PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL 2 mL Vial Carton

NDC 70700-174-22 Rx only

Docetaxel Injection, USP
** 20 mg/2 mL (10 mg/mL)**

For Intravenous Infusion only
** Ready to add to infusion solution**
** Caution: Cytotoxic Agent**
** Discard unused portion**
** 1 x 2 mL**
** Single-dose vial**

** PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 2 mL Vial Label**

NDC 70700-174-22** Rx only**

Docetaxel Injection, USP
** 20 mg/2 mL (10 mg/mL)**

For Intravenous Infusion only
2 mL Single-dose vial, Discard unused portion
** One-vial formulation**
** Caution: Cytotoxic Agent**

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NDC 70700-175-22 Rx only

Docetaxel Injection, USP

80 mg/8 mL (10 mg/mL)

For Intravenous Infusion only
** Ready to add to infusion solution**
** Caution: Cytotoxic Agent**
** 1 x 8 mL**
** Multi-dose vial**

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NDC 70700-175-22 Rx only****

Docetaxel Injection, USP

8 mL Multi-dose vial 80 mg/8 mL (10 mg/mL)

For Intravenous Infusion only

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 16 mL Carton Label

NDC 70700-176-22 Rx only

Docetaxel Injection, USP
** 160 mg/16 mL (10 mg/mL)**

For Intravenous Use only
** Ready to add to infusion solution**
** Caution: Cytotoxic Agent**
** 1 x 16 mL**
** Multi-dose vial**

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 16 mL Vial Label

NDC 70700-176-22 Rx only

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Docetaxel Injection, USP

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16 mL Multi-dose vial 160 mg/16 mL (10 mg/mL)

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** For Intravenous Infusion only**

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RECENT MAJOR CHANGES SECTION

Highlight: Warnings and Precautions (5.8, 5.14) 11/2020

RECENT MAJOR CHANGES

Warnings and Precautions (5.8, 5.14) 11/2020

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DESCRIPTION SECTION

11 DESCRIPTION

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 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 (anhydrous) has the following structural formula:


Docetaxel is a white to almost-white, crystalline powder with an empirical formula of C43H53NO14 and a molecular weight of 807.88. It is highly lipophilic and practically insoluble in water.

Docetaxel Injection, USP is a sterile, non-pyrogenic, clear, colorless to pale yellow solution at 10 mg/mL concentration.

Each mL contains 10 mg docetaxel (anhydrous) USP, 260 mg polysorbate 80 NF, 4 mg anhydrous citric acid, USP 23% v/v, dehydrated alcohol, USP and polyethylene glycol 300, NF.

Docetaxel Injection is available in single-dose vials containing 20 mg (2 mL) docetaxel (anhydrous), and multiple-dose vials containing 80 mg (8 mL) or 160 mg (16 mL) docetaxel (anhydrous).

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

CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

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 Pharmacokinetics

Absorption

The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20 mg/m2 to 115 mg/m2 in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m2 to 115 mg/m2with 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 minutes, 36 minutes, and 11.1 hours, respectively. Mean total body clearance was 21 L/h/m2.

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 vitrostudies showed that docetaxel is about 94% protein bound, mainly to α1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the invitro 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 (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/m2. 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), Use in Specific Populations (8.6)].

Effect of Race

Mean total body clearance for Japanese patients dosed at the range of 10 mg/m2 to 90 mg/m2was similar to that of European/American populations dosed at 100 mg/m2, 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 coadministered with ketoconazole [see Dosage andAdministration (2.7), 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 metastatic castration-resistant 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/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) 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.

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INDICATIONS & USAGE SECTION

Highlight: Docetaxel Injection is a microtubule inhibitor indicated for:

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

1 INDICATIONS AND USAGE

1.1 Breast Cancer

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

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

1.2 Non-small Cell Lung Cancer

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

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

1.3 Prostate Cancer

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

1.4 Gastric Adenocarcinoma

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

1.5 Head and Neck Cancer

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

DOSAGE FORMS & STRENGTHS SECTION

Highlight: * 20 mg/2 mL (10 mg/mL) single-dose vial (3)

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

3 DOSAGE FORMS AND STRENGTHS

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

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

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CONTRAINDICATIONS SECTION

Highlight: * Hypersensitivity to docetaxel or polysorbate 80 (4)

• Neutrophil counts of <1500 cells/mm3 (4)

4 CONTRAINDICATIONS

Docetaxel Injection is contraindicated in patients with:

• neutrophil counts of <1500 cells/mm3 [see Warnings and Precautions (5.3)].
• 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 (5.5)].

