FDA Label for Docetaxel

Warning:Toxic Deaths, Hepatotoxicity, Neutropenia, Hypersensitivity Reactions, And Fluid Retention

The incidence of treatment-related mortality associated with docetaxel 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 as a single agent at a dose of 100 mg/m ²[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 × ULN concomitant with alkaline phosphatase >2.5 × ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated elevations of transaminase >1.5 × ULN also had a higher rate of febrile neutropenia 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 ³. 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 (5.4)] . Docetaxel Injection must not be given to patients who have a history of severe hypersensitivity reactions to docetaxel 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 (5.5)].

1.1 Breast Cancer

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

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

1.2 Non-Small Cell Lung Cancer

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

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

1.3 Prostate Cancer

Docetaxel Injection in combination with prednisone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer.

1.4 Gastric Adenocarcinoma

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

1.5 Head And Neck Cancer

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

2. Dosage And Administration

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

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

2.1 Breast Cancer

• For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of Docetaxel Injection is 60 mg/m ² to 100 mg/m ² administered intravenously over 1 hour every 3 weeks.
• For the adjuvant treatment of operable node-positive breast cancer, the recommended Docetaxel Injection dose is 75 mg/m ² administered 1-hour after doxorubicin 50 mg/m ² and cyclophosphamide 500 mg/m ² every 3 weeks for 6 courses. Prophylactic granulocyte - colony stimulating factor (G-CSF) may be used to mitigate the risk of hematological toxicities [see Dosage and Administration (2.7)].

2.2 Non-Small Cell Lung Cancer

• For treatment after failure of prior platinum-based chemotherapy, docetaxel was evaluated as monotherapy, and the recommended dose is 75 mg/m ² administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m ² in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized, controlled trials [see Boxed Warning, Dosage and Administration (2.7), Warnings and Precautions (5), Clinical Studies (14)] .
• For chemotherapy-naïve patients, docetaxel was evaluated in combination with cisplatin. The recommended dose of Docetaxel Injection is 75 mg/m ² administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m ² over 30 to 60 minutes every 3 weeks [see Dosage and Administration (2.7)] .

2.3 Prostate Cancer

• For hormone-refractory metastatic prostate cancer, the recommended dose of Docetaxel Injection is 75 mg/m ² every 3 weeks as a 1 hour intravenous infusion. Prednisone 5 mg orally twice daily is administered continuously [see Dosage and Administration (2.7)] .

2.4 Gastric Adenocarcinoma

• For gastric adenocarcinoma, the recommended dose of Docetaxel Injection is 75 mg/m ² as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m ², as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m ² per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration (2.7)] .

2.5 Head And Neck Cancer

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

• Induction chemotherapy followed by radiotherapy (TAX323)
  For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m ² as a 1 hour intravenous infusion followed by cisplatin 75 mg/m ² intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m ² per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy. [see Dosage and Administration (2.7)] .
• Induction chemotherapy followed by chemoradiotherapy (TAX324)
  For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m ² as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m ² administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m ²/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy [see Dosage and Administration (2.7)] .

2.6 Premedication Regimen

• All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to Docetaxel Injection administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.4)] .
• For hormone-refractory metastatic 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 (5.4)] .

2.8 Administration Precautions

Docetaxel Injection is a cytotoxic anticancer drug. Follow special handling and disposal procedures when preparing Docetaxel Injection solutions. ¹

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.

Two-vial formulation (Injection with Diluent)

Docetaxel Injection requires two dilutions prior to administration. Please follow the preparation instructions provided below. Note: Both the Docetaxel Injection and the diluent vials contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with the entire contents of the accompanying diluent, there is an initial diluted solution containing 10 mg/mL docetaxel.

The table below provides the fill range of the Diluent, the approximate extractable volume of Diluent when the entire contents of the diluent vial are withdrawn, and the concentration of the initial diluted solution for Docetaxel Injection 20 mg and Docetaxel Injection 80 mg (see Table 3).

One-vial formulation (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.

2.10 Stability

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

4. Contraindications

• Docetaxel Injection is contraindicated in patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80. Severe reactions, including anaphylaxis, have occurred [see Warnings and Precautions (5.4)].
• Docetaxel Injection should not be used in patients with neutrophil counts of <1500 cells/mm ³.

5.2 Hepatic Impairment

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)].

5.3 Hematologic Effects

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 ³ and platelets recover to a level >100,000 cells/mm ³.

A 25% reduction in the dose of Docetaxel Injection is recommended during subsequent cycles following severe neutropenia (<500 cells/mm ³) 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 ³) occurs in virtually all patients given 60 mg/m ² to 100 mg/m ² of docetaxel and grade 4 neutropenia (<500 cells/mm ³) occurs in 85% of patients given 100 mg/m ² and 75% of patients given 60 mg/m ². 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 ³.

