1.1 Breast Cancer

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

BEIZRAY in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer.

1.2 Non-small Cell Lung Cancer

BEIZRAY 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.

BEIZRAY in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition.

1.3 Prostate Cancer

BEIZRAY in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer.

1.4 Gastric Adenocarcinoma

BEIZRAY in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease.

1.5 Head and Neck Cancer

BEIZRAY in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

2.1 Important Dosage and Administration Instructions

Do notsubstitute BEIZRAY for or with other docetaxel products because BEIZRAY has different administration instructions from other docetaxel products.
For all indications, toxicities may warrant dosage adjustments [see Dosage and Administration ( 2.8)] .

Administer in a facility equipped to manage possible complications (e.g. anaphylaxis).

See additional premedication recommendations for the indicated populations [see Dosage and Administration ( 2.7)]

2.2 Recommended Dosage for Breast Cancer

For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of BEIZRAY is 60 mg/m 2to 100 mg/m 2administered intravenously over 1 hour every 3 weeks.

For the adjuvant treatment of operable node-positive breast cancer, the recommended BEIZRAY dose is 75 mg/m 2administered 1 hour after doxorubicin 50 mg/m 2and cyclophosphamide 500 mg/m 2every 3 weeks for 6 courses. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities [see Dosage and Administration ( 2.7)] .

2.3 Recommended Dosage for Non-small Cell Lung Cancer

For treatment after failure of prior platinum-based chemotherapy, BEIZRAY was evaluated as monotherapy, and the recommended dose is 75 mg/m 2administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m 2in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized controlled trials [see Boxed Warning, Dosage and Administration ( 2.7), Warnings and Precautions ( 5), Clinical Studies ( 14)] . 

For chemotherapy-naive patients, BEIZRAY was evaluated in combination with cisplatin. The recommended dose of BEIZRAY is 75 mg/m 2administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m 2over 30-60 minutes every 3 weeks [see Dosage and Administration ( 2.7)] .

2.4 Recommended Dosage for Prostate Cancer

For metastatic castration-resistant prostate cancer, the recommended dose of BEIZRAY is 75 mg/m 2every 3 weeks as a 1 hour intravenous infusion. Prednisone 5 mg orally twice daily is administered continuously [see Dosage and Administration ( 2.7)] .

2.5 Recommended Dosage for Gastric Adenocarcinoma

For gastric adenocarcinoma, the recommended dose of BEIZRAY is 75 mg/m 2as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m 2, as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m 2per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration ( 2.7)] .

2.6 Recommended Dosage for Head and Neck Cancer

Must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the BEIZRAY containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.

Induction Chemotherapy Followed by Radiotherapy (TAX323)

For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of BEIZRAY is 75 mg/m 2as a 1 hour intravenous infusion followed by cisplatin 75 mg/m 2intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m 2per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy [see Dosage and Administration ( 2.7)] .

Induction Chemotherapy Followed by Chemoradiotherapy (TAX324)

For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of BEIZRAY is 75 mg/m 2as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m 2administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m 2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy [see Dosage and Administration ( 2.7)] .

2.7 Corticosteroid 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 BEIZRAY 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  (5.5)].
For metastatic castration-resistant 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 BEIZRAY infusion [see Warnings and Precautions (5.5)].

2.8 Dosage Adjustments during Treatment

Breast Cancer
Patients who are dosed initially at 100 mg/m 2and who experience either febrile neutropenia, neutrophils <500 cells/mm 3for more than 1 week, or severe or cumulative cutaneous reactions during BEIZRAY therapy should have the dosage adjusted from 100 mg/m 2to 75 mg/m 2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m 2to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m 2and who do not experience febrile neutropenia, neutrophils <500 cells/mm 3for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during BEIZRAY therapy may tolerate higher doses. Patients who develop grade 3 peripheral neuropathy should have BEIZRAY treatment discontinued entirely.

Combination Therapy with BEIZRAY in the Adjuvant Treatment of Breast Cancer
BEIZRAY in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is 1,500 cells/mm 3. Patients who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their BEIZRAY dose reduced to 60 mg/m 2. Patients who experience grade 3 or 4 stomatitis should have their BEIZRAY dose decreased to 60 mg/m 2. Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during BEIZRAY therapy should have their dosage of BEIZRAY reduced from 75 mg/m 2to 60 mg/m 2. If the patient continues to experience these reactions at 60 mg/m 2, treatment should be discontinued.

