Docefrez

docetaxel

Dosage Form: injection
FULL PRESCRIBING INFORMATION

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

The incidence of treatment-related mortality associated with docetaxel therapy 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/m2 [see Warnings and Precautions (5.1)].

 

Docefrez should not be given to 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 grade 4 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 grade 4 but did not have an increased incidence of toxic death. Bilirubin, AST or ALT, and alkaline phosphatase values should be obtained prior to each cycle of Docefrez therapy [see Warnings and Precautions (5.2)].

 

Docefrez therapy should not be given to patients with neutrophil counts of <1500 cells/mm3. In order to monitor the occurrence of neutropenia, which may be severe and result in infection, frequent blood cell counts should be performed on all patients receiving Docefrez [see Warnings and Precautions (5.3)].

 

Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who received a 3-day dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the Docefrez infusion and administration of appropriate therapy [see Warnings and Precautions (5.4)]. Docefrez must not be given to patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80 [see Contraindications (4)].

 

Severe fluid retention occurred in 6.5% (6/92) of patients despite use of a 3-day dexamethasone premedication regimen. 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 (5.5)].

Indications and Usage for Docefrez

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.

Prostate Cancer

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

Docefrez 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).

Breast Cancer

• For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of Docefrez is 60 mg/m2 to 100 mg/m2 administered intravenously over 1 hour every 3 weeks.

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/m2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m2 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)].

Prostate Cancer

• For hormone-refractory metastatic prostate cancer, the recommended dose of Docefrez is 75 mg/m2 every 3 weeks as a 1 hour intravenous infusion. Prednisone 5 mg orally twice daily is administered continuously [see Dosage and Administration (2.7)].

Premedication Regimen

All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to Docefrez administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.4)]. This regimen was evaluated in 92 patients with metastatic breast cancer previously treated with chemotherapy given docetaxel at a dose of 100 mg/m2 every 3 weeks.


For hormone-refractory metastatic prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour before the Docefrez infusion [see Warnings and Precautions (5.4)].

Dosage Adjustments During Treatment

Breast Cancer

 

Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, or severe or cumulative cutaneous reactions during Docefrez therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during Docefrez therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have Docefrez treatment discontinued entirely.

 

Non-Small Cell Lung Cancer


Monotherapy with Docefrez for NSCLC treatment after failure of prior platinum-based chemotherapy

 

Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during Docefrez treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop ≥grade 3 peripheral neuropathy should have Docefrez treatment discontinued entirely.

 

Prostate Cancer


Combination therapy with Docefrez  for hormone-refractory metastatic prostate cancer

 

Docefrez should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docefrez therapy should have the dosage of Docefrez reduced from 75 to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment should be discontinued.

 

Combination Therapy with Strong CYP3A4 inhibitors:


Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole).  There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require co-administration of a strong CYP3A4 inhibitor. [see Drug Interactions (7), Clinical Pharmacology (12.3)].

Administration Precautions

Docefrez is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Docefrez solutions. The use of gloves is recommended. Please refer to [see How Supplied/ Storage and Handling (16.3)].


If Docefrez  lyophilized powder, reconstituted solution, or infusion solution should come into contact with the skin, immediately and thoroughly wash with soap and water. If Docefrez lyophilized powder, reconstituted solution or infusion solution should come into contact with mucosa, immediately and thoroughly wash with water.


Contact of the Docefrez reconstituted solution with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the  Docefrez infusion solution should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

 

Docefrez (Lyophilized Powder for Injection and Diluent)

 


Docefrez for Injection requires reconstitution with Diluent and one further dilution with infusion solution prior to administration. Please follow the preparation instructions provided below.


The table below provides the fill range of the Diluent, the volume of Diluent to be added for the reconstitution and the concentration of the reconstituted solution for Docefrez 20 mg and Docefrez 80 mg (See Table 1).

Table 1- Reconstitution of Docefrez (docetaxel) for Injection

Product	Fill Range of the Diluent (35.4% w/w ethanol in polysorbate 80)	Volume of Diluent to be added for the reconstitution	Concentration of the reconstituted solution
Docetaxel 20 mg vial	1.10 – 1.15 mL	1 mL	20 mg/0.8 mL
Docetaxel 80 mg vial	4.13 – 4.29 mL	4 mL	24 mg/mL

Preparation and Administration

Docefrez (Lyophilized Powder for Injection and Diluent)

 

A. Preparation of the Reconstituted Solution

1. Docefrez vials should be stored between 2°C and 8°C (36°F and 46°F). Allow the appropriate number of vials of Docefrez (docetaxel) for Injection and diluent (35.4% ethanol in polysorbate 80) vials to stand at room temperature for approximately 5 minutes.


