Docetaxel

Breast Cancer

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

Non-Small Cell Lung Cancer

DOCEFREZ 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.

DOCEFREZ 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.

Prostate Cancer

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

Docetaxel may cause serious side effects including death. See the Black Box Warning.

• Acute Myeloid Leukemia (AML), a type of blood cancer, can happen in people who take docetaxel along with certain other medicines. Tell your doctor about all the medicines you take.
• Other blood disorders or changes in blood counts due to leukemia and other blood disorders may occur years after treatment with docetaxel.
• Skin reactions including redness and swelling of your arms and legs with peeling of your skin may occur.
• Neurologic symptoms including numbness, tingling, or burning in your hands and feet can happen with this medication.

Before you receive docetaxel, tell your doctor if you:

• are allergic to any medicines
• have liver problems
• have any other medical conditions
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Docetaxel may affect the way other medicines work, and other medicines may affect the way docetaxel works.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. It has been shown that use of docetaxel in pregnant women caused some babies to be born with problems. However, in some serious situations, the benefit of using this medication may be greater than the risk of harm to the baby.

• Breast Cancer
• Breast Cancer and Coping With Stress
• Breast Cancer and Lymphedema
• Breast Cancer Clinical Trials
• Breast Cancer During Pregnancy
• Breast Cancer in Young Women
• Breast Cancer Prevention
• Breast Cancer Recurrence

• A semisynthetic taxoid produced from the needles of the European yew (Taxus baccata) tree.1 2 3 4 5 6 Structurally and pharmacologically similar to paclitaxel.2 4 5 7 8

• Disrupts the microtubular network in cells that is essential for mitotic and interphase cellular function.1

• Importance of recognizing and reporting adverse effects including myalgia, neurologic effects, and cutaneous reactions.1 84 85 86

• Importance of reading the patient information leaflet.1 84 85 86

• Importance of recognizing and reporting signs of alcohol intoxication (e.g., confusion, stumbling, drowsiness).1 84 85 86 90 Advise patients to avoid driving, operating machinery, or performing other dangerous activities for 1–2 hours following administration of the drug.90

• Risk of cystoid macular edema.1 84 85 86

• Importance of recognizing and immediately reporting manifestations of a hypersensitivity reaction (e.g., difficulty breathing or swallowing, facial swelling, rash).1 84 85 86

• Importance of taking the oral corticosteroid premedication as directed to prevent severe hypersensitivity reactions and minimize incidence and severity of fluid retention; importance of patients informing clinicians of noncompliance.1 84 85 86

• Importance of recognizing and reporting signs of fluid retention (e.g., peripheral edema in lower extremities, weight gain, dyspnea).1 84 85 86

• Importance of obtaining routine blood cell counts; inform patients to monitor temperature frequently and immediately inform clinician of fever.1 84 85 86

• Risk of nausea, vomiting, diarrhea, constipation, fatigue, excessive tearing, infusion site reactions, and alopecia.1 84 85 86

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy and to use an effective method of contraception during therapy.1 84 85 86 Advise pregnant women of risk to fetus.1 84 85 86

• Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illness.1 84 85 86

• Importance of informing patients of other important precautionary information.1 84 85 86 (See Cautions.)

The most serious adverse reactions from Docetaxel are:

•   Toxic Deaths [see Boxed Warning ,Warnings and Precautions (5.1) ]
•   Hepatotoxicity [see Boxed Warning ,Warnings and Precautions (5.2) ]
•   Neutropenia [see Boxed Warning ,Warnings and Precautions (5.3) ]
•   Hypersensitivity [see Boxed Warning ,Warnings and Precautions (5.4) ]
•   Fluid Retention [see Boxed Warning ,Warnings and Precautions (5.5) ]

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.

Clinical Trial 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).

Table 3 – Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/ m2

* 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
Adverse Reaction	All Tumor Types  Normal LFTs*  n = 2045 %	All Tumor Types  Elevated LFTs**  n = 61 %	Breast Cancer  Normal LFTs*  n = 965  %
Hematologic Neutropenia      <2000 cells/mm3      <500 cells/mm3 Leukopenia      <4000 cells/mm3      <1000 cells/mm3 Thrombocytopenia      <100,00cells/mm3 Anemia      <11 g/dL      <8 g/dL Febrile Neutropenia***	96 75   96 32   8   90 9 11	96 88   98 47   25   92 31 26	99 86   99 44   9   94 8 12
Septic Death Non-Septic Death	2 1	5 7	1 1
Infections      Any      Severe	22 6	33 16	22 6
Fever in Absence of Infection      Any      Severe	31 2	41 8	35 2
Hypersensitivity Reactions Regardless of Premedication      Any      Severe With 3-day Premedication      Any      Severe	21 4 n = 92 15 2	20 10 n = 3 33 0	18 3 n = 92 15 2
Fluid Retention Regardless of Premedication      Any      Severe With 3-day Premedication      Any      Severe	47 7 n = 92 64 7	39 8 n = 3 67 33	60 9 n = 92 64 7
Neurosensory      Any      Severe	49 4	34 0	58 6
Cutaneous      Any      Severe	48 5	54 10	47 5
Nail Changes      Any      Severe	31 3	23 5	41 4
Gastrointestinal Nausea Vomiting Diarrhea      Severe	39 22 39 5	38 23 33 5	42 23 43 6
Stomatitis      Any      Severe	42 6	49 13	52 7
Alopecia	76	62	74
Asthenia      Any      Severe	62 13	53 25	66 15
Myalgia      Any      Severe	19 2	16 2	21 2
Arthralgia	9	7	8
Infusion Site Reactions	4	3	4

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/mm3  with 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 (5.4)]. 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 (5.5)].

Cutaneous Reactions

Severe skin toxicity is discussed elsewhere in the label [see Warnings and Precautions (5.7)]. 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(5.8)].

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 occurred rarely. 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 Tables 4 and 5).