Non-small Cell Lung Cancer
Monotherapy with BEIZRAY for NSCLC treatment after failure of prior platinum-based chemotherapy Patients who are dosed initially at 75 mg/m 2and who experience either febrile neutropenia, neutrophils <500 cells/mm 3for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during BEIZRAY treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m 2. Patients who develop grade 3 peripheral neuropathy should have BEIZRAY treatment discontinued entirely.

Combination therapy with BEIZRAY for chemotherapy-naive NSCLC

For patients who are dosed initially at BEIZRAY 75 mg/m 2in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm 3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the BEIZRAY dosage in subsequent cycles should be reduced to 65 mg/m 2. In patients who require a further dose reduction, a dose of 50 mg/m 2is recommended. For cisplatin dosage adjustments, see manufacturers prescribing information.

Prostate Cancer

Combination therapy with BEIZRAY for metastatic castration-resistant prostate cancer

BEIZRAY should be administered when the neutrophil count is 1,500 cells/mm 3. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm 3for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during BEIZRAY therapy should have the dosage of BEIZRAY reduced from 75 mg/m 2to 60 mg/m 2. If the patient continues to experience these reactions at 60 mg/m 2, the treatment should be discontinued.

Gastric or Head and Neck Cancer

BEIZRAY in combination with cisplatin and fluorouracil in gastric cancer or head and neck cancer

Patients treated with BEIZRAY in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines. In both studies, G-CSF was recommended during the second and/or subsequent cycles in case of febrile neutropenia, or documented infection with neutropenia, or neutropenia lasting more than 7 days. If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the BEIZRAY dose should be reduced from 75 mg/m 2to 60 mg/m 2. If subsequent episodes of complicated neutropenia occur the BEIZRAY dose should be reduced from 60 mg/m 2to 45 mg/m 2. In case of grade 4 thrombocytopenia the BEIZRAY dose should be reduced from 75 mg/m 2to 60 mg/m 2. Do not retreat patients with subsequent cycles of BEIZRAY until neutrophils recover to a level >1,500 cells/mm 3[see Contraindications ( 4)] . Avoid retreating patients until platelets recover to a level >100,000 cells/mm 3. Discontinue treatment if these toxicities persist [see Warnings and Precautions ( 5.3)] .

Recommended dose modifications for toxicities in patients treated with BEIZRAY in combination with cisplatin and fluorouracil are shown in Table 1.

Liver dysfunction: In case of AST/ALT >2.5 to 5 × ULN and AP 2.5 × ULN, or AST/ALT >1.5 to 5 × ULN and AP >2.5 to 5 × ULN, BEIZRAY should be reduced by 20%.

In case of AST/ALT >5 × ULN and/or AP >5 × ULN BEIZRAY should be stopped.

The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below.

Cisplatin dose modifications and delays
Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCI-CTCAE grade:

• Grade 2: Reduce cisplatin dose by 20%.
• Grade 3: Discontinue treatment.

Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.

Nephrotoxicity: In the event of a rise in serum creatinine grade 2 (>1.5 × normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2).

For other cisplatin dosage adjustments, also refer to the manufacturers prescribing information.

Fluorouracil dose modifications and treatment delays

For diarrhea and stomatitis, see Table 1.

In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%.

For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade ≤1 and then recommenced, if medically appropriate.

For other fluorouracil dosage adjustments, also refer to the manufacturers’ prescribing information.

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 coadministration of a strong CYP3A4 inhibitor [see Drug Interactions ( 7), Clinical Pharmacology ( 12.3)] .

2.9 Administration Precautions

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

If BEIZRAY or final infusion solution should come into contact with the skin, immediately and thoroughly wash with soap and water. If BEIZRAY or final infusion solution should come into contact with mucosa, immediately and thoroughly wash with water.

The final BEIZRAY infusion solution should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin).

Please follow the preparation instructions provided below.

2.10 Preparation and Administration

Preparation

Read this entire section carefully before mixing and diluting. BEIZRAY needs to be diluted with 0.9% Sodium Chloride Injection to ensure a final concentration between 0.14 mg/mL and 0.31 mg/mL in the final infusion solution.