Febrile neutropenia occurred in about 12% of patients given 100 mg/m ² but was very uncommon in patients given 60 mg/m ². Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related [see Adverse Reactions (6.1), Clinical Studies (14)].

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

5.4 Hypersensitivity Reactions

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 premedicated 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.

Hypersensitivity reactions may occur within a few minutes following initiation of a Docetaxel Injection infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of Docetaxel Injection [see Dosage and Administration (2.6)]

5.5 Fluid Retention

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

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

Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m ². 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 ². Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of docetaxel to resolution (range: 0 to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).

5.6 Acute Myeloid Leukemia

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, 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.

5.8 Neurologic Reactions

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

5.9 Eye Disorders

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

5.10 Asthenia

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

5.11 Alcohol Content

Cases of intoxication have been reported with some formulations of docetaxel due to the alcohol content. The alcohol content in a dose of Docetaxel Injection may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in Docetaxel Injection on the ability to drive or use machines immediately after the infusion.

For Two-vial formulation (Injection with Diluent)
Each administration of Docetaxel Injection at 100 mg/m ² delivers 0.15 g/m ²of ethanol. For a patient with a BSA of 2.0 m ², this would deliver 0.3 grams of ethanol [ see Description (11)]. Other docetaxel products may have a different amount of alcohol.

For One-vial formulation (Injection)
Each administration of Docetaxel Injection at 100 mg/m ² delivers 1.975 g/m ² of ethanol. For a patient with a BSA of 2.0 m ², this would deliver 3.95 grams of ethanol [ see Description (11)]. Other docetaxel products may have a different amount of alcohol.

5.12 Use In Pregnancy

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)].

6. Adverse Reactions

The most serious adverse reactions from docetaxel are:

• Toxic Deaths [see Boxed Warning, Warnings and Precautions (5.1)]
• Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.2)]
• Neutropenia [see Boxed Warning, Warnings and Precautions (5.3)]
• Hypersensitivity [see Boxed Warning, Warnings and Precautions (5.4)]
• Fluid Retention [see Boxed Warning, Warnings and Precautions (5.5)]
• Acute Myeloid Leukemia [see Warnings and Precautions (5.6)]
• Cutaneous Reactions [see Warnings and Precautions (5.7)]
• Neurologic Reactions [see Warnings and Precautions (5.8)]
• Eye Disorders [see Warnings and Precautions (5.9)]
• Asthenia [see Warnings and Precautions (5.10)]
• Alcohol Intoxication [see Warnings and Precautions (5.11)]



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

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

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

6.2 Post-Marketing Experiences

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.

Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction.

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: abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, ischemic colitis, colitis, intestinal obstruction, ileus, neutropenic enterocolitis 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 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.

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.

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: cases of hyponatremia have been reported.

7. Drug Interactions

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)].

8. Use In Specific Populations

8.1 Pregnancy

Pregnancy Category D. [see 'Warnings and Precautions' section]

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.

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 ² basis), administered during the period of organogenesis, have shown that docetaxel 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.

8.3 Nursing Mothers

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.

8.4 Pediatric Use

The safety and effectiveness of Docetaxel Injection in pediatric patients have not been established. The alcohol content of Docetaxel Injection should be taken into account when given to pediatric patients [ see Warnings and Precautions (5.11)].

8.5 Geriatric Use

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-naïve patients with NSCLC (TAX326), 148 patients (36%) in the docetaxel+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+cisplatin group, patients < 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+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+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 < the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively).

When docetaxel was combined with carboplatin for the treatment of chemotherapy-naïve, 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+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 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 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 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 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 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 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.

8.6 Hepatic Impairment

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 (5.11)].

10. Overdosage

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 ² and the other received 200 mg/m ² 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 ² on a mg/m ² 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 ² 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 ² on a mg/m ² basis) and was associated with abnormal mitosis and necrosis of multiple organs.

11. Description

Docetaxel 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 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. Docetaxel has the following structural formula:

Docetaxel Injection - docetaxel injection image01

Docetaxel is a white to off-white powder with an empirical formula of C ₄₃H ₅₃NO ₁₄ and a molecular weight of 807.88. It is highly lipophilic and practically insoluble in water.

Two-vial formulation (Injection with Diluent)

Docetaxel Injection USP is a clear yellow to brownish-yellow viscous solution. Docetaxel Injection USP is sterile, non-pyrogenic, and is available in single-dose vials containing 20 mg (0.5 mL) or 80 mg (2 mL) docetaxel anhydrous USP. Each mL contains 40 mg docetaxel anhydrous USP, 60 mg dehydrated alcohol and 1040 mg polysorbate 80. Citric acid (anhydrous) may be used to adjust the pH.