Table 4 – 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 ¾ and fever >38.1°C.
	Docetaxel 100 mg/m2		Docetaxel 60 mg/m2
Adverse Reaction	Normal LFTs* n = 730 %	Elevated LFTs** n = 18 %	Normal LFTs* n = 174 %
Neutropenia      Any <2000 cells/mm3       Grade 4 <500 cells/mm3	98 84	100 94	95 75
Thrombocytopenia     Any <100,000 cells/mm3       Grade 4 <20,000cells/mm3	11 1	44 17	14 1
Anemia <11 g/dL	95	94	65
Infection***      Any      Grade 3 and 4	23 7	39 33	1 0
Febrile Neutropenia****      By Patient      By Course	12  2	33 9	0 0
Septic Death	2	6	1
Non-Septic Death	1	11	0

Table 5 – 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

NA = not available
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/ m2dose.
	Docetaxel 100 mg/ m2		Docetaxel 60 mg/ m2
Adverse Reaction	Normal LFTs* n = 730 %	Elevated LFTs** n = 18 %	Normal LFTs* n = 174 %
Acute Hypersensitivity ReactionRegardless of Premedication      Any      Severe	13 1	6 0	1 0
Fluid Retention*** Regardless of Premedication      Any      Severe	56 8	61 17	13 0
Neurosensory      Any      Severe	57 6	50 0	20 0
Myalgia	23	33	3
Cutaneous      Any      Severe	45 5	61 17	31 0
Asthenia      Any      Severe	65 17	44 22	66 0
Diarrhea      Any      Severe	42 6	28 11	NA
Stomatitis      Any      Severe	53 8	67 39	19 1

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 ¾ 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 vs. 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).

Table 6 – 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.
	Docetaxel 75 mg/m2  + Doxorubicin 50 mg/ m2 + Cyclophosphamide 500 mg/m2 (TAC)  n = 744  %		Fluorouracil 500 mg/m2  + Doxorubicin 50 mg/ m2  +Cyclophosphamide 500 mg/m2 (FAC)  n = 736  %
Adverse Reaction	Any	Grade 3/4	Any	Grade 3/4
Anemia	92	4	72	2
Neutropenia	71	66	82	49
Fever in absence of infection	47	1	17	0
Infection	39	4	36	2
Thrombocytopenia	39	2	28	1
Febrile neutropenia	25	N/A	3	N/A
Neutropenic infection	12	N/A	6	N/A
Hypersensitivity reactions	13	1	4	0
Lymphedema	4	0	1	0
Fluid Retention* Peripheral edema Weight gain	35 27 13	1 0 0	15 7 9	0 0 0
Neuropathy sensory	26	0	10	0
Neuro-cortical	5	1	6	1
Neuropathy motor	4	0	2	0
Neuro-cerebellar	2	0	2	0
Syncope	2	1	1	0
Alopecia	98	N/A	97	N/A
Skin toxicity	27	1	18	0
Nail disorders	19	0	14	0
Nausea	81	5	88	10
Stomatitis	69	7	53	2
Vomiting	45	4	59	7
Diarrhea	35	4	28	2
Constipation	34	1	32	1
Taste perversion	28	1	15	0
Anorexia	22	2	18	1
Abdominal Pain	11	1	5	0
Amenorrhea	62	N/A	52	N/A
Cough	14	0	10	0
Cardiac dysrhythmias	8	0	6	0
Vasodilatation	27	1	21	1
Hypotension	2	0	1	0
Phlebitis	1	0	1	0
Asthenia	81	11	71	6
Myalgia	27	1	10	0
Arthralgia	19	1	9	0
Lacrimation disorder	11	0	7	0
Conjunctivitis	5	0	7	0

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

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 ¾ 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.

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 vs. one patient in the FAC arm. Five of the 7 TAC-treated patients required treatment discontinuation; no deaths due to these events occurred.

Cardiovascular Reactions

More cardiovascular reactions were reported in the TAC arm vs. the FAC arm; dysrhythmias, all grades (7.9% vs. 6.0%), hypotension, all grades (2.6% vs. 1.1%) and CHF (2.3% vs. 0.9%, at 70 months median follow-up). One patient in each arm died due to heart failure.

Acute Myeloid Leukemia (AML)

Treatment-related acute myeloid leukemia or myelodysplasia is known to occur in patients treated with anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. AML occurs at a higher frequency when these agents are given in combination with radiation therapy. AML occurred in the adjuvant breast cancer trial (TAX316). The cumulative risk of developing treatment-related AML at 5 years in TAX316 was 0.4% for TAC-treated patients and 0.1% for FAC-treated patients. This risk of AML is comparable to the risk observed for other anthracyclines/cyclophosphamide containing adjuvant breast chemotherapy regimens.

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.

Table 7 – 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.
	Docetaxel 75 mg/m2 n = 176 %	Best Supportive Care  n = 49  %	Vinorelbine/Ifosfamide  n = 119  %
Neutropenia      Any      Grade 3/4	84 65	14 12	83 57
Leukopenia      Any      Grade 3/4	84 49	6 0	89 43
Thrombocytopenia      Any      Grade 3/4	8 3	0 0	8 2
Anemia      Any      Grade 3/4	91 9	55 12	91 14
Febrile Neutropenia**	6	NA†	1
Infection      Any      Grade 3/4	34 10	29 6	30 9
Treatment Related Mortality	3	NA†	3
Hypersensitivity Reactions      Any      Grade 3/4	6 3	0 0	1 0
Fluid Retention      Any      Severe	34 3	ND††	23 3
Neurosensory      Any      Grade 3/4	23 2	14 6	29 5
Neuromotor      Any      Grade 3/4	16 5	8 6	10 3
Skin      Any      Grade 3/4	20 1	6 2	17 1
Gastrointestinal Nausea      Any      Grade ¾ Vomiting     Any      Grade ¾ Diarrhea      Any      Grade 3/4	34 5   22 3   23 3	31 4   27 2   6 0	31 8   22 6   12 4
Alopecia	56	35	50
Asthenia      Any      Severe***	53 18	57 39	54 23
Stomatitis      Any      Grade 3/4	26 2	6 0	8 1
Pulmonary      Any      Grade 3/4	41 21	49 29	45 19
Nail Disorder      Any      Severe***	11 1	0 0	2 0
Myalgia      Any      Severe***	6 0	0 0	3 0
Arthralgia      Any      Severe***	3 0	2 0	2 1
Taste Perversion      Any      Severe***	6 1	0 0	0 0

Combination therapy with Docetaxel in chemotherapy-na ve 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.

