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Docetaxel Anhydrous

FDA Drug Information • Also known as: Docetaxel, Docetaxel Anhydrous

Brand Names
Docetaxel, Docetaxel Anhydrous
Drug Class
Microtubule Inhibitor [EPC]
Route
INTRAVENOUS
Dosage Form
INJECTION, SOLUTION
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION 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 x ULN concomitant with alkaline phosphatase >2.5 x ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated elevations of transaminase >1.5 x ULN also had a higher rate of febrile neutropenia. 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 <1500 cells/mm 3 . Monitor blood counts frequently as neutropenia may be severe and result in infection [ see Warnings and Precautions (5.3) ] . Do not administer Docetaxel Injection to patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80 [ see Contraindications (4) ] . Severe hypersensitivity reactions have been reported in patients despite dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the Docetaxel Injection infusion and administration of appropriate therapy [ see Warnings and Precautions (5.5) ] . Severe fluid retention occurred in 6.5% (6/92) of patients despite use of dexamethasone premedication. It was characterized by one or more of the following events: poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites) [ see Warnings and Precautions (5.6) ] . WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning.

  • Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m 2 ( 5.1 )
  • Avoid use of Docetaxel Injection if bilirubin > ULN, or if AST and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle ( 5.2 )
  • Do not administer Docetaxel Injection to patients with neutrophil counts <1500 cells/mm 3 . Obtain frequent blood counts to monitor for neutropenia ( 4 , 5.3 )
  • Severe hypersensitivity, including fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy ( 5.5 )
  • Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 ( 4 )
  • Severe fluid retention may occur despite dexamethasone ( 5.6 )

    • Description

    11 DESCRIPTION Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine, N- tert -butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one-4-acetate 2-benzoate. Docetaxel (anhydrous) has the following structural formula: Docetaxel, USP (anhydrous) is a white or 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, soluble in methanol 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, USP (anhydrous), 260 mg polysorbate 80 NF, 4 mg anhydrous citric acid USP, 23% v/v alcohol USP (equivalent to 22.08% v/v absolute alcohol), and polyethylene glycol 300 NF. Docetaxel Injection, USP is available in single-dose vials containing 20 mg (2 mL) docetaxel (anhydrous) USP, and multiple-dose vials containing 80 mg (8 mL) or 160 mg (16 mL) docetaxel (anhydrous) USP. Docetaxel Injection requires NO prior dilution with a diluent and is ready to add to the infusion solution. structural formula

    What Is Docetaxel Anhydrous Used For?

    1 INDICATIONS AND USAGE 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 ) 1.1 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 and Administration

    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 hour 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-naïve: 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-hour IV (days 1 to 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-hour IV (days 1 to 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-hour IV (days 1 to 4); for 3 cycles ( 2.5 ) For all patients:
  • Premedicate with oral corticosteroids ( 2.6 )
  • Adjust dose as needed ( 2.7 ) 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 was evaluated as monotherapy, and the recommended dose is 75 mg/m 2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m 2 in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized controlled trials [ see Boxed Warning , Dosage and Administration (2.7) , Warnings and Precautions (5) , Clinical Studies (14) ].
  • For chemotherapy-naïve patients, docetaxel was evaluated in combination with cisplatin. The recommended dose of Docetaxel Injection is 75 mg/m 2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m 2 over 30 to 60 minutes every 3 weeks [ see Dosage and Administration (2.7) ]....

    • Side Effects (Adverse Reactions)

    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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or 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 <2000 cells/mm 3 96 96 99 <500 cells/mm 3 75 88 86 Leukopenia <4000...

    • Drug Interactions

    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 )

    • Contraindications

    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 )

    • Pregnancy and Breastfeeding

    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...

    Overdosage

    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.

    How Supplied

    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, clear, colorless to pale yellow color solution. Discard unused portion of the single-dose vial. The following strengths is available in a one-vial formulation: Unit of Sale Concentration NDC 67457-531-02 Carton of 1 single-dose vial 20 mg/2 mL (10 mg/mL) NDC 67457-532-08 Carton of 1 multiple-dose vial 80 mg/8 mL (10 mg/mL) NDC 67457-533-16 Carton of 1 multiple-dose vial 160 mg/16 mL (10 mg/mL) 16.2 Storage Store at 20º to 25°C (68º 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, USP multiple-dose vials are stable for up to 28 days when stored between 2° and 8°C (36° and 46°F) and protected from light. 16.3 Handling and Disposal Docetaxel Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.