Docetaxel Injection USP requires dilution with Diluent prior to addition to the infusion bag. A sterile, non-pyrogenic, single-dose diluent is supplied for that purpose. The diluent for Docetaxel Injection USP contains 13% polyethylene glycol 400 in water for injection, and is supplied in vials.

One-vial formulation (Injection)

Docetaxel Injection USP is a sterile, non-pyrogenic, pale yellow to brownish-yellow solution at 20 mg/mL concentration.

Each mL contains 20 mg docetaxel anhydrous USP, 4 mg anhydrous citric acid, 520 mg polysorbate 80 and 395 mg dehydrated alcohol solution.

Docetaxel Injection USP is available in single dose and multiple dose vials containing 20 mg (1 mL), 80 mg (4 mL) or 160 mg (8 mL) docetaxel anhydrous USP.

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

12.1 Mechanism Of Action

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.

12.3 Human Pharmacokinetics

Absorption: The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20 mg/m ² to 115 mg/m ² in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m ² to 115 mg/m ² 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 ²

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 ₁ -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 ¹⁴C-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 (< 8%) of unchanged drug.

Effect of Age: A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m ². Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of docetaxel were 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 ² to 90 mg/m ² was similar to that of European/American populations dosed at 100 mg/m ², suggesting no significant difference in the elimination of docetaxel in the two populations.

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/m ² intravenous) alone or docetaxel (10 mg/m ² 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-administration with ketoconazole [see Dosage and Administration (2.7) and Drug-Drug Interactions (7)]

Effect of Combination Therapies:

• Dexamethasone: Docetaxel total body clearance was not modified by pretreatment with dexamethasone.
• Cisplatin: Clearance of docetaxel in combination therapy with cisplatin was similar to that previously observed following monotherapy with docetaxel. The pharmacokinetic profile of cisplatin in combination therapy with docetaxel was similar to that observed with cisplatin alone.
• Cisplatin and Fluorouracil: The combined administration of docetaxel, cisplatin and fluorouracil in 12 patients with solid tumors had no influence on the pharmacokinetics of each individual drug.
• Prednisone: A population pharmacokinetic analysis of plasma data from 40 patients with hormone-refractory metastatic prostate cancer indicated that docetaxel systemic clearance in combination with prednisone is similar to that observed following administration of docetaxel alone.
• Cyclophosphamide and Doxorubicin: A study was conducted in 30 patients with advanced breast cancer to determine the potential for drug-drug-interactions between docetaxel (75 mg/m ²), doxorubicin (50 mg/m ²), and cyclophosphamide (500 mg/m ²) when administered in combination. The coadministration of docetaxel had no effect on the pharmacokinetics of doxorubicin and cyclophosphamide when the three drugs were given in combination compared to coadministration of doxorubicin and cyclophosphamide only. In addition, doxorubicin and cyclophosphamide had no effect on docetaxel plasma clearance when the three drugs were given in combination compared to historical data for docetaxel monotherapy.

13. Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies with docetaxel have not been performed.

Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K ₁ cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60 ^th to 1/15 ^th the recommended human dose on a mg/m ² 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 ^th the recommended human dose on a mg/m ² 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 ^rd and 1/15 ^th the recommended human dose on a mg/m ² basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.

14. Clinical Studies

14.1 Locally Advanced Or Metastatic Breast Cancer

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

14.2 Adjuvant Treatment Of Breast Cancer

A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of another formulation of docetaxel 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 75 mg/m ² administered 1-hour after doxorubicin 50 mg/m ² and cyclophosphamide 500 mg/m ² (TAC arm), or doxorubicin 50 mg/m ² followed by fluorouracil 500 mg/m ² and cyclosphosphamide 500 mg/m ² (FAC arm). Both regimens were administered every 3 weeks for 6 cycles.

Docetaxel 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.

Figure 1 - TAX316 Disease Free Survival K-M curve

Docetaxel Injection - docetaxel injection image02

Figure 2 - TAX316 Overall Survival K-M curve

The following table describes the results of subgroup analyses for DFS and OS (See Table 15).

14.3 Non-Small Cell Lung Cancer (Nsclc)

The efficacy and safety of another formulation of docetaxel 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-naïve.

14.4 Hormone Refractory Prostate Cancer

The safety and efficacy of another formulation of docetaxel in combination with prednisone in patients with androgen independent (hormone refractory) metastatic 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:

• Docetaxel 75 mg/m ² every 3 weeks for 10 cycles.
• Docetaxel 30 mg/m ² administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles.
• Mitoxantrone 12 mg/m ² every 3 weeks for 10 cycles.

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

In the docetaxel every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the docetaxel every 3 week arm versus the control arm are summarized in Table 19 and Figure 5.