Table 8 – Adverse Reactions Regardless of Relationship to Treatment in Chemotherapy-Naïve Advanced Non-Small Cell Lung Cancer Patients Receiving Docetaxel in Combination with Cisplatin

*   Replaces NCI Term “Allergy”.
** COSTART term and grading system.
Adverse Reaction	Docetaxel 75 mg/m2 +  Cisplatin 75 mg/ m2  n = 406  %	Vinorelbine 25 mg/m2 +  Cisplatin 100 mg/ m2  n = 396  %
Neutropenia      Any      Grade 3/4	91 74	90 78
Febrile Neutropenia	5	5
Thrombocytopenia      Any      Grade 3/4	15 3	15 4
Anemia      Any      Grade 3/4	89 7	94 25
Infection      Any      Grade 3/4	35 8	37 8
Fever in absence of infection      Any      Grade 3/4	33 <1	29 1
Hypersensitivity Reaction*      Any      Grade 3/4	12 3	4 <1
Fluid Retention**       Any      All severe or life-threatening events  Pleural effusion       Any      All severe or life-threatening events  Peripheral edema       Any      All severe or life-threatening events  Weight gain       Any      All severe or life-threatening events	54 2    23 2     34 <1    15 <1	42 2    22 2      18 <1     9 <1
Neurosensory      Any      Grade 3/4	47 4	42 4
Neuromotor      Any      Grade 3/4	19 3	17 6
Skin      Any      Grade 3/4	16 <1	14 1
Nausea      Any      Grade 3/4	72 10	76 17
Vomiting      Any      Grade 3/4	55 8	61 16
Diarrhea      Any      Grade 3/4	47 7	25 3
Anorexia**      Any      All severe or life-threatening events	42 5	40 5
Stomatitis      Any      Grade 3/4	24 2	21 1
Alopecia      Any      Grade 3	75 <1	42 0
Asthenia**      Any      All severe or life-threatening events	74 12	75 14
Nail Disorder**      Any      All severe events	14 <1	<1 0
Myalgia**      Any      All severe events	18 <1	12 <1

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).

Table 9 – 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
	Docetaxel 75 mg/m2 every 3 weeks+ prednisone 5 mg twice daily n = 332 %		Mitoxantrone 12 mg/m2 every 3 weeks + prednisone 5 mg twice daily n = 335 %
Adverse Reaction	Any	Grade 3/4	Any	Grade 3/4
Anemia	67	5	58	2
Neutropenia	41	32	48	22
Thrombocytopenia	3	1	8	1
Febrile Neutropenia	3	N/A	2	N/A
Infection	32	6	20	4
Epistaxis	6	0	2	0
Allergic Reactions	8	1	1	0
Fluid Retention* Weight Gain* Peripheral Edema*	24 8 18	1 0 0	5 3 2	0 0 0
Neuropathy Sensory	30	2	7	0
Neuropathy Motor	7	2	3	1
Rash/Desquamation	6	0	3	1
Alopecia	65	N/A	13	N/A
Nail Changes	30	0	8	0
Nausea	41	3	36	2
Diarrhea	32	2	10	1
Stomatitis/Pharyngitis	20	1	8	0
Taste Disturbance	18	0	7	0
Vomiting	17	2	14	2
Anorexia	17	1	14	0
Cough	12	0	8	0
Dyspnea	15	3	9	1
Cardiac left ventricular function	10	0	22	1
Fatigue	53	5	35	5
Myalgia	15	0	13	1
Tearing	10	1	2	0
Arthralgia	8	1	5	1

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).

Table 10 – 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.
	Docetaxel Injection 75 mg/m2 + cisplatin 75 mg/ m2 + fluorouracil 750 mg/m2 n = 221		Cisplatin 100 mg/m2 + fluorouracil 1000 mg/m2 n = 224
Adverse Reaction	Any %	Grade 3/4 %	Any %	Grade 3/4 %
Anemia	97	18	93	26
Neutropenia	96	82	83	57
Fever in the absence of infection	36	2	23	1
Thrombocytopenia	26	8	39	14
Infection	29	16	23	10
Febrile neutropenia	16	N/A	5	N/A
Neutropenic infection	16	N/A	10	N/A
Allergic reactions	10	2	6	0
Fluid retention*	15	0	4	0
Edema*	13	0	3	0
Lethargy	63	21	58	18
Neurosensory	38	8	25	3
Neuromotor	9	3	8	3
Dizziness	16	5	8	2
Alopecia	67	5	41	1
Rash/itch	12	1	9	0
Nail changes	8	0	0	0
Skin desquamation	2	0	0	0
Nausea	73	16	76	19
Vomiting	67	15	73	19
Anorexia	51	13	54	12
Stomatitis	59	21	61	27
Diarrhea	78	20	50	8
Constipation	25	2	34	3
Esophagitis/dysphagia/ odynophagia	16	2	14	5
Gastrointestinal pain/cramping	11	2	7	3
Cardiac dysrhythmias	5	2	2	1
Myocardial ischemia	1	0	3	2
Tearing	8	0	2	0
Altered hearing	6	0	13	2

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.