2. Aseptically withdraw 1 mL from the diluent vial for Docefrez 20 mg or 4 ml from the diluent vial for Docefrez 80 mg into a syringe by partially inverting the vial, and transfer it to the appropriate vial of Docefrez (docetaxel) for Injection. Shake the reconstituted vial well in order to completely dissolve the docetaxel powder present in the vial. For the 20 mg vial, the resultant concentration is 20 mg/0.8 mL. For the 80 mg vial, the resultant concentration is 24 mg/mL.  


3. The reconstituted Docefrez solution should be clear; however, there may be some air bubbles in the solution due to the polysorbate 80. Allow the solution to stand for a few minutes to allow any air bubbles to dissipate.

The reconstituted solution may be used immediately or stored either in the refrigerator or at room temperature for a maximum of 8 hours.

 

B. Preparation of the Infusion Solution

1. Aseptically withdraw the required amount of reconstituted Docefrez solution with a calibrated syringe and inject into a 250 mL infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 to 0.74 mg/mL. If a dose greater than 200 mg of Docefrez is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/ml docetaxel is not exceeded.


2. Thoroughly mix the infusion by manual rotation.


3. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If the Docefrez reconstituted solution or infusion solution is not clear or appears to have precipitation, these should be discarded.

The final Docefrez infusion solution should be administered intravenously as a 1-hour infusion under ambient room temperature and lighting conditions.

Stability

Docefrez infusion solution, if stored between 2°C and 25°C (36°F and 77°F) is stable for 4 hours. Docefrez infusion solution (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 1 hour intravenous administration).

Dosage Forms and Strengths

Docefrez (Lyophilized Powder for Injection and Diluent)


Docefrez 80 mg


Docefrez (docetaxel) for Injection 80 mg: 80 mg docetaxel and Diluent for Docefrez 80 mg (35.4% (w/w) ethanol in polysorbate 80). Both items are in a tray in one carton.

 

Docefrez 20 mg


Docefrez (docetaxel) for Injection 20 mg: 20 mg docetaxel and Diluent for Docefrez 20 mg (35.4% (w/w) ethanol in polysorbate 80). Both items are in a tray in one carton.

Contraindications

• Docefrez is contraindicated in patients who have 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 (5.4)]. 


• Docefrez should not be used in patients with neutrophil counts of <1500 cells/mm3.

Warnings and Precautions

Toxic Deaths

Breast Cancer


Docefrez administered at 100 mg/m2 was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients dosed at 60 mg/m2, mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function. Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths.

 

Non-Small Cell Lung Cancer


Docefrez administered at a dose of 100 mg/m2 in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies). There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m2 dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m2 dose level, 3 of 5 patients had an ECOG PS of 2 at study entry [see Dosage and Administration (2.2), Clinical Studies (14)].

Hepatic Impairment

Patients with combined abnormalities of transaminases and alkaline phosphatase should not be treated with Docefrez [see Boxed Warning, Use in Specific Populations (8.6), Clinical studies (14)].

Hematologic Effects

Perform frequent peripheral blood cell counts on all patients receiving Docefrez. Patients should not be retreated with subsequent cycles of Docefrez until neutrophils recover to a level > 1500 cells/mm3 and platelets recover to a level > 100,000 cells/mm3.

 

A 25% reduction in the dose of Docefrez is recommended during subsequent cycles following severe neutropenia (<500 cells/mm3) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a Docefrez cycle [see Dosage and Administration (2.7)].

 

Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 mg/m2 to 100 mg/m2 of docetaxel and grade 4 neutropenia (<500 cells/mm3) occurs in 85% of patients given 100 mg/m2 and 75% of patients given 60 mg/m2. Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. Docefrez should not be administered to patients with neutrophils <1500 cells/mm3.

 

Febrile neutropenia occurred in about 12% of patients given 100 mg/m2 but was very uncommon in patients given 60 mg/m2. Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related [see Adverse Reactions (6.1), Clinical Studies (14)].

 

Three breast cancer patients with severe liver impairment (bilirubin >1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia. [see Dosage and Administration (2.7), Adverse Reactions (6)].

Hypersensitivity Reactions

Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the Docefrez infusion and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with Docefrez.

 

Hypersensitivity reactions may occur within a few minutes following initiation of a Docefrez infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of Docefrez [see Dosage and Administration (2.6)].

Fluid Retention

Severe fluid retention has been reported following docetaxel therapy. Patients should be premedicated with oral corticosteroids prior to each Docefrez administration to reduce the incidence and severity of fluid retention [see Dosage and Administration (2.6)]. Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions.