BOXED WARNING SECTION

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA,HYPERSENSITIVITY

REACTIONS, and FLUID RETENTION

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DRUG INTERACTIONS SECTION

Highlight: * Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel metabolism. (7)

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 [seeDosage and Administration (2.7), Clinical Pharmacology (12.3)].

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: * Lactation: Advise women not to breastfeed. (8.2)

• Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of Docetaxel Injection. (8.3)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Docetaxel Injection contains alcohol [see Warnings and Precautions (5.13)]. Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development.

Data

Animal data

Intravenous administration of ≥0.3 and 0.03 mg/kg/day docetaxel to pregnant rats and rabbits, respectively, during the period of organogenesis caused an increased incidence of intrauterine mortality, resorptions, reduced fetal weights, and fetal ossification delays. Maternal toxicity was also observed at these doses, which were approximately 0.02 and 0.003 times the daily maximum recommended human dose based on body surface area, respectively.

8.2 Lactation

Risk Summary

There is no information regarding the presence of docetaxel in human milk, or on its effects on milk production or the breastfed child. No lactation studies in animals have been conducted. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Docetaxel Injection and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating Docetaxel Injection.

Contraception

Females

Docetaxel Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of Docetaxel Injection.

Males

Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of Docetaxel Injection.

Infertility

Based on findings in animal studies, Docetaxel Injection may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The alcohol content of Docetaxel Injection should be taken into account when given to pediatric patients [see Warnings and Precautions (5.13)].

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-fluorouracil (TCF).

Docetaxel Monotherapy

Docetaxel monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12.5 years, range 1-22 years) with a variety of refractory solid tumors. The recommended dose was 125 mg/m2 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 1-26 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/m2) in combination with cisplatin (75 mg/m2) and 5-fluorouracil (750 mg/m2) (TCF) or to cisplatin (80 mg/m2) and 5-fluorouracil (1000 mg/m2/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/m2 to 235 mg/m2 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/m2.

Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF), at dose levels of 75 mg/m2 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/m2, 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)].

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 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+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 less than 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 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.

8.6 Hepatic Impairment

Avoid Docetaxel Injection in patients with bilirubin > ULN and patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN [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 (5.13)].

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ADVERSE REACTIONS SECTION

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

To report SUSPECTED ADVERSE REACTIONS, contact Xiromed, LLC at 844-XIROMED (1-844-947-6633)or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6 ADVERSE REACTIONS

The most serious adverse reactions from docetaxel are:

• Toxic Deaths [see Boxed Warning, Warnings and Precautions (5.1)]

• Hepatic Impairment [see Boxed Warning, Warnings and Precautions (5.2)]

• Hematologic Effects [see Boxed Warning, Warnings and Precautions (5.3)]

• Enterocolitis and Neutropenic Colitis [see Warnings and Precautions (5.4)]

• Hypersensitivity Reactions [see Boxed Warning, Warnings and Precautions (5.5)]

• Fluid Retention [see Boxed Warning, Warnings and Precautions (5.6)]

• Second Primary Malignancies [see Warnings and Precautions (5.7)]

• Cutaneous Reactions [see Warnings and Precautions (5.8)]

• Neurologic Reactions [see Warnings and Precautions (5.9)]

• Eye Disorders [see Warnings and Precautions (5.10)]

• Asthenia [see Warnings and Precautions (5.11)]

• Alcohol Content [see Warnings and Precautions (5.13)]

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.

6.1 Clinical Trials Experience

Breast Cancer

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

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

Table3: Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m****2

• 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 Reactions

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

Febrile neutropenia (<500 cells/mm3with fever >38°C with intravenous antibiotics and/or hospitalization) occurred in 11% of patients with solid tumors, in 12.3% of patients with metastatic breast cancer, and in 9.8% of 92 breast cancer patients premedicated with 3-day corticosteroids.