Table 11 – 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
	TAX323 (n = 355)				TAX324  (n =494)
	Docetaxel Injection arm  (n = 174)		Comparator arm  (n = 181)		Docetaxel Injection arm  (n = 251)		Comparator arm  (n = 243)
Adverse Reaction (by Body System)	Any %	Grade 3/4 %	Any %	Grade 3/4 %	Any %	Grade 3/4 %	Any %	Grade 3/4 %
Neutropenia	93	76	87	53	95	84	84	56
Anemia	89	9	88	14	90	12	86	10
Thrombocytopenia	24	5	47	18	28	4	31	11
Infection	27	9	26	8	23	6	28	5
Febrile neutropenia*	5	N/A	2	N/A	12	N/A	7	N/A
Neutropenic infection	14	N/A	8	N/A	12	N/A	8	N/A
Cancer pain	21	5	16	3	17	9	20	11
Lethargy	41	3	38	3	61	5	56	10
Fever in the absence of infection	32	1	37	0	30	4	28	3
Myalgia	10	1	7	0	7	0	7	2
Weight loss	21	1	27	1	14	2	14	2
Allergy	6	0	3	0	2	0	0	0
Fluid retention** Edema only Weight gain only	20 13 6	0 0 0	14 7 6	1 0 0	13 12  0	1 1 0	7 6 1	2 1 0
Dizziness	2	0	5	1	16	4	15	2
Neurosensory	18	1	11	1	14	1	14	0
Altered hearing	6	0	10	3	13	1	19	3
Neuromotor	2	1	4	1	9	0	10	2
Alopecia	81	11	43	0	68	4	44	1
Rash/itch	12	0	6	0	20	0	16	1
Dry skin	6	0	2	0	5	0	3	0
Desquamation	4	1	6	0	2	0	5	0
Nausea	47	1	51	7	77	14	80	14
Stomatitis	43	4	47	11	66	21	68	27
Vomiting	26	1	39	5	56	8	63	10
Diarrhea	33	3	24	4	48	7	40	3
Constipation	17	1	16	1	27	1	38	1
Anorexia	16	1	25	3	40	12	34	12
Esophagitis/dysphagia/Odynophagia	13	1	18	3	25	13	26	10
Taste, sense of smell altered	10	0	5	0	20	0	17	1
Gastrointestinal pain/cramping	8	1	9	1	15	5	10	2
Heartburn	6	0	6	0	13	2	13	1
Gastrointestinal bleeding	4	2	0	0	5	1	2	1
Cardiac dysrhythmia	2	2	2	1	6	3	5	3
Venous***	3	2	6	2	4	2	5	4
Ischemia myocardial	2	2	1	0	2	1	1	1
Tearing	2	0	1	0	2	0	2	0
Conjunctivitis	1	0	1	0	1	0	0.4	0

Post-Marketing Experiences

The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.

Body as a Whole

Diffuse pain, chest pain, radiation  recall  phenomenon.

Cardiovascular

Atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction.

Cutaneous

Very rare cases of cutaneous lupus erythematosus and rare cases of bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal  necrolysis, and Scleroderma-like changes usually preceded by peripheral lymphedema. In some cases multiple factors may have contributed to the development of these effects. Severe hand and foot syndrome has been reported.

Gastrointestinal

Abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, ischemic colitis, colitis, intestinal obstruction, ileus, neutropenic enterocolitis and dehydration as a consequence to gastrointestinal events have been reported.

Hematologic

Bleeding episodes. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported. Cases of acute myeloid leukemia and myelodysplasic syndrome have been reported in association with Docetaxel when used in combination with other chemotherapy agents and/or radiotherapy.

Hypersensitivity

Rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication.

Hepatic

Rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.

Neurologic

Confusion, rare cases of seizures or transient loss of consciousness have been observed, sometimes appearing during the infusion of the drug.

Ophthalmologic

Conjunctivitis,  lacrimation or lacrimation with or without conjunctivitis. Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion.

Hearing

Rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs.

Respiratory

Dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis have rarely been  reported and may be associated with fatal outcome. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

Renal

Renal insufficiency and renal failure have been reported, the majority of these cases were associated with concomitant nephrotoxic drugs.

Metabolism and Nutrition Disorders

Cases of hyponatremia have been reported.

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 is a white to almost-white 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 clear, colorless to pale yellow solution. Docetaxel Injection, USP is sterile, non-pyrogenic and 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).

Each mL contains 10 mg Docetaxel (anhydrous) in 260 mg polysorbate 80 NF, 4 mg Anhydrous Citric Acid USP, 23% v/v Dehydrated Alcohol USP and Polyethylene Glycol 300 NF.

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

Patient Information

Docetaxel (Doe-se-TAKS-el) Injection

Intravenous Infusion

Read this Patient Information before you receive your first treatment with Docetaxel Injection and each time before you are treated. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about Docetaxel Injection?

Docetaxel Injection can cause serious side effects, including death.

1    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

2.   Docetaxel Injection can affect your blood cells. Your doctor 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 doctor may not treat you with Docetaxel until you have enough white blood cells. People with low white blood counts can develop life-threatening infections. The earliest sign of infection may be fever. Follow your doctor's instructions for how often to take your temperature while taking Docetaxel Injection. Call your doctor right away if you have a fever.

3.   Serious allergic reactions can happen in people who take Docetaxel Injection. Serious allergic reactions are medical emergencies that can lead to death and must be treated right away.

      Tell your doctor right away if you have any of these signs of a serious 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

4.   Your body may hold too much fluid (severe fluid retention) during treatment with Docetaxel Injection. This can be life threatening. To decrease the chance of this happening, you must take another medicine, a corticosteroid, before each Docetaxel Injection treatment. You must take the corticosteroid exactly as your doctor tells you. Tell your doctor or nurse before your Docetaxel Injection treatment if you forget to take the corticosteroid dose or do not take it as your doctor tells you.

What is Docetaxel Injection ?