Inject IV Solution Stabilizer directly into the 0.9% Sodium Chloride Injection bag or bottle. Do not use IV Solution Stabilizer to dilute BEIZRAY.

Follow the preparation instructions provided below.

Step 1 – Calculate the required amounts of BEIZRAY and IV Solution Stabilizer (25% Human Albumin)

The calculation formula for the required amounts of BEIZRAY and IV Solution Stabilizer (25% Human Albumin) is as follows:

• The required amount of BEIZRAY(mL) = the recommended dose of docetaxel (mg/m 2) × body surface area (m 2) ÷ 20 (mg/mL)
• The required amount of IV Solution Stabilizer (25% Human Albumin)(mL) = the required amount of BEIZRAY(mL) × 6

Step 2 - Determine the required amount of 0.9% Sodium Chloride Injection

According to the prescribed amount of BEIZRAY, determine the required amount of 0.9% Sodium Chloride Injectionin Table 3.

Step 3 – Add IV Solution Stabilizer to the Infusion Bag

1. Add the required amount of IV Solution Stabilizer (25% Human albumin) to the 0.9% Sodium Chloride Injection bag or bottle.
2. Thoroughly mix the dilution solution by gently inverting the bag or bottle for at least 5 times. Do not shake. This solution should be used immediately after preparation.

Step 4 – Add BEIZRAY to the final infusion solution

1. If the BEIZRAY vials are stored under refrigeration, allow the required number of BEIZRAY vials to stand at room temperature for approximately 5 minutes before use.
2. Aseptically withdraw the calculated amount of BEIZRAY (20 mg/mL) with a calibrated syringe and inject via a single injection into the infusion bag or bottle containing the initial dilution solution to produce a final concentration between 0.14 mg/mL and 0.31 mg/mL.
3. After injection, remove the syringe and immediately thoroughly mix the final infusion solution by gently inverting the bag or bottle for at least 10 times. Do not shake.

Discard any unused portion of BEIZRAY vial(s) and IV Solution Stabilizer (25% Human Albumin) vial(s).

Administration

Prior to administration, visually inspect BEIZRAY final infusion solution for particulate matter or discoloration whenever the solution and container permit. Discard the diluted BEIZRAY infusion solution if the solution is not clear, discolored or appears to have precipitation, it should be discarded.

BEIZRAY infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must discarded.

The BEIZRAY infusion solution should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25℃) and lighting conditions.

2.11 Stability

BEIZRAY final infusion solution should be used immediately. However, if stored between 2°C and 8°C (36°F and 46°F), infusion solution is stable for 24 hours. If stored at 25°C (77°F), the final infusion solution is stable for 4 hours. BEIZRAY final infusion solution (in 0.9% Sodium Chloride Injection) should be used within 4 hours (including the 1 hour intravenous administration).

5.1 Toxic Deaths

Breast Cancer
BEIZRAY administered at 100 mg/m 2was 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/m 2, 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
BEIZRAY administered at a dose of 100 mg/m 2in 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/m 2dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m 2dose level, 3 of 5 patients had an ECOG PS of 2 at study entry [see Dosage and Administration ( 2.2), Clinical Studies ( 14)] .

5.2 Hepatic Impairment

Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death.

Avoid BEIZRAY in patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN [see Warnings and Precautions ( 5.1)] .

For patients with isolated elevations of transaminase >1.5 × ULN, consider BEIZRAY dose modifications [see Dosage and Administration ( 2.7)] .

Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of BEIZRAY therapy.

5.3 Hematologic Effects

Perform frequent peripheral blood cell counts on all patients receiving BEIZRAY. Do not retreat patients with subsequent cycles of BEIZRAY until neutrophils recover to a level >1500 cells/mm 3[see Contraindications ( 4)] . Avoid retreating patients until platelets recover to a level >100,000 cells/mm 3.

A 25% reduction in the dose of BEIZRAY is recommended during subsequent cycles following severe neutropenia (<500 cells/mm 3) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a BEIZRAY cycle [see Dosage and Administration ( 2.7)] .