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

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

Hypersensitivity Reactions

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

Fluid Retention

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

Cutaneous Reactions

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

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

Neurologic Reactions

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

Gastrointestinal Reactions

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

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

Cardiovascular Reactions

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

Infusion Site Reactions

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

Hepatic Reactions

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

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

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

Table4: Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests

• 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

Table5: Non-Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at Docetaxel 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests

• 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

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

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

Combination Therapy with Docetaxel in the Adjuvant Treatment of Breast Cancer

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

Table6: Clinically Important Treatment-Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving Docetaxel in Combination with Doxorubicin and Cyclophosphamide (TAX316)

*COSTART term and grading system for events related to treatment.

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

Fever and Infection

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

Gastrointestinal Reactions

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

Cardiovascular Reactions

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

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

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

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

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

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

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

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

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

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

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

Lung Cancer

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

Docetaxel 75 mg/m2: Treatment-emergent adverse drug reactions are shown in Table 7. Included

in this table are safety data for a total of 176 patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who were treated in two randomized, controlled trials.

These reactions were described using NCI Common Toxicity Criteria regardless of relationship to study treatment, except for the hematologic toxicities or where otherwise noted.

Table7: Treatment-Emergent Adverse Reactions Regardless of Relationship to Treatment in Patients Receiving Docetaxel as Monotherapy for Non-small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy*

• 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.

‡ Not Applicable

§ Not Done

¶ COSTART term and grading system

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

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

Table8: Adverse Reactions Regardless of Relationship to Treatment in Chemotherapy-Naїve Advanced Non-small Cell Lung Cancer Patients Receiving Docetaxel in Combination with Cisplatin

• Replaces NCI term “Allergy”

† COSTART term and grading system

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

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

Prostate Cancer

Combination Therapy with Docetaxel in Patients with Prostate Cancer

The following data are based on the experience of 332 patients, who were treated with docetaxel

75 mg/m2 every 3 weeks in combination with prednisone 5 mg orally twice daily (see Table 9).

Table9: Clinically Important Treatment-Emergent Adverse Reactions (Regardless of Relationship) in Patients with Prostate Cancer who Received Docetaxel in Combination with Prednisone (TAX327)

• Related to treatment

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/m2 in combination with cisplatin and fluorouracil (see Table 10).

Table10: Clinically Important Treatment-Emergent Adverse Reactions Regardless of Relationship to Treatment in the Gastric Cancer Study

Clinically important treatment-emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction.

• Related to treatment.

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/m2 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.

Table11: 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)

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

6.2 Post marketing Experience

The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

**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, in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide may be associated with fatal outcome.

**Cutaneous:**cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme and severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalized exanthematous pustulosis, scleroderma-like changes (usually preceded by peripheral lymphedema), severe palmar-plantar erythrodysesthesia, and permanent alopecia.

Gastrointestinal: enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, which may be fatal. Abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, intestinal obstruction, ileus, and dehydration as a consequence of gastrointestinal events.

**Hearing:**ototoxicity, hearing disorders and/or hearing loss, including during use with other ototoxic drugs.

**Hematologic:**bleeding episodes, disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure.

**Hepatic:**hepatitis, sometimes fatal, primarily in patients with pre- existing liver disorders.

**Hypersensitivity:**anaphylactic shock with fatal outcome in patients who received premedication. Severe hypersensitivity reactions with fatal outcome with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.

**Metabolism and Nutrition Disorders:**electrolyte imbalance, including hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia. Tumor lysis syndrome, sometimes fatal.

**Neurologic:**confusion, seizures or transient loss of consciousness, sometimes appearing during the infusion of the drug.

**Ophthalmologic:**conjunctivitis, lacrimation or lacrimation with or without conjunctivitis, cystoid macular edema (CME). Excessive tearing which may be attributable to lacrimal duct obstruction. Transient visual disturbances (flashes, flashing lights, scotomata), typically occurring during drug infusion and reversible upon discontinuation of the infusion, in association with hypersensitivity reactions.

**Respiratory:**dyspnea, acute pulmonary edema, acute respiratory distress syndrome/ pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis, which may be fatal. Radiation pneumonitis in patients receiving concomitant radiotherapy.

**Renal:**renal insufficiency and renal failure, the majority of cases were associated with concomitant nephrotoxic drugs.

Second Primary Malignancies: second primary malignancies, including AML, MDS, NHL, and renal cancer [see Warnings and Precautions (5.7)].

Musculoskeletal Disorder: myositis.

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

14.1 Locally Advanced or Metastatic Breast Cancer

The efficacy and safety 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).