• Docetaxel Injection is a prescription anti-cancer medicine used to treat certain people with:

            ◦   breast cancer

            ◦   non-small cell lung cancer

            ◦   prostate cancer

            ◦   stomach cancer

            ◦   head and neck cancer

It is not known if Docetaxel Injection is effective in children.

Who should not take Docetaxel Injection?

Do not take Docetaxel Injection if you:

•   have had a severe allergic reaction to:

            ◦   Docetaxel, the active ingredient in Docetaxel Injection or

            ◦   any other medicines that contain polysorbate 80. Ask your doctor or pharmacist if you are not sure.

See "What is the most important information I should know about Docetaxel Injection?" for the signs and symptoms of a severe allergic reaction.

•   have a low white blood cell count.

What should I tell my doctor before receiving Docetaxel Injection? 

Before you receive Docetaxel Injection tell your doctor if you:

• are allergic to any medicines. See "Who should not take Docetaxel Injection ? " Also, see the end of this leaflet for a complete list of the ingredients in Docetaxel Injection.
• have liver problems
• have any other medical conditions
• are pregnant or plan to become pregnant. Docetaxel Injection can harm your unborn baby.
• are breast-feeding or plan to breast-feed. It is not known if Docetaxel Injection passes into your breast milk. You and your doctor should decide if you will take Docetaxel Injection or breast-feed.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Docetaxel Injection may affect the way other medicines work, and other medicines may affect the way Docetaxel Injection works. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How will I receive Docetaxel Injection?

• Docetaxel Injection will be given to you as an intravenous (IV) injection into your vein, usually over 1 hour.
• Docetaxel Injection is usually given every 3 weeks.
• Your doctor will decide how long you will receive treatment with Docetaxel Injection.
• Your doctor will check your blood cell counts and other blood tests during your treatment with Docetaxel Injection to check for side effects of Docetaxel Injection.
• Your doctor may stop your treatment, change the timing of your treatment, or change the dose of your treatment if you have certain side effects while taking Docetaxel Injection.

What are the possible side effects of Docetaxel Injection? 

Docetaxel Injection may cause serious side effects including death. 

• See "What is the most important information should know about Docetaxel Injection? "
• Acute Myeloid Leukemia(AML) , a type of blood cancer, can happen in people who take Docetaxel Injection along with certain other medicines.
• Other Blood Disorders Changes in blood counts due to leukemia and other blood disorders may occur years after treatment with Docetaxel Injection.
• Skin Reactions including redness and swelling of your arms and legs with peeling of your skin.
• Neurologic Symptoms including numbness, tingling, or burning in your hands and feet.
• Vision Problems including blurred vision or loss of vision.
• Docetaxel Injection contains alcohol. The alcohol content in Docetaxel injection may impair your ability to drive or use machinery right after receiving Docetaxel injection. Consider whether you should drive, operate machinery or do other dangerous activities right after you receive Docetaxel injection treatment.

The most common side effects of Docetaxel Injection include:

• changes in your sense of taste
• feeling short of breath
• constipation
• decreased appetite
• changes in your fingernails or toenails
• swelling of your hands, face or feet
• feeling weak or tired
• joint and muscle pain
• nausea and vomiting
• diarrhea
• mouth or lips sores
• hair loss
• rash
• redness of the eye, excess tearing
• skin reactions at the site of Docetaxel Injection administration such as increased skin pigmentation, redness, tenderness, swelling, warmth or dryness of the skin.
• tissue damage if Docetaxel Injection leaks out of the vein into the tissues

Tell your doctor if you have any side effect that bothers you or does not go away.

These are not all the possible side effects of Docetaxel Injection. For more information ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about Docetaxel Injection

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. This Patient Information leaflet summarizes the most important information about Docetaxel Injection. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Docetaxel Injection that is written for healthcare professionals.

What are the ingredients in Docetaxel Injection?

Active ingredient: Docetaxel (anhydrous)

Inactive ingredients include: Dehydrated Alcohol, Polylobate 80, Polyethylene Glycol 300 and Anhydrous Citric acid

Every three-week injection of Docetaxel Injection for breast, nonsmall cell lung, and stomach, and head and neck cancers Take your oral corticosteroid medicine as your doctor tells you. Oral corticosteroid dosing: Day 1     Date: ___________       Time:  ___________ AM     ___________ PM Day 2     Date: ___________       Time:  ___________ AM     ___________ PM   (Docetaxel Injection Treatment Day) Day 3     Date: ___________       Time:  ___________ AM     ___________ PM

Every three-week injection of Docetaxel Injection for prostate cancer Take your oral corticosteroid medicine as your doctor tells you. Oral corticosteroid dosing: Date: ___________       Time: ___________ Date: ___________       Time: ___________ (Docetaxel Injection Treatment Day)                                         Time: ___________

This Patient Information has been approved by the U.S Food and Drug Administration.

Revision: September 2017

Manufactured for:

Ingenus Pharmaceuticals, LLC

4190 Millenia Boulevard, Orlando, FL 32839-6408

Manufactured by:

Ingenus Pharmaceuticals, GmbH

Via Cadepiano 24, Barbengo-Lugano

6917, Switzerland

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Concentrate, Intravenous:

Taxotere: 20 mg/mL (1 mL); 80 mg/4 mL (4 mL) [contains alcohol, usp, polysorbate 80]

Generic: 20 mg/mL (1 mL); 80 mg/4 mL (4 mL); 160 mg/8 mL (8 mL); 200 mg/10 mL (10 mL); 20 mg/0.5 mL (0.5 mL); 80 mg/2 mL (2 mL)

Concentrate, Intravenous [preservative free]:

Generic: 20 mg/mL (1 mL); 80 mg/4 mL (4 mL); 140 mg/7 mL (7 mL [DSC]); 160 mg/8 mL (8 mL)

Solution, Intravenous:

Generic: 20 mg/2 mL (2 mL); 80 mg/8 mL (8 mL); 160 mg/16 mL (16 mL); 200 mg/20 mL (20 mL [DSC]); 20 mg/mL (1 mL); 80 mg/4 mL (4 mL); 160 mg/8 mL (8 mL)

Solution Reconstituted, Intravenous:

Docefrez: 20 mg (1 ea [DSC]); 80 mg (1 ea [DSC]) [contains alcohol, usp, polysorbate 80]

Note: Premedicate with corticosteroids for 3 days, beginning one day prior to docetaxel administration, to reduce the severity of hypersensitivity reactions and fluid retention. Patients being treated for prostate cancer with concurrent prednisone should be premedicated with oral dexamethasone at 12 hours, 3 hours, and 1 hour prior to docetaxel administration.

