Docetaxel

1 INDICATIONS AND USAGE Docetaxel Injection, USP is a microtubule inhibitor indicated for: Breast Cancer (BC) : single agent for locally advanced or metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC ( 1.1 ) Non-small Cell Lung Cancer (NSCLC) : single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC ( 1.2 ) Castration-Resistant Prostate Cancer (CRPC) : with prednisone in metastatic castration-resistant prostate cancer ( 1.3 ) Gastric Adenocarcinoma (GC) : with cisplatin and fluorouracil for untreated, advanced GC, including the gastroesophageal junction ( 1.4 ) Squamous Cell Carcinoma of the Head and Neck (SCCHN) : with cisplatin and fluorouracil for induction treatment of locally advanced SCCHN ( 1.5 ) 1.1 Breast Cancer Docetaxel Injection, USP is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. Docetaxel Injection, USP 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, USP 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, USP 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, USP in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer. 1.4 Gastric Adenocarcinoma Docetaxel Injection, USP 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, USP in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

2 DOSAGE AND ADMINISTRATION For all indications, toxicities may warrant dosage adjustments [see Dosage and Administration ( 2.7 )] . Administer in a facility equipped to manage possible complications (e.g. anaphylaxis). Administer in a facility equipped to manage possible complications (e.g., anaphylaxis). Administer intravenously (IV) over 1 hr every 3 weeks. PVC equipment is not recommended. Use only a 21 gauge needle to withdraw Docetaxel Injection from the vial. BC locally advanced or metastatic: 60 mg/m 2 to 100 mg/m 2 single agent (2.1) BC adjuvant: 75 mg/m 2 administered 1 hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 every 3 weeks for 6 cycles (2.1) NSCLC: after platinum therapy failure: 75 mg/m 2 single agent (2.2) NSCLC: chemotherapy-naive: 75 mg/m 2 followed by cisplatin 75 mg/m 2 (2.2) CRPC: 75 mg/m 2 with 5 mg prednisone twice a day continuously (2.3) GC: 75 mg/m 2 followed by cisplatin 75 mg/m 2 (both on day 1 only) followed by fluorouracil 750 mg/m 2 per day as a 24-hr IV (days 1-5), starting at end of cisplatin infusion (2.4) SCCHN: 75 mg/m 2 followed by cisplatin 75 mg/m 2 IV (day 1), followed by fluorouracil 750 mg/m 2 per day as a 24-hr IV (days 1-5), starting at end of cisplatin infusion; for 4 cycles (2.5) SCCHN: 75 mg/m 2 followed by cisplatin 100 mg/m 2 IV (day 1), followed by fluorouracil 1000 mg/m 2 per day as a 24-hr IV (days 1-4); for 3 cycles (2.5) For all patients: Premedicate with oral corticosteroids (2.6) Adjust dose as needed (2.6) 2.1 Breast Cancer For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of docetaxel injection is 60 mg/m 2 to 100 mg/m 2 administered intravenously over 1 hour every 3 weeks. For the adjuvant treatment of operable node-positive breast cancer, the recommended docetaxel injection dose is 75 mg/m 2 administered 1 hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 every 3 weeks for 6 courses. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities [see Dosage and Administration ( 2.7 )]. 2.2 Non-small Cell Lung Cancer For treatment after failure of prior platinum-based chemotherapy, docetaxel injection was evaluated as monotherapy, and the recommended dose is 75 mg/m 2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m 2 in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized controlled trials [see Boxed Warning , Dosage and Administration ( 2.7 ), Warnings and Precautions ( 5 ), Clinical Studies ( 14 )]. For chemotherapy-naive patients, docetaxel injection was evaluated in combination with cisplatin. The recommended dose of docetaxel injection is 75 mg/m 2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m 2 over 30-60 minutes every 3 weeks [see Dosage and Administration ( 2.7 )]. 2.3 Prostate Cancer For metastatic castration-resistant prostate cancer, the recommended dose of docetaxel injection is 75 mg/m 2 every 3 weeks as a 1 hour intravenous infusion. Prednisone 5 mg orally twice daily is administered continuously [see Dosage and Administration ( 2.7 )]. 2.4 Gastric Adenocarcinoma For gastric adenocarcinoma, the recommended dose of docetaxel injection is 75 mg/m 2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m 2 , as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m 2 per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration ( 2.7 )] . 2.5 Head and Neck Cancer Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic i …

3 DOSAGE FORMS AND STRENGTHS Injection:One-vial formulation Docetaxel Injection: Single-dose vials 20 mg/mL, 80 mg/4 mL (20 mg/mL), and 160 mg/8 mL (20 mg/mL) (3) One-vial Docetaxel Injection, USP Docetaxel Injection, USP 20 mg/mL Docetaxel Injection, USP 20 mg/1 mL single-dose vial: 20 mg docetaxel in 1 mL 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol. Docetaxel Injection, USP 80 mg/4 mL Docetaxel Injection, USP 80 mg/4 mL single-dose vial: 80 mg docetaxel in 4 mL 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol. ​Docetaxel Injection, USP 160 mg/8 mL Docetaxel Injection, USP 160 mg/8 mL single-dose vial: 160 mg docetaxel in 8 mL 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol.