Neutropenia (<2000 neutrophils/mm 3) occurs in virtually all patients given 60 mg/m 2to 100 mg/m 2of BEIZRAY and grade 4 neutropenia (<500 cells/mm 3) occurs in 85% of patients given 100 mg/m 2and 75% of patients given 60 mg/m 2. Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. BEIZRAY should not be administered to patients with neutrophils <1500 cells/mm 3. Febrile neutropenia occurred in about 12% of patients given 100 mg/m 2but was very uncommon in patients given 60 mg/m 2. 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. In gastric cancer patients treated with docetaxel in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not. Patients receiving TCF should be closely monitored during the first and subsequent cycles for febrile neutropenia and neutropenic infection [see Dosage and Administration ( 2.7), Adverse Reactions ( 6)] .

5.4 Enterocolitis and Neutropenic Colitis

Enterocolitis and neutropenic colitis (typhlitis) have occurred in patients treated with BEIZRAY alone and in combination with other chemotherapeutic agents, despite the coadministration of G-CSF. Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications. Enterocolitis and neutropenic enterocolitis may develop at any time, and could lead to death as early as the first day of symptom onset. Monitor patients closely from onset of any symptoms of gastrointestinal toxicity. Inform patients to contact their healthcare provider with new, or worsening symptoms of gastrointestinal toxicity [see Dosage and Administration ( 2), Warnings and Precautions ( 5.3), Adverse Reactions ( 6.2)] .

5.5 Hypersensitivity Reactions

Monitor patients closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the BEIZRAY infusion and aggressive therapy. Do not rechallenge patients with a history of severe hypersensitivity reactions with BEIZRAY [see Contraindications ( 4)] .

Patients who have previously experienced a hypersensitivity reaction to paclitaxel may develop a hypersensitivity reaction to docetaxel that may include severe or fatal reactions such as anaphylaxis. Monitor patients with a previous history of hypersensitivity to paclitaxel closely during initiation of BEIZRAY therapy. Hypersensitivity reactions may occur within a few minutes following initiation of a BEIZRAY 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 BEIZRAY. [see Dosage and Administration ( 2.6)] .

5.6 Fluid Retention

Severe fluid retention has been reported following BEIZRAY therapy. Patients should be premedicated with oral corticosteroids prior to each BEIZRAY 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/m 2. 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/m 2. Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of BEIZRAY to resolution (range: 0 to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).

5.7 Second Primary Malignancies

Second primary malignancies, notably acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), non-Hodgkin’s lymphoma (NHL), and renal cancer, have been reported in patients treated with docetaxel-containing regimens. These adverse reactions may occur several months or years after docetaxel-containing therapy.

Treatment-related AML or MDS has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. In the adjuvant breast cancer trial (TAX316) AML occurred in 3 of 744 patients who received docetaxel, doxorubicin and cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, doxorubicin, and cyclophosphamide [see Clinical Studies ( 14.2)] . In TAC-treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up. Monitor patients for second primary malignancies [see Adverse Reactions ( 6.1)] .

5.8 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.

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with docetaxel treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and monitored closely. Permanent treatment discontinuation should be considered in patients who experience SCARs.

5.9 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).

5.10 Eye Disorders

Cystoid macular edema (CME) has been reported in patients treated with docetaxel. Patients with impaired vision should undergo a prompt and comprehensive ophthalmologic examination. If CME is diagnosed, BEIZRAY treatment should be discontinued and appropriate treatment initiated. Alternative non-taxane cancer treatment should be considered.

5.11 Asthenia

Cystoid macular edema (CME) has been reported in patients treated with docetaxel. Patients with impaired vision should undergo a prompt and comprehensive ophthalmologic examination. If CME is diagnosed, BEIZRAY treatment should be discontinued and appropriate treatment initiated. Alternative non-taxane cancer treatment should be considered.

5.12 Embryo-Fetal Toxicity

Based on findings from animal reproduction studies and its mechanism of action, BEIZRAY can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1)] . Available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify pregnancy status in females of reproductive potential prior to initiating BEIZRAY. Advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of BEIZRAY. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of BEIZRAY [see Use in Specific Populations ( 8.1, 8.3)] .

5.13 Alcohol Content

Cases of intoxication have been reported with some formulations of docetaxel due to the alcohol content. The alcohol content in a dose of BEIZRAY Injection may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in BEIZRAY Injection on the ability to drive or use machines immediately after the infusion. Each administration of BEIZRAY Injection at 100 mg/m 2delivers 4.0 g/m 2of ethanol. For a patient with a BSA of 2.0 m 2, this would deliver 8.0 grams of ethanol [see Description ( 11)] . Other docetaxel products may have a different amount of alcohol.