Breast cancer: IV:

Locally advanced or metastatic: 60 to 100 mg/m2 every 3 weeks (as a single agent)

Operable, node-positive (adjuvant treatment): TAC regimen: 75 mg/m2 every 3 weeks for 6 courses (in combination with doxorubicin and cyclophosphamide) (Mackey 2013; Martin 2005)

Adjuvant treatment (off-label dosing): 75 mg/m2 every 21 days (in combination with cyclophosphamide) for 4 cycles (Jones 2006) or 75 mg/m2 every 21 days (in combination with carboplatin and trastuzumab) for 6 cycles (Slamon 2011)

Neoadjuvant treatment (off-label dosing): 75 mg/m2 (cycle 1; if tolerated, may increase to 100 mg/m2 in subsequent cycles) every 21 days for a total of 4 cycles (in combination with trastuzumab and pertuzumab) (Gianni 2012)

Metastatic treatment (off-label dosing):

Every-3-week administration: 75 mg/m2 (cycle 1; may increase to 100 mg/m2 in subsequent cycles) every 21 days for at least 6 cycles (in combination with trastuzumab and pertuzumab) (Baselga 2012; Swain 2013) or 100 mg/m2 every 21 days (in combination with trastuzumab) for at least 6 cycles (Marty 2005) or 75 mg/m2 every 21 days (in combination with capecitabine) until disease progression or unacceptable toxicity (O’Shaughnessy 2002) or 60 mg/m2, 75 mg/m2, or 100 mg/m2 every 21 days for at least 6 cycles until disease progression, unacceptable toxicity, or discontinuation (Harvey 2006)

Weekly administration: 40 mg/m2/dose once a week (as a single agent) for 6 weeks followed by a 2-week rest, repeat until disease progression or unacceptable toxicity (Burstein 2000) or 35 mg/m2/dose once weekly for 3 weeks, followed by a 1-week rest, may increase to 40 mg/m2 once weekly for 3 weeks followed by a 1-week rest with cycle 2 (Rivera 2008) or 35 mg/m2/dose once weekly (in combination with trastuzumab) for 3 weeks followed by a 1-week rest; repeat until disease progression or unacceptable toxicity (Esteva 2002)

Gastric adenocarcinoma: IV: 75 mg/m2 every 3 weeks (in combination with cisplatin and fluorouracil)

Sequential chemotherapy and chemoradiation (off-label dosing): Induction: 75 mg/m2 on days 1 and 22 (in combination with cisplatin) for 2 cycles, followed by chemoradiation: 20 mg/m2 weekly for 5 weeks (in combination with cisplatin and radiation) (Ruhstaller 2009)

Locally advanced or metastatic disease (off-label dosing): 50 mg/m2 on day 1 every 2 weeks (in combination with fluorouracil, leucovorin, and oxaliplatin) until disease progression or unacceptable toxicity up to a maximum of 8 cycles (Al-Batran 2008)

Head and neck cancer: IV: 75 mg/m2 every 3 weeks (in combination with cisplatin and fluorouracil) for 3 or 4 cycles, followed by radiation therapy

Non-small cell lung cancer: IV: 75 mg/m2 every 3 weeks (as a single agent or in combination with cisplatin)

Prostate cancer: IV: 75 mg/m2 every 3 weeks (in combination with prednisone)

Bladder cancer, metastatic (off-label use): IV: 100 mg/m2 every 3 weeks (as a single agent) (McCaffrey 1997) or 35 mg/m2 on days 1 and 8 of a 21-day cycle (in combination with gemcitabine and cisplatin) for at least 6 cycles or until disease progression or unacceptable toxicity (Pectasides 2002)

Esophageal cancer (off-label use): IV:

Sequential chemotherapy and chemoradiation: Induction: 75 mg/m2 on days 1 and 22 (in combination with cisplatin) for 2 cycles, followed by chemoradiation: 20 mg/m2 weekly for 5 weeks (in combination with cisplatin and radiation) (Ruhstaller 2009)

Definitive chemoradiation: 60 mg/m2 on days 1 and 22 (in combination with cisplatin and radiation) for 1 cycle (Li 2010)

Locally advanced or metastatic disease: 75 mg/m2 on day 1 every 3 weeks (in combination with cisplatin and fluorouracil) (Ajani 2007; Van Cutsem 2006) or 50 mg/m2 on day 1 every 2 weeks (in combination with fluorouracil, leucovorin, and oxaliplatin) until disease progression or unacceptable toxicity up to a maximum of 8 cycles (Al-Batran 2008) or 35 mg/m2 on days 1, 8, 15, 29, 36, 43, 50, and 57 (in combination with cisplatin, fluorouracil, and radiotherapy; neoadjuvant setting) (Pasini 2013)

Ewing sarcoma or osteosarcoma (recurrent or progressive; off-label uses): IV: 100 mg/m2 on day 8 of a 21-day cycle (in combination with gemcitabine) (Navid 2008)

Ovarian cancer (off-label use): IV: 60 mg/m2 every 3 weeks (in combination with carboplatin) for up to 6 cycles (Markman 2001) or 75 mg/m2 every 3 weeks (in combination with carboplatin) for 6 cycles (Vasey 2004) or 35 mg/m2 (maximum dose: 70 mg) weekly for 3 weeks followed by a 1-week rest (in combination with carboplatin) (Kushner 2007)

Prostate cancer, metastatic, hormone-sensitive (off-label use): 75 mg/m2 on day 1 every 3 weeks (in combination with androgen deprivation therapy and prednisolone) for 6 cycles (James 2016) or 75 mg/m2 on day 1 every 3 weeks (in combination with androgen deprivation therapy; daily prednisone not required) for 6 cycles (Sweeney 2015).