 

When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg.

 

Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m2. Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention. The median cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m2.

 

Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of docetaxel to resolution (range: 0 to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).

Acute Myeloid Leukemia

Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. The risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up.

Cutaneous Reactions

Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended [see Dosage and Administration (2.7)]. The discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued docetaxel due to skin toxicity.

Neurologic Reactions

Severe neurosensory symptoms (e.g.paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued [see Dosage and Administration (2.7)]. Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks). Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965).

Asthenia

Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease.

Use in Pregnancy

Docefrez can cause fetal harm when administered to a pregnant woman. Docetaxel caused embryofetal toxicities including intrauterine mortality when administered to pregnant rats and rabbits during the period of organogenesis. Embryofetal effects in animals occurred at doses as low as 1/50 and 1/300 the recommended human dose on a body surface area basis.

 

There are no adequate and well-controlled studies in pregnant women using Docefrez. If Docefrez is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Docefrez [see Use in Specific Populations (8.1)].

Adverse Reactions

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 for docetaxel 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 Trials Experience

Breast Cancer


Monotherapy with docetaxel for locally advanced or metastatic breast cancer after failure of prior chemotherapy


Docetaxel 100 mg/m2: Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received docetaxel administered at 100 mg/m2 as a 1-hour infusion every 3 weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to docetaxel. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving docetaxel for the treatment of breast cancer and in patients with other tumor types (See Table 2).

Table 2 - Summary of Adverse Reactions in Patients Receiving Docetaxel at 100 mg/m2

Adverse Reaction	All Tumor Types Normal LFTs* n=2045 %	All Tumor Types Elevated LFTs† n=61 %	Breast Cancer Normal LFTs* n=965 %
* 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 >38oC with intravenous antibiotics and/or hospitalization
Hematologic
Neutropenia
<2000 cells/mm3	96	96	99
<500 cells/mm3	75	88	86
Leukopenia
<4000 cells/mm3	96	98	99
<1000 cells/mm3	32	47	44
Thrombocytopenia
<100,000 cells/mm3	8	25	9
Anemia
<11 g/dL	90	92	94
<8 g/dL	9	31	8
Febrile Neutropenia‡	11	26	12
Septic Death	2	5	1
Non-Septic Death	1	7	1
Infections
Any	22	33	22
Severe	6	16	6
Fever in Absence of Infection
Any	31	41	35
Severe	2	8	2
Hypersensitivity Reactions
Regardless of Premedication
Any	21	20	18
Severe	4	10	3
With 3-day Premedication	n=92	n=3	n=92
Any	15	33	15
Severe	2	0	2
Fluid Retention
Regardless of Premedication
Any	47	39	60
Severe	7	8	9
With 3-day Premedication	n=92	n=3	n=92
Any	64	67	64
Severe	7	33	7
Neurosensory
Any	49	34	58
Severe	4	0	6
Cutaneous
Any	48	54	47
Severe	5	10	5
Nail Changes
Any	31	23	41
Severe	3	5	4
Gastrointestinal
Nausea	39	38	42
Vomiting	22	23	23
Diarrhea	39	33	43
Severe	5	5	6
Stomatitis
Any	42	49	52
Severe	6	13	7
Alopecia	76	62	74
Asthenia
Any	62	53	66
Severe	13	25	15
Myalgia
Any	19	16	21
Severe	2	2	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 Docefrez [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 patients (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 3 and 4).

Table 3 - 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

Adverse Reaction	Docetaxel 100 mg/m2		Docetaxel 60 mg/m2
	Normal LFTs* n=730 %	Elevated LFTs† n=18 %	Normal LFTs* n=174 %
* Normal Baseline LFTs: Transaminases ≤ 1.5 times ULN or alkaline phosphatase ≤ 2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN † Elevated Baseline LFTs: AST and/or ALT > 1.5 times ULN concurrent with alkaline phosphatase > 2.5 times ULN ‡ Incidence of infection requiring hospitalization and/or intravenous antibiotics was 8.5% (n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46 patients had grade 4 neutropenia. § Febrile Neutropenia: For 100 mg/m2, ANC grade 4 and fever > 38°C with intravenous antibiotics and/or hospitalization; for 60 mg/m2, ANC grade 3/4 and fever > 38.1°C
Neutropenia
Any <2000 cells/mm3	98	100	95
Grade 4 <500 cells/mm3	84	94	75
Thrombocytopenia
Any <100,000 cells/mm3	11	44	14
Grade 4 <20,000 cells/mm3	1	17	1
Anemia <11 g/dL	95	94	65
Infection