5.14 Tumor Lysis Syndrome

Tumor lysis syndrome has been reported with docetaxel [see Adverse Reactions ( 6.2)] . Patients at risk of tumor lysis syndrome (e.g., with renal impairment, hyperuricemia, bulky tumor) should be closely monitored prior to initiating BEIZRAY and periodically during treatment. Correction of dehydration and treatment of high uric acid levels are recommended prior to initiation of treatment.

5.15 Transmissible Infectious Agents

BEIZRAY final infusion solution contains human albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote.

No cases of transmission of viral diseases or CJD have ever been identified for albumin.

6.1 Clinical Trials Experience

Breast Cancer

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

Docetaxel 100 mg/m 2: Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received docetaxel administered at 100 mg/m 2as 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 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/mm 3) 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/mm 3with 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/mm 3) associated with fatal gastrointestinal hemorrhage has been reported.

Hypersensitivity reactions

Severe hypersensitivity reactions have been reported [see Boxed Warning, Warnings and Precautions ( 5.5)] . 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 ( 5.6)].

Cutaneous reactions
Severe skin toxicity is discussed elsewhere in the label [see Warnings and Precautions (5.8)] . 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 ( 5.9)] .

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 have occurred. Seven of 86 (8.1%) of metastatic breast cancer patients receiving docetaxel 100 mg/m 2in 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/m 2in 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/m 2who had normal LFTs (see Tables 5and 6).

In the three-arm monotherapy trial, TAX313, which compared docetaxel 60 mg/m 2, 75 mg/m 2and 100 mg/m 2in advanced breast cancer, grade 3/4 or severe adverse reactions occurred in 49.0% of patients treated with docetaxel 60 mg/m 2compared to 55.3% and 65.9% treated with 75 mg/m 2and 100 mg/m 2, respectively. Discontinuation due to adverse reactions was reported in 5.3% of patients treated with 60 mg/m 2versus 6.9% and 16.5% for patients treated at 75 and 100 mg/m 2, respectively. Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m 2compared to 5.3% and 1.6% for patients treated at 75 mg/m 2and 100 mg/m 2, respectively.

The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m 2, 75 mg/m 2, and 100 mg/m 2, 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/m 2every 3 weeks in combination with doxorubicin and cyclophosphamide (see Table 7).

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

During the treatment period, 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 3/4 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 during the treatment period.

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

Cardiovascular reactions

More cardiovascular reactions were reported in the TAC arm versus the FAC arm during the treatment period: arrhythmias, all grades (6.2% vs 4.9%), and hypotension, all grades (1.9% vs 0.8%). Twenty-six (26) patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm
developed CHF during the study period. All except one patient in each arm were diagnosed with CHF during the follow-up period. Two (2) patients in TAC arm and 4 patients in FAC arm died due to CHF. The risk of CHF was higher in the TAC arm in the first year, and then was similar in both treatment arms.

Adverse reactions during the follow-up period (median follow-up time of 8 years)

In study TAX316, the most common adverse reactions that started during the treatment period and persisted into the follow-up period in TAC and FAC patients are described below (median follow-up time of 8 years).

Nervous system disorders
In study TAX316, peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2%) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm.

Skin and subcutaneous tissue disorders

In study TAX316, alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients (92.3%) and 645 of 736 FAC patients (87.6%). At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to
be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

Reproductive system and breast disorders
In study TAX316, amenorrhea that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 202 of 744 TAC patients (27.2%) and 125 of 736 FAC patients (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%).

General disorders and administration site conditions
In study TAX316, peripheral edema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16.0%) and 23 of 736 FAC patients (3.1%). At the end of the follow-up period (actual median follow-up time of 8 years), peripheral edema was ongoing in 19 TAC patients (2.6%) and 4 FAC
patients (0.5%).

In study TAX316, lymphedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1.5%) and 1 of 736 FAC patients (0.1%). At the end of the follow-up period (actual median follow-up
time of 8 years), lymphedema was observed to be ongoing in 6 TAC patients (0.8%) and 1 FAC patient (0.1%).