Randomized Trials

In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with docetaxel (100 mg/m2 every 3 weeks) or the combination of mitomycin (12 mg/m2 every 6 weeks) and vinblastine (6 mg/m2 every 3 weeks). Two hundred three patients were randomized to docetaxel and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the docetaxel 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).

Table12: Efficacy of Docetaxel in the Treatment of Breast Cancer Patients Previously Treated with an Anthracycline-Containing Regimen (Intent- to-Treat Analysis)

• For the risk ratio, a value less than 1.00 favors Docetaxel

In a second randomized trial, patients previously treated with an alkylating- containing regimen were assigned to treatment with docetaxel (100 mg/m2) or doxorubicin (75 mg/m2) every 3 weeks. One hundred sixty-one patients were randomized to docetaxel 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).

Table13: Efficacy of Docetaxel in the Treatment of Breast Cancer Patients Previously Treated with an Alkylating-Containing Regimen (Intent-to- Treat Analysis)

• For the risk ratio, a value less than 1.00 favors docetaxel.

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 monotherapy 60 mg/m2 (n=151), 75 mg/m2 (n=188) or 100 mg/m2 (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 dose: 19.9% for the 60 mg/ m2 group compared to 22.3% for the 75 mg/m2 and 29.8% for the 100 mg/m2 group; pair-wise comparison between the 60 mg/m2 and 100 mg/m2 groups was statistically significant (p=0.037).

Single Arm Studies

Docetaxel at a dose of 100 mg/m2 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: 31.0–44.8) and the complete response rate was 2.1%.

Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m2, 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: 17.2–55.7), similar to the response rate in single arm studies of 100 mg/m2.

14.2 Adjuvant Treatment of Breast Cancer

A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety 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 (1-3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2 (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.



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

Table14: Subset Analyses-Adjuvant Breast Cancer Study

• A hazard ratio of less than 1 indicates that TAC is associated with a longer disease free survival or overall survival compared to FAC.

14.3 Non-small Cell Lung Cancer (NSCLC)

The efficacy and safety 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.

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

Two randomized, controlled trials established that a docetaxel dose of 75 mg/m2 was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel at a dose of 100 mg/m2, however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used [see Boxed Warning, Dosageand 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 or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to docetaxel 100 mg/m2 or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m2. A total of 104 patients were randomized in this amended study to either docetaxel 75 mg/m2 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 75 mg/m2, docetaxel 100 mg/m2 and a treatment in which the investigator chose either vinorelbine 30 mg/m2 days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m2 days 1-3 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 75 mg/m2 arm and the comparator arms are summarized in Table 15 and Figure 3 and 4 showing the survival curves for the two studies.

Table15: Efficacy of Docetaxel in the Treatment of Non-small Cell Lung Cancer Patients Previously Treated with a Platinum-Based Chemotherapy Regimen (Intent-to-Treat Analysis)

• Vinorelbine/Ifosfamide

† a value less than 1.00 favors docetaxel

‡ p≤0.05

§ Uncorrected for multiple comparisons

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 75 mg/m2.

Figure3: TAX317 Survival K-M Curves Docetaxel 75 mg/m2 vs. Best Supportive Care

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Figure4: TAX320 Survival K-M Curves Docetaxel 75 mg/m2 vs. Vinorelbine or Ifosfamide Control

****

Patients treated with docetaxel at a dose of 75 mg/m2 experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.

Combination Therapy with Docetaxel for Chemotherapy-Naïve 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 75 mg/m2 as a 1 hour infusion immediately followed by cisplatin 75 mg/m2 over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m2 administered over 6 - 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m2 administered on day 1 of cycles repeated every 4 weeks; or a combination of docetaxel and carboplatin.

The primary efficacy endpoint was overall survival. Treatment with docetaxel+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 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+cisplatin arm and the comparator arm are summarized in Table 16.

Table16: Survival Analysis of Docetaxel in Combination Therapy for Chemotherapy-Naїve NSCLC

*From the superiority test (stratified log rank) comparing docetaxel+cisplatin to vinorelbine+cisplatin.

† Hazard ratio of docetaxel+cisplatin versus vinorelbine+cisplatin. A hazard ratio of less than 1 indicates that docetaxel+cisplatin is associated with a longer survival.

‡Adjusted for interim analysis and multiple comparisons.

