysorbate 80, and ethanol

 

For more information call 1-800-432-8534.

This Patient Information has been approved by the U.S. Food and Drug Administration.

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Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Rev. A 11/2018

 infections feeling weak or tired
 low white blood cells (help fight infections), low red blood cells (anemia) and low platelets (help blood to clot) joint and muscle pain
nausea and vomiting
allergic reactions (See “What is the most important information I should know about Docetaxel Injection?”)  diarrhea mouth or lip sores
changes in your sense of taste hair loss: in some people, permanent hair loss has been reported
shortness of breath   redness of the eye, excess tearing
 constipation decreased appetite changes in your fingernails or toenails skin reactions at the site of Docetaxel Injection administration such as increased skin pigmentation, redness, tenderness, swelling, warmth or dryness of the skin
  swelling of your hands, face or feet   tissue damage if Docetaxel Injection leaks out of the vein into the tissues

Actavis

Rx Only

NDC 45963-734-54

Docetaxel Injection

20 mg/mL

For Intravenous Infusion OnlyREADY TO ADD TOINFUSION SOLUTION

CAUTION: Cytotoxic Agent

Contains 1 mLSingle-Use Vial

Actavis

Rx Only

NDC 45963-765-52

Docetaxel Injection

80 mg/4 mL20 mg/mL

For Intravenous Infusion OnlyREADY TO ADD TOINFUSION SOLUTION

CAUTION: Cytotoxic Agent

Contains 1 mLSingle-Use Vial

Actavis

Rx Only

NDC 45963-790-56

Docetaxel Injection

160 mg/8 mL20 mg/mL

For Intravenous Infusion OnlyREADY TO ADD TOINFUSION SOLUTION

CAUTION: Cytotoxic Agent

Contains 1 mLSingle-Use Vial

Manufacturer

Actavis Pharma, Inc.

Active Ingredients

Source

Drugs and Medications [49 Associated Drugs and Medications listed on BioPortfolio]

Docetaxel [sandoz inc.]

These highlights do not include all the information needed to use DOCETAXEL INJECTION safely and effectively. See full prescribing information for DOCETAXEL INJECTION. DOCETAXEL INJECTION, for intrave...

Docetaxel [accord healthcare inc.]

These highlights do not include all the information needed to use DOCETAXEL INJECTION safely and effectively. See full prescribing information for DOCETAXEL INJECTION DOCETAXEL injection, for intraven...

Docetaxel [ingenus pharmaceuticals, llc]

These highlights do not include all the information needed to use DOCETAXEL INJECTION, safely and effectively. See full prescribing information for DOCETAXEL INJECTION.DOCETAXEL injection, For intrave...

Docetaxel [mckesson packaging services a business unit of mckesson corporation]

These highlights do not include all the information needed to use DOCETAXEL INJECTION safely and effectively. See full prescribing information for DOCETAXEL INJECTION DOCETAXEL injection, for intraven...

Docetaxel anhydrous [cipla usa inc.]

These highlights do not include all the information needed to use DOCETAXEL INJECTION safely and effectively. See full prescribing information for DOCETAXEL INJECTION.DOCETAXEL injection, for intraven...

Clinical Trials [1153 Associated Clinical Trials listed on BioPortfolio]

Multicenter Study of Pharmacokinetic-Guided Docetaxel in Breast Cancer Patients Receiving Docetaxel and Cyclophosphamide

The purpose of this study is to adjust the amount of docetaxel participants receive based on the level of docetaxel measured in their blood. This method of dose adjustment is called pharma...

Gemcitabine and Docetaxel With Or Without Bevacizumab in Leiomyosarcoma, Malignant Fibrous Histiocytoma and Angiosarcoma

The purpose of this study is to test whether an experimental drug called bevacizumab given together with gemcitabine and docetaxel, a standard chemotherapy regimen for sarcoma, can help sa...

A Phase 2 Study in Patients With Advanced Non-Small Cell Lung Cancer Using New Agents With and Without Docetaxel.

To determine the effectiveness of CP-868,596 + docetaxel, AG-013736 + docetaxel and CP-868,596 + AG-013736 + docetaxel in patients previously treated for non-small cell lung cancer.

Phase II Study of Perioperative S-1 Plus Docetaxel in Patients With Localized Advanced Gastric Cancer

This study is an open-label, single center, and a single arm phase II study to evaluate the clinical response and safety of perioperative S-1 plus docetaxel. Perioperative chemotherapy is ...

A Study to Test Radium-223 With Docetaxel in Patients With Prostate Cancer

The purpose of this study is to compare any good and bad effects of using radium-223 along with docetaxel chemotherapy treatment versus using docetaxel alone.

PubMed Articles [107 Associated PubMed Articles listed on BioPortfolio]

Preparation, characterization and in vitro activity of a docetaxel-albumin conjugate.

Docetaxel is one of the most effective anticancer drugs. However, the current formulation of docetaxel contains Tween 80 and ethanol as the solvent, which can cause severe side effects. Consequently, ...

A new method for the determination of total and released docetaxel from docetaxel-entrapped core-crosslinked polymeric micelles (CriPec®) by LC-MS/MS and its clinical application in plasma and tissues in patients with various tumours.

A sensitive, high-performance liquid chromatographic method was developed and validated, for determination of docetaxel from docetaxel-entrapped core-crosslinked polymeric micelles (CriPec®) in human...

Effects of prednisone on docetaxel pharmacokinetics in men with metastatic prostate cancer: A randomized drug-drug interaction study.

Docetaxel has been approved for the treatment of metastatic prostate cancer in combination with prednisone. Since prednisone is known to induce the cytochrome P450 iso-enzyme CYP3A4, which is the main...

Targeting the androgen receptor (AR) with AR degradation enhancer ASC-J9 led to increase docetaxel sensitivity via suppressing the p21 expression.

Chemotherapy with docetaxel remains as the effective therapy to suppress castration resistant prostate cancer (CRPC) in some patients. However, most chemotherapy with docetaxel eventually fails with t...

Phase II randomized study of radiotherapy and three-year androgen deprivation with or without concurrent weekly docetaxel in high-risk localized prostate cancer patients.

Docetaxel improves survival in patients with metastatic prostate cancer (PC). This randomized phase II trial aimed to assess the activity of weekly docetaxel with radiotherapy (RT) plus androgen depri...

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