Docetaxel

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

BOXED WARNING SECTION

Treatment-related mortality associated with docetaxel is increased in patients with abnormal liver function, in patients receiving higher doses, and in patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who receive docetaxel as a single agent at a dose of 100 mg/m 2 [ see Warnings and Precautions ( 5.1 ) ]. Avoid the use of Docetaxel Injection in patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated elevations of transaminase >1.5 × ULN also had a higher rate of febrile neutropenia. Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of Docetaxel Injection [ see Warnings and Precautions ( 5.2 ) ]. Do not administer Docetaxel Injection to patients with neutrophil counts of

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

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).

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

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

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

Docetaxel Injection is contraindicated in patients with: neutrophil counts of

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

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.

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

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 ), Clinical Pharmacology ( 12.3 ) ].

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

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

DESCRIPTION SECTION

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 C 43 H 53 NO 14 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.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

15 REFERENCES

REFERENCES SECTION

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

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

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 2 months after the last dose of Docetaxel Injection. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of Docetaxel Injection [ see 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 ) ]. Patient Information Docetaxel (doe-se-TAKS-el) Injection for intravenous use What is the most important information I should know about Docetaxel Injection? Docetaxel Injection can cause serious side effects, including death. The chance of death in people who receive Docetaxel Injection is higher if you: have liver problems receive high doses of Docetaxel Injection have non-small cell lung cancer and have been treated with chemotherapy medicines that contain platinum Docetaxel Injection can affect your blood cells. Your healthcare provider should do routine blood tests during treatment with Docetaxel Injection. This will include regular checks of your white blood cell counts. If your white blood cells are too low, your healthcare provider may not treat you with Docetaxel Injection until you have enough white blood cells. People with low white blood cell counts can develop life-threatening infections. The earliest sign of infection may be fever. Follow your healthcare provider’s instructions for how often to take your temperature during treatment with Docetaxel Injection. Call your healthcare provider right away if you have a fever. Swelling (inflammation) of the small intestine and colon. This can happen at any time during treatment and could lead to death as early as the first day you get symptoms. Tell your healthcare provider right away if you develop new or worse symptoms of intestinal problems, including stomach (abdominal) pain or tenderness or diarrhea, with or without fever. Severe allergic reactions are medical emergencies that can happen in people who receive Docetaxel Injection and can lead to death. You may be at higher risk of developing a severe allergic reaction to Docetaxel Injection if you are allergic to paclitaxel. Your healthcare provider will monitor you closely for allergic reactions during your Docetaxel Injection infusion. Tell your healthcare provider right away if you have any of these signs of a severe allergic reaction: trouble breathing sudden swelling of your face, lips, tongue, throat, or trouble swallowing hives (raised bumps), rash, or redness all over your body Your body may hold too much fluid (se...

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 2 mL Carton Label

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 68083- 399 -01 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 2 mL Rx only NDC 68083- 399 -01 Docetaxel Injection, USP 20 mg/2 mL (10 mg/mL) For Intravenous Infusion only Single-dose vial, Discard unused portion One-vial formulation Caution: Cytotoxic Agent PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 8 mL Carton Label NDC 68083- 400 -01 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 PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 8 mL Vial Label 8 mL NDC 68083- 400 -01 Multi-dose vial Rx only Docetaxel Injection, USP 80 mg/8 mL (10 mg/mL) For Intravenous Infusion only PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 16 mL Carton Label NDC 68083- 401 -01 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 16 mL NDC 68083- 401 -01 Multi-dose vial Rx only Docetaxel Injection, USP 160 mg/16 mL (10 mg/mL) For Intravenous Infusion only