The second comparison in the same three-arm study, vinorelbine + cisplatin versus docetaxel + carboplatin, did not demonstrate superior survival associated with the docetaxel arm (Kaplan-Meier estimate of median survival was 9.1 months for docetaxel +carboplatin compared to 10.0 months on the vinorelbine + cisplatin arm) and the docetaxel + 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 + cisplatin and vinorelbine + cisplatin with respect to objective response and time to progression (see Table 17).

Table17: Response and TTP Analysis of Docetaxel in Combination Therapy for Chemotherapy-Naїve NSCLC

*Adjusted for multiple comparisons.

†Kaplan-Meier estimates.

14.4 Castration-Resistant Prostate Cancer

The safety and efficacy of docetaxel 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:

• Docetaxel 75 mg/m2 every 3 weeks for 10 cycles.
• Docetaxel 30 mg/m2 administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles.
• Mitoxantrone 12 mg/m2 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 18 and Figure 5.

Table18: Efficacy of Docetaxel in the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer (Intent-to-Treat Analysis)

• Stratified log-rank test. Threshold for statistical significance=0.0175 because of 3 arms.

Figure5: TAX327 Survival K-M Curves

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14.5 Gastric Adenocarcinoma

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/m2 on day 1) in combination with cisplatin (C) (75 mg/m2 on day 1) and fluorouracil (F) (750 mg/m2 per day for 5 days) or cisplatin (100 mg/m2 on day 1) and fluorouracil (1000 mg/m2 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 1-16) for the TCF arm compared to 4 (with a range of 1-12) 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: 1.19-1.83) 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: 1.04-1.61). Efficacy results are summarized in Table 19 and Figure 6 and 7.

Table19: Efficacy of Docetaxel Injection in the Treatment of Patients with Gastric Adenocarcinoma

†Unstratified log-rank test.

• For the hazard ratio (TCF/CF), values less than 1.00 favor the Docetaxel Injection arm.

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

Figure6: Gastric Cancer Study (TAX325) Time to Progression K-M Curve

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Figure7: Gastric Cancer Study (TAX325) Survival K-M Curve

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14.6 Head and Neck Cancer

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/m2 followed by cisplatin (P) 75 mg/m2 on Day 1, followed by fluorouracil (F) 750 mg/m2 per day as a continuous infusion on Days 1-5. 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/m2 on Day 1, followed by fluorouracil (F) 1000 mg/m2/day as a continuous infusion on Days 1-5. 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-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.

Table20: Efficacy of Docetaxel Injection in the Induction Treatment of Patients with Inoperable Locally Advanced SCCHN (Intent-to-Treat Analysis)

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

Figure8: TAX323 Progression-Free Survival K-M Curve

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Figure9: TAX323 Overall Survival K-M Curve

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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 70-72 Gy). Surgery on the primary site of disease and/or neck could be considered at any time 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.

Table21: Efficacy of Docetaxel Injection in the Induction Treatment of Patients with Locally Advanced SCCHN (Intent-to-Treat Analysis)

A Hazard ratio of less than 1 favors Docetaxel Injection + cisplatin + fluorouracil.

*unadjusted log-rank test.

NE - not estimable.

Figure10: TAX324 Overall Survival K-M Curve

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OVERDOSAGE SECTION

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/m2 and the other received 200 mg/m2 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/m2 on a mg/m2 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/m2 basis). In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m2 on a mg/m2 basis) and was associated with abnormal mitosis and necrosis of multiple organs.

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NONCLINICAL TOXICOLOGY SECTION

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-K1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60th to 1/15th the recommended human dose on a mg/m2 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 1/50th the recommended human dose on a mg/m2 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 1/3rd and 1/15th the recommended human dose on a mg/m2 basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.

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INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Bone Marrow Suppression

Advise patients that periodic assessment of their blood count will be performed to detect neutropenia, thrombocytopenia, and/or anemia [see Contraindications (4), Warnings and Precautions (5.3)]. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever.

Enterocolitis and Neutropenic Colitis

Advise patients of the symptoms of colitis, such as abdominal pain or tenderness, and/or diarrhea, with or without fever, and instruct patients to promptly contact their healthcare provider if they experience these symptoms [see Dosage and Administration (2.7), Warnings and Precautions (5.4)].