Table 19 - Efficacy of Docetaxel in the Treatment of Patients with Androgen Independent (Hormone Refractory) Metastatic Prostate Cancer (Intent-to-Treat Analysis)

	Docetaxel + Prednisone every 3 weeks	Mitoxantrone + Prednisone every 3 weeks
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 Stratified log rank test. Threshold for statistical significance = 0.0175 because of 3 arms.	0.0094	--

Figure 5 - TAX327 Survival K-M Curves

Docetaxel Injection - docetaxel injection image06

14.5 Gastric Adenocarcinoma

A multicenter, open-label, randomized trial was conducted to evaluate the safety and efficacy of another formulation of docetaxel 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 (T) (75 mg/m ² on day 1) in combination with cisplatin (C) (75 mg/m ² on day 1) and fluorouracil (F) (750 mg/m ² per day for 5 days) or cisplatin (100 mg/m ² on day 1) and fluorouracil (1000 mg/m ² 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 20 and Figures 6 and 7.

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

Figure 6 - Gastric Cancer Study (TAX325) Time to Progression K-M Curve

Docetaxel - docetaxel injection image07

Figure 7 - Gastric Cancer Study (TAX325) Survival K-M Curve

14.6 Head And Neck Cancer

15. References

• “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16. How Supplied/Storage And Handling

16.1 How Supplied

Two-vial formulation (Injection with Diluent)

Docetaxel Injection is supplied in single dose vials for 80 mg/mL and 20 mg/mL as a sterile, pyrogen-free, non-aqueous, viscous solution with an accompanying sterile, non-pyrogenic, diluent vial.

Docetaxel Injection 80 mg/2 mL with Diluent for Docetaxel Injection USP 80 mg: Both items are in a blister pack in one carton. NDC 16729-228-50

Docetaxel Injection 20 mg/0.5 mL with Diluent for Docetaxel Injection USP 20 mg: Both items are in a blister pack in one carton. NDC 16729-120-49

One-vial formulation (Injection)

Docetaxel Injection is supplied in single dose and multiple dose vials as a sterile, pyrogen-free, non-aqueous solution.

Docetaxel Injection Single Dose Vials

Docetaxel Injection 160 mg/8 mL: The vial is in one carton. NDC 16729-231-65

Docetaxel Injection 80 mg/4 mL: The vial is in one carton. NDC 16729-231-64

Docetaxel Injection 20 mg/1 mL: The vial is in one carton. NDC 16729-231-63

Docetaxel Injection Multiple Dose Vials

Docetaxel Injection 160 mg/8 mL: The vial is in one carton. NDC 16729-267-65

Docetaxel Injection 80 mg/4 mL: The vial is in one carton. NDC 16729-267-64

Docetaxel Injection 20 mg/1 mL: The vial is in one carton. NDC 16729-267-63

16.2 Storage

Two-vial formulation (Injection with Diluent)

Store at 25°C (77°F); excursions permitted from 15°C - 30°C (59°-86°F) [see USP Controlled Room Temperature]. Protect from light.

One-vial formulation (Injection)

Store between 15°C and 25°C (59°F and 77°F); Retain in the original package to protect from light. Freezing does not adversely affect the product.

After initial puncture, Docetaxel Injection multiple dose vials are stable for 28 days when stored at room temperature, with protection from light.

16.3 Handling And Disposal

Follow procedures for proper handling and disposal of anticancer drugs. ¹

17. Patient Counseling Information

Package Label-Principal Display Panel - 80 Mg/2 Ml -Before Initial Dilution

NDC 16729- 120-33

Docetaxel

Injection USP

80 mg/2 mL

Before Initial Dilution

Rx Only

80 mg/2 mL docetaxel in

polysorbate 80

FOR INTRAVENOUS INFUSION
ONLY AFTER FINAL DILUTION

Package Label-Principal Display Panel - 80 Mg-Diluent

NDC 16729- 121-33

DILUENT for

Docetaxel Injection USP

80 mg

(13% polyethylene glycol 400

in water for injection)

Rx Only

Package Label-Principal Display Panel - 20 Mg/05 - Before Initial Dilution

NDC 16729- 120-31

Docetaxel

Injection USP

20mg/0.5 mL

Before Initial Dilution

Rx Only

20 mg/0.5 mL docetaxel in

polysorbate 80

FOR INTRAVENOUS INFUSION
ONLY AFTER FINAL DILUTION

Package Label-Principal Display Panel - 20 Mg-Diluent

NDC 16729- 121-31

DILUENT for

Docetaxel Injection USP

20 mg

(13% polyethylene glycol 400

in water for injection)

Rx Only

One-Vial Formulation (Injection Concentrate)- Multiple Dose

Docetaxel Injection USP 160 mg/8 mL (NDC 16729-267-65)