Small cell lung cancer, relapsed (off-label use): IV: 100 mg/m2 every 3 weeks (Smyth 1994)

Soft tissue sarcoma (off-label use): IV: 100 mg/m2 on day 8 of a 3-week treatment cycle (in combination with gemcitabine and filgrastim or pegfilgrastim) (Leu 2004; Maki 2007)

Unknown-primary, adenocarcinoma (off-label use): IV: 65 mg/m2 every 3 weeks (in combination with carboplatin) (Greco 2000) or 75 mg/m2 on day 8 of a 3-week treatment cycle (in combination with gemcitabine) for up to 6 cycles (Pouessel 2004) or 60 mg/m2 on day 1 of a 3-week treatment cycle (in combination with cisplatin) (Mukai 2010)

Dosing adjustment for concomitant CYP3A4 inhibitors: Avoid the concomitant use of strong CYP3A4 inhibitors with docetaxel. If concomitant use of a strong CYP3A4 inhibitor cannot be avoided, consider reducing the docetaxel dose by 50% (based on limited pharmacokinetic data).

Storage and stability may vary by manufacturer, refer to specific prescribing information.

Docetaxel 10 mg/mL: Store intact vials between 2°C to 25°C (36°F to 77°F) (actual recommendations may vary by generic manufacturer; consult manufacturer’s labeling). Protect from bright light. Freezing does not adversely affect the product. Multi-use vials (80 mg/8 mL and 160 mg/16 mL) are stable for up to 28 days after first entry when stored between 2°C to 8°C (36°F to 46°F) and protected from light. Solutions diluted for infusion should be used within 4 hours of preparation, including infusion time.

Docetaxel 20 mg/mL concentrate/solution:

Taxotere: Store intact vials between 2°C to 25°C (36°F to 77°F). Protect from bright light. Freezing does not adversely affect the product. Solutions diluted for infusion in D5W or NS in non-PVC containers should be used within 6 hours of preparation, including infusion time, when stored between 2°C to 25°C (36°F to 77°F) or within 48 hours when stored between 2°C to 8°C (36°F to 46°F).

Generic formulations: Store intact vials at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from light. Solutions diluted for infusion in D5W or NS should be used within 4 hours of preparation, including infusion time.

Non-alcohol formulation: Store intact vials at 20°C to 25°C (68°F to 77°F). Protect from light. After the first use and following multiple needle entries and withdrawals, multi-use vials (80 mg/4 mL and 160 mg/8 mL) are stable for up to 28 days when stored between 2°C to 8°C (36°F to 46°F) and protected from light. Solutions diluted for infusion in NS or D5W are stable for 24 hours when stored between 2°C to 8°C (36°F to 46°F).

Docetaxel lyophilized powder (Docefrez): Store intact vials between 2°C to 8°C (36°F to 46°F). Protect from light. Allow vials (and provided diluent) to stand at room temperature for 5 minutes prior to reconstitution. After reconstitution, may be stored refrigerated or at room temperature for up to 8 hours. Solutions diluted for infusion in D5W or NS should be used within 6 hours of preparation, including infusion time. According to the manufacturer, physical and chemical in-use stability of the infusion solution (prepared as recommended) has been demonstrated in non-PVC bags up to 48 hours when stored between 2°C and 8°C (36°F and 46°F).

Two-vial formulation (generic; concentrate plus diluent formulation): Reconstituted solutions of the two-vial formulation are stable in the vial for 8 hours at room temperature or under refrigeration. Solutions diluted for infusion in NS or D5W in polyolefin containers should be used within 4 hours of preparation, including infusion time.

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Patients with an absolute neutrophil count <1,500/mm3 should not receive docetaxel. Monitor blood counts frequently to monitor for neutropenia (which may be severe and result in infection). The dose-limiting toxicity is neutropenia. Platelets should recover to >100,000/mm3 prior to treatment. Patients with increased liver function tests experienced more episodes of neutropenia with a greater number of severe infections; monitor liver function tests frequently. Hematologic toxicity may require dose reduction or therapy discontinuation.

• Cutaneous reactions: Cutaneous reactions, including erythema (with edema) and desquamation, have been reported; may require dose reduction.

• Extravasation: Docetaxel is an irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

• Fluid retention: [US Boxed Warning]: Severe fluid retention, characterized by pleural effusion (requiring immediate drainage), ascites with pronounced abdominal distention, peripheral edema (poorly tolerated), dyspnea at rest, cardiac tamponade, generalized edema, and weight gain, has been reported (despite the use of premedication with 3 days of dexamethasone). Fluid retention may begin as lower extremity peripheral edema and become generalized with a median weight gain of 2 kg. In patients with breast cancer, the median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m2; fluid retention resolves in a median of 16 weeks after discontinuation. Patients should be premedicated with a corticosteroid (starting 1 day prior to administration) to reduce the incidence and severity of fluid retention. Closely monitor patients with existing effusions.

• Hypersensitivity reactions: [US Boxed Warning]: Severe hypersensitivity reactions, characterized by generalized rash/erythema, hypotension, bronchospasms, or rare anaphylaxis may occur (may be fatal; has occurred in patients receiving a 3-day corticosteroid premedication). Hypersensitivity reactions require immediate discontinuation of the docetaxel infusion and administration of appropriate therapy. Do not administer to patients with a history of severe hypersensitivity to docetaxel or polysorbate 80. Minor reactions including flushing or localized skin reactions may also occur. Observe for hypersensitivity, especially with the first 2 infusions. Discontinue for severe reactions; do not rechallenge if severe. Patients should be premedicated with a corticosteroid (starting 1 day prior to administration) to prevent or reduce the severity of hypersensitivity reactions.