Hypersensitivity Reactions

Ask patients whether they have previously received paclitaxel therapy, and if they have experienced a hypersensitivity reaction to paclitaxel. Instruct patients to immediately report to their healthcare provider signs of a hypersensitivity reaction [see Contraindications (4), Warnings and Precautions (5.5)].

Fluid Retention

Advise patients to report signs of fluid retention such as peripheral edema in the lower extremities, weight gain, and dyspnea immediately to their healthcare provider [see Warnings and Precautions (5.6)].

Second Primary Malignancies

Advise patients on the risk of second primary malignancies during treatment with Docetaxel Injection [see Warnings and Precautions (5.7)].

Cutaneous Reactions

Advise patients that localized erythema of the extremities and severe skin toxicities may occur. Instruct patients to immediately report severe cutaneous reactions to their healthcare provider [see Dosage and Administration (2.7), Warnings and Precautions (5.8)].

Neurologic Reactions

Advise patients that neurosensory symptoms or peripheral neuropathy may occur. Instruct patients to immediately report neurologic reactions to their healthcare provider [see Dosage and Administration (2.7), Warnings and Precautions (5.9)].

Eye Disorders

Advise patients that vision disturbances and excessive tearing are associated with Docetaxel Injection administration. Instruct patients to immediately report any vision changes to their healthcare provider [see Warnings and Precautions (5.10)].

Gastrointestinal Reactions

Explain to patients that nausea, vomiting, diarrhea, and constipation are associated with Docetaxel Injection administration. Instruct patients to report any severe events to their healthcare provider [see Adverse Reactions (6)].

Cardiac Disorders

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

Other Common Adverse Reactions

Advise patients that other common adverse reactions associated with Docetaxel Injection may include alopecia (cases of permanent hair loss have been reported), asthenia, anorexia, dysgeusia, mucositis, myalgia, nail disorders, or pain. Instruct patients to report these reactions to their healthcare provider if serious events occur [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 to their healthcare provider if they were not compliant with the oral corticosteroid regimen [see Dosage and Administration (2.6)].

Embryo-Fetal Toxicity

Docetaxel Injection can cause fetal harm. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise patients to avoid becoming pregnant while receiving this drug. Advise female patients of reproductive potential to use effective contraceptives during treatment and for 6 months after the last dose of Docetaxel Injection. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of Docetaxel Injection [see Warnings and Precautions (5.12), Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women not to breastfeed during Docetaxel Injection treatment and for 1 week after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise males of reproductive potential that Docetaxel Injection may impair fertility [see Nonclinical Toxicology (13.1)].

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 (5.13)].

Tumor Lysis Syndrome

Advise patients of the potential risk of tumor lysis syndrome and to immediately report any signs or symptoms associated with this event (nausea, vomiting, confusion, shortness of breath, seizure, irregular heartbeat, dark or cloudy urine, reduced amount of urine, unusual tiredness, muscle cramps) to their healthcare provider. Advise patients of the importance of keeping scheduled appointment for blood work or other laboratory tests and of drinking adequate fluids to avoid dehydration. [see Warnings and Precautions (5.14)].

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 (5.13)]. 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)].

Manufactured for:
Xiromed, LLC
Florham Park, NJ 07932
Product of India
10/2021 PI-174-01
LEA-020385-01

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Docetaxel Injection, USP is supplied in single-dose or multiple- dose vials as a sterile, pyrogen-free, non-aqueous colorless to pale yellow solution. Discard unused portion of the single-dose vial. The following strengths are available in a one-vial formulation:

• Docetaxel Injection, USP 20 mg/2 mL (10 mg/mL) single-dose vials in cartons containing 1 vial each (NDC 70700-174-22)
• Docetaxel Injection, USP 80 mg/8 mL (10 mg/mL) multiple-dose vials in cartons containing 1 vial each (NDC 70700-175-22)
• Docetaxel Injection, USP 160 mg/16 mL (10 mg/mL) multiple-dose vials in cartons containing 1 vial each (NDC 70700-176-22)

16.2 Storage

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. Retain in the original package to protect from light. Freezing does not adversely affect the product. After first use and following multiple needle entries and product withdrawals, Docetaxel Injection multiple-dose vials are stable for up to 28 days when stored between 2°C and 8°C (36°F and 46°F) and protected from light.

16.3 Handling and Disposal

Docetaxel Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

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REFERENCES SECTION

15 REFERENCES

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

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