4 CONTRAINDICATIONS Docetaxel Injection is contraindicated in patients with: neutrophil counts of <1500 cells/mm 3 [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 )]. Hypersensitivity to docetaxel or polysorbate 80 ( 4 ) Neutrophil counts of <1500 cells/mm 3 ( 4 )

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. 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 Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Breast Cancer Monotherapy with docetaxel for locally advanced or metastatic breast cancer after failure of prior chemotherapy Docetaxel 100 mg/m 2 : Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received docetaxel administered at 100 mg/m 2 as a 1-hour infusion every 3 weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to docetaxel. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving docetaxel for the treatment of breast cancer and in patients with other tumor types. (See Table 3.) Table 3: Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m 2 Adverse Reaction All Tumor Types Normal LFTs Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN n=2045 % All Tumor Types Elevated LFTs Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN n=61 % Breast Cancer Normal LFTs n=965 % Hematologic Neutropenia 38°C with intravenous antibiotics and/or hospitalization 11 26 12 Septic Death 2 5 1 Non-Septic D …

7 DRUG INTERACTIONS Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4. In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of Docetaxel Injection and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In patients receiving treatment with Docetaxel Injection, close monitoring for toxicity and a Docetaxel Injection dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration ( 2.7 ), Clinical Pharmacology ( 12.3 )] . Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel metabolism. ( 7 )

8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. (8.2) Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of docetaxel. (8.3) 8.1 Pregnancy Risk Summary Based on findings in animal reproduction studies and its mechanism of action, docetaxel 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 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 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 and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Based on findings in animals, docetaxel can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating docetaxel. Contraception Females Based on genetic toxicity findings, advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of docetaxel. Males Based on genetic toxicity findings, 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. Infertility Based on findings in animal studies, docetaxel 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 ha …

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.

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, USP is (2R,3S)-N-carboxy-3-phenylisoserine,N- tert -butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, anhydrous. Docetaxel, USP has the following structural formula: Docetaxel, USP is a white to almost-white powder with an empirical formula of C 43 H 53 NO 14 , and a molecular weight of 807.88. It is highly lipophilic and practically insoluble in water. One-vial Docetaxel Injection, USP Docetaxel Injection, USP is a sterile, non-pyrogenic, clear, viscous, colorless to pale yellow solution, without macroscopic particles in solution at 20 mg/mL docetaxel concentration. Each mL contains 20 mg docetaxel, USP, citric acid anhydrous (6 mg), kollidon 12 PF (povidone P12) (100 mg), polysorbate 80 (424 mg) and ethanol (400 mg, 50% v/v). Docetaxel Injection, USP is available in single-dose vials containing 20 mg (1 mL) or 80 mg (4 mL), docetaxel. Docetaxel Injection, USP requires NO prior dilution with a diluent and is ready to add to the infusion solution. c3e54dbf-figure-01

10 OVERDOSAGE There is no known antidote for Docetaxel Injection overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed. In two reports of overdose, one patient received 150 mg/m 2 and the other received 200 mg/m 2 as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident. In mice, lethality was observed following single intravenous doses that were ≥154 mg/kg (about 4.5 times the human dose of 100 mg/m 2 on a mg/m 2 basis); neurotoxicity associated with paralysis, non-extension of hind limbs, and myelin degeneration was observed in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m 2 basis). In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m 2 on a mg/m 2 basis) and was associated with abnormal mitosis and necrosis of multiple organs.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied One-vial Docetaxel Injection, USP Docetaxel Injection, USP, 20 mg/mL, (one-vial formulation) is supplied in a single-dose vial as a sterile, pyrogen-free, nonaqueous solution. Discard unused portion. Docetaxel Injection, USP 20 mg/mL (NDC 57884-3041-1) Docetaxel Injection, USP 20 mg/1 mL : 20 mg docetaxel in 1 mL 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol. The vial is in a blister pack in one carton. Docetaxel Injection, USP 80 mg/4mL (NDC 57884-3042-1) Docetaxel Injection, USP 80 mg/4 mL : 80 mg docetaxel in 4 mL 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol. The vial is in a blister pack in one carton. Docetaxel Injection, USP 160 mg/8mL (NDC 57884-3043-1) Docetaxel Injection, USP 160 mg/8 mL : 160 mg docetaxel in 8 mL 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol. The vial is in a blister pack in one carton. 16.2 Storage Store between 2°C and 25°C (36°F and 77°F). Retain in the original package to protect from light. Freezing does not adversely affect the product. 16.3 Handling and Disposal Docetaxel Injection, USP is a hazardous drug. Follow applicable special handling and disposal procedures.