• Neurosensory symptoms: Dosage adjustment is recommended with severe neurosensory symptoms (paresthesia, dysesthesia, pain); persistent symptoms may require discontinuation. Reversal of symptoms may be delayed after discontinuation.

• Ocular adverse effects: Cystoid macular edema (CME) has been reported; if vision impairment occurs, a prompt comprehensive ophthalmic exam is recommended. If CME is diagnosed, initiate appropriate CME management and discontinue docetaxel (consider non-taxane treatments). In a study of patients receiving docetaxel for the adjuvant treatment of breast cancer, a majority of patients experienced tearing, which occurred in patients with and without lacrimal duct obstruction at baseline. Onset was generally after cycle 1, but subsided in most patients within 4 months after therapy completion (Chan 2013).

• Secondary malignancies: Treatment-related acute myeloid leukemia or myelodysplasia occurred in patients receiving docetaxel in combination with anthracyclines and/or cyclophosphamide.

• Treatment-related mortality: [US Boxed Warning]: Patients with abnormal liver function, those receiving higher doses, and patients with non–small cell lung cancer and a history of prior treatment with platinum derivatives who receive single-agent docetaxel at a dose of 100 mg/m2 are at higher risk for treatment-related mortality.

• Weakness: Fatigue and weakness (may be severe) have been reported; symptoms may last a few days up to several weeks. In patients with progressive disease, weakness may be associated with a decrease in performance status.

Disease-related concerns:

• Heart failure: In a scientific statement from the American Heart Association, docetaxel has been determined to be an agent that may either cause direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate) (AHA [Page 2016]).

• Hepatic impairment: [US Boxed Warning]: Avoid use in patients with bilirubin exceeding upper limit of normal (ULN) or AST and/or ALT >1.5 times ULN in conjunction with alkaline phosphatase >2.5 times ULN. Patients with bilirubin elevations or abnormal transaminases (with concurrent abnormal alkaline phosphatase) are at increased risk for grade 4 neutropenia, neutropenic fever, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated transaminase elevations >1.5 times ULN also had a higher rate of grade 4 neutropenic fever, although no increased incidence of toxic death. Monitor bilirubin, AST or ALT, and alkaline phosphatase prior to each docetaxel cycle. The alcohol content of the docetaxel formulation should be taken into account when administering to patients with hepatic impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Alcohol content: Some docetaxel formulations contain alcohol (content varies by formulation), which may affect the central nervous system and cause symptoms of alcohol intoxication. Consider alcohol content and use with caution in patients for whom alcohol intake should be avoided or minimized. Patients should avoid driving or operating machinery immediately after the infusion. An FDA-approved non-alcohol generic formulation (20 mg/mL) is available.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

Other warnings/precautions:

• Premedication: Premedication with oral corticosteroids is recommended to decrease the incidence and severity of fluid retention and severity of hypersensitivity reactions. The manufacturer recommends dexamethasone 16 mg/day (8 mg twice daily) orally for 3 days, starting the day before docetaxel administration; for prostate cancer, when prednisone is part of the antineoplastic regimen, dexamethasone 8 mg orally is administered at 12 hours, 3 hours, and 1 hour prior to docetaxel.

Single agent after platinum failure: 75 mg/m2 IV over 1 hour every 3 weeks

Chemotherapy-naive: docetaxel 75 mg/m2 IV over 1 hour immediately followed by cisplatin 75 mg/m2 over 30 to 60 minutes; repeat treatment every 3 weeks

Comments:
-Premedicate with oral corticosteroids (e.g. dexamethasone 8 mg twice a day starting 1 day prior to chemotherapy)
-Adjust dose as needed for toxicity
-Patients should receive appropriate cisplatin premedication with antiemetics and hydration

Uses:
-As a single agent for locally advanced or metastatic non-small cell lung cancer (NSCLC) after platinum therapy failure.
-In combination with cisplatin for unresectable, locally advanced or metastatic NSCLC in patients who have not previously received chemotherapy for this condition.

Data not available

US BOXED WARNINGS:
Toxic Deaths:
-Increased incidence of treatment-related mortality associated with use in patients with abnormal liver function, use at higher doses, and in patients with non-small cell lung cancer (NSCLC) and prior platinum-based-therapy who received docetaxel at 100 mg/m2.
Hepatotoxicity:
-This drug should not be given to patients with bilirubin levels above the upper limit of normal or to patients with AST and/or ALT levels greater than 1.5 times the upper limit of normal (1.5 x ULN) concomitant with alkaline phosphatase greater than 2.5 x ULN.
-Grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death are associated with bilirubin elevations and with transaminase abnormalities concurrent with alkaline phosphatase elevations; isolated transaminase elevations greater than 1.5 x ULN also had a higher rate of grade 4 febrile neutropenia but was not associated with an increased incidence of toxic death.
-Bilirubin, AST or ALT, and alkaline phosphatase levels should be obtained prior to each treatment cycle.
Neutropenia:
-Neutropenia may be severe and result in infection.
-Perform frequent blood cell counts to monitor for the occurrence of neutropenia; do not give this drug to patients with neutrophil counts less than 1500 cells/mm3.
Hypersensitivity Reactions:
-Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who have received a 3-day dexamethasone premedication; immediate discontinuation and administration of appropriate therapy is required for severe hypersensitivity reactions.
-Do not administer this drug to patients with a history of severe hypersensitivity reactions to docetaxel or other drugs formulated with polysorbate 80.
Fluid Retention:
-Severe fluid retention occurred in 6.5% (6/92) of patients despite a 3-day dexamethasone premedication regimen; events included poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, and pronounced abdominal distension due to ascites.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.