In study TAX316, asthenia that started during the treatment period and persisted into the followup period after the end of chemotherapy was reported in 236 of 744 TAC patients (31.7%) and 180 of 736 FAC patients (24.5%). At the end of the follow-up period (actual median follow-up
time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

Acute myeloid leukemia (AML)/Myelodysplastic syndrome (MDS)

AML occurred in the adjuvant breast cancer trial (TAX316). The cumulative risk of developing treatment-related AML at median follow-up time of 8 years in TAX316 was 0.4% for TACtreated patients and 0.1% for FAC-treated patients. One TAC patient (0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of 8 years). Myelodysplastic syndrome occurred in 2 of 744 (0.3%) patients who received TAC and in 1 of 736 (0.1%) patients who received FAC. AML occurs at a higher frequency when these agents are given in combination with radiation therapy.

Lung Cancer

Monotherapy with docetaxel for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapy

Docetaxel 75 mg/m 2: Treatment-emergent adverse drug reactions are shown in Table 8. 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.

Combination therapy with docetaxel in chemotherapy-naive advanced unresectable or metastatic NSCLC

Table 9presents 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.

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/m 2every 3 weeks in combination with prednisone 5 mg orally twice daily (see Table 10).

Gastric Cancer

Combination therapy with docetaxel 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 75 mg/m 2in combination with cisplatin and fluorouracil (see Table 11).

Head and Neck Cancer

Combination therapy with docetaxel in head and neck cancer

Table 12summarizes the safety data obtained from patients that received induction chemotherapy with docetaxel 75 mg/m 2in 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a whole:diffuse pain, chest pain, radiation recall phenomenon, injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) at the site of previous extravasation.

Cardiovascular:atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction. Ventricular arrhythmia, including ventricular tachycardia, in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide may be associated with fatal outcome.

Cutaneous:cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme and severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalized exanthematous pustulosis, scleroderma-like changes (usually preceded by peripheral lymphedema), severe palmar-plantar erythrodysesthesia, and permanent alopecia.

Gastrointestinal:enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, which may be fatal. Abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, intestinal obstruction, ileus, and dehydration as a consequence of gastrointestinal events.

Hearing:ototoxicity, hearing disorders and/or hearing loss, including during use with other ototoxic drugs. 

Hematologic:bleeding episodes, disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure.

Hepatic:hepatitis, sometimes fatal, primarily in patients with pre-existing liver disorders.

Hypersensitivity:anaphylactic shock with fatal outcome in patients who received premedication. Severe hypersensitivity reactions with fatal outcome with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.

Metabolism and nutrition disorders:electrolyte imbalance, including hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia. Tumor lysis syndrome, sometimes fatal.

Neurologic:confusion, seizures or transient loss of consciousness, sometimes appearing during the infusion of the drug.

Ophthalmologic:conjunctivitis, lacrimation or lacrimation with or without conjunctivitis, cystoid macular edema (CME). Excessive tearing which may be attributable to lacrimal duct obstruction. Transient visual disturbances (flashes, flashing lights, scotomata), typically occurring during drug infusion and reversible upon discontinuation of the infusion, in association with hypersensitivity reactions.

Respiratory:dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis, which may be fatal. Radiation pneumonitis in patients receiving concomitant
radiotherapy.

Renal:renal insufficiency and renal failure, the majority of cases were associated with concomitant nephrotoxic drugs.

Second primary malignancies:second primary malignancies, including AML, MDS, NHL, and renal cancer [see Warnings and Precautions ( 5.7)].

Musculoskeletal disorder:myositis.

8.1 Pregnancy

Risk Summary

Based on findings in animal reproduction studies and its mechanism of action, BEIZRAY can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1)] . Available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. BEIZRAY contains alcohol which can interfere with neurobehavioral development [see Clinical Considerations]. In animal reproductive studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused an increased incidence of embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively [see Data]. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

BEIZRAY contains alcohol [see Warnings and Precautions ( 5.13)] . Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development.

Data

Animal data

Intravenous administration of ≥ 0.3 and 0.03 mg/kg/day docetaxel to pregnant rats and rabbits, respectively, during the period of organogenesis caused an increased incidence of intrauterine mortality, resorptions, reduced fetal weights, and fetal ossification delays. Maternal toxicity was also observed at these doses, which were approximately 0.02 and 0.003 times the daily maximum recommended human dose based on body surface area, respectively.

8.2 Lactation

Risk Summary

There is no information regarding the presence of docetaxel in human milk, or on its effects on milk production or the breastfed child. No lactation studies in animals have been conducted. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with BEIZRAY and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

Based on findings in animals, BEIZRAY can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)] .

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating BEIZRAY.

Contraception

Females

Based on genetic toxicity findings, advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of BEIZRAY.

Males

Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of BEIZRAY.

Infertility

Based on findings in animal studies, BEIZRAY may impair fertility in males of reproductive potential [see Nonclinical Toxicology ( 13.1)] .

8.4 Pediatric Use

The alcohol content of BEIZRAY Injection should be taken into account when given to pediatric patients [see Warnings and Precautions ( 5.13)] .

The efficacy of BEIZRAY in pediatric patients as monotherapy or in combination has not been established. The overall safety profile of BEIZRAY in pediatric patients receiving monotherapy or TCF was consistent with the known safety profile in adults.

Docetaxel has been studied in a total of 289 pediatric patients: 239 in 2 trials with monotherapy and 50 in combination treatment with cisplatin and 5-fluorouracil (TCF).

Docetaxel Monotherapy

Docetaxel monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12.5 years, range 1-22 years) with a variety of refractory solid tumors. The recommended dose was 125 mg/m 2as a 1-hour intravenous infusion every 21 days. The primary
dose limiting toxicity was neutropenia.

The recommended dose for docetaxel monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1-26 years) with a variety of recurrent/refractory solid tumors. Efficacy was not established with tumor response rates ranging from one complete response (CR) (0.6%) in a patient with undifferentiated sarcoma to four partial responses (2.2%) seen in one patient each with Ewing Sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma.

Docetaxel in Combination

Docetaxel was studied in combination with cisplatin and 5-fluorouracil (TCF) versus cisplatin and 5-fluorouracil (CF) for the induction treatment of nasopharyngeal carcinoma (NPC) in pediatric patients prior to chemoradiation consolidation. Seventy-five patients (median age 16 years, range 9 to 21 years) were randomized (2:1) to docetaxel (75 mg/m 2) in combination with cisplatin (75 mg/m 2) and 5-fluorouracil (750 mg/m 2) (TCF) or to cisplatin (80 mg/m 2) and 5-fluorouracil (1000 mg/m 2/day) (CF). The primary endpoint was the CR rate following induction treatment of NPC. One patient out of 50 in the TCF group (2%) had a complete response while none of the 25 patients in the CF group had a complete response.

Pharmacokinetics

Pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials. Following docetaxel administration at 55 mg/m 2to 235 mg/m 2in a 1-hour intravenous infusion every 3 weeks in 25 patients aged 1 to 20 years (median 11 years), docetaxel clearance was 17.3±10.9 L/h/m 2.

Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF), at dose levels of 75 mg/m 2in a 1-hour intravenous infusion day 1 in 28 patients aged 10 to 21 years (median 16 years, 17 patients were older than 16). Docetaxel clearance was 17.9±8.75 L/h/m 2, corresponding to an AUC of 4.20±2.57 μg∙h/mL.

In summary, the body surface area adjusted clearance of docetaxel monotherapy and TCF combination in children were comparable to those in adults [see Clinical Pharmacology ( 12.3)] .

8.5 Geriatric Use

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients.

Non-small Cell Lung Cancer

In a study conducted in chemotherapy-naive patients with NSCLC (TAX326), 148 patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater. There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In the docetaxel+cisplatin group, patients less than 65 years of age had a median survival of 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% CI: 9.3 months, 14 months). In patients 65 years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). Patients treated with docetaxel+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively). When docetaxel was combined with carboplatin for the treatment of chemotherapy-naive, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with docetaxel+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin.

Prostate Cancer

Of the 333 patients treated with docetaxel every three weeks plus prednisone in the prostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with docetaxel every three weeks, the following treatmentemergent adverse reactions occurred at rates ≥10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs 59%), infection (37% vs 24%), nail changes (34% vs 23%), anorexia (21% vs 10%), weight loss (15% vs 5%), respectively.

Breast Cancer

In the adjuvant breast cancer trial (TAX316), docetaxel in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. The number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients.

Gastric Cancer

Among the 221 patients treated with docetaxel in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years. In this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. However, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients. The incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored.

Head and Neck Cancer

Among the 174 and 251 patients who received the induction treatment with docetaxel in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively. These clinical studies of docetaxel in combination with cisplatin and fluorouracil in patients with SCCHN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients.

8.6 Hepatic Impairment

Avoid BEIZRAY in patients with bilirubin >ULN and patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN [see Boxed Warning, Warnings and Precautions ( 5.2), Clinical Pharmacology ( 12.3)] .

The alcohol content of BEIZRAY Injection should be taken into account when given to patients with hepatic impairment [see Warnings and Precautions ( 5.13)] .

12.1 Mechanism of Action

Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel’s binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use.

12.2 Pharmacodynamics

Docetaxel exposure-response relationships and the time course of pharmacodynamic response are unknown.

12.3 Pharmacokinetics

Absorption

The pharmacokinetics of docetaxel has been evaluated in cancer patients after administration of 20 mg/m 2to 115 mg/m 2in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m 2to 115 mg/m 2with infusion times of 1 to 2 hours. Docetaxel’s pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with initial rapid distribution phase and the late (terminal) phase.

Distribution

Mean steady state volume of distribution was 113 L. Docetaxel is approximately 94% protein bound in vitro, mainly to α1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was approximately 97%. Dexamethasone does not affect the protein binding of docetaxel.

Elimination

With extended plasma sampling up to 8 to 22 days post infusion, the estimated mean total body clearance was 18 L/h/m 2(range of means: 14 to 23) and mean terminal elimination half-life was 116 hours (range of means: 92 to 135).

Metabolism

Docetaxel is metabolized by the CYP3A4 isoenzyme in vitro [see Drug Interactions ( 7)] .

Excretion
In three cancer patients urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively, within 7 days. About 80% of the radioactivity recovered in feces was excreted during the first 48 hours as 1 major and 3 minor metabolites with less than 8% as unchanged drug.

Specific Populations

Effect of Age: A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m 2. Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of docetaxel was not influenced by age.

Effect of Gender: The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel.

Hepatic Impairment: The population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment (AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN), total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients. Patients with combined abnormalities of transaminase and alkaline phosphatase should not be treated with docetaxel. Patients with severe hepatic impairment have not been studied [see Warnings and Precautions (5.2), Use in Specific Populations (8.6)].

Effect of Race: Mean total body clearance for Japanese patients dosed at the range of 10 mg/m 2 to 90 mg/m 2was similar to that of European/American populations dosed at 100 mg/m 2, suggesting no significant difference in the elimination of docetaxel in the two populations.

Drug Interaction Studies

Effect of Ketoconazole: The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients were randomized to receive either docetaxel (100 mg/m 2intravenous) alone or docetaxel (10 mg/m 2intravenous) in combination with ketoconazole (200 mg orally once daily for 3 days) in a crossover design with a 3-week washout period. The results of this study indicated that the mean dose-normalized AUC of docetaxel was increased 2.2-fold and its clearance was reduced by 49% when docetaxel was coadministered with ketoconazole [see Dosage and Administration ( 2.7), Drug Interactions ( 7)] .

Effect of combination therapies

• Dexamethasone: Docetaxel total body clearance was not modified by pretreatment with dexamethasone.
• Cisplatin: Clearance of docetaxel in combination therapy with cisplatin was similar to tha previously observed following monotherapy with docetaxel. The pharmacokinetic profile of cisplatin in combination therapy with docetaxel was similar to that observed with cisplatin alone.
• Cisplatin and Fluorouracil: The combined administration of docetaxel, cisplatin and fluorouracil in 12 patients with solid tumors had no influence on the pharmacokinetics of each individual drug.
• Prednisone: A population pharmacokinetic analysis of plasma data from 40 patients with metastatic castration-resistant prostate cancer indicated that docetaxel systemic clearance in combination with prednisone is similar to that observed following administration of docetaxel alone.
• Cyclophosphamide and Doxorubicin: A study was conducted in 30 patients with advanced breast cancer to determine the potential for drug-drug interactions between docetaxel (75 mg/m 2), doxorubicin (50 mg/m 2), and cyclophosphamide (500 mg/m 2) when administered in combination. The coadministration of docetaxel had no effect on the pharmacokinetics of doxorubicin and cyclophosphamide when the three drugs were given in combination compared to coadministration of doxorubicin and cyclophosphamide only. In addition, doxorubicin and cyclophosphamide had no effect on docetaxel plasma clearance when the three drugs were given in combination compared to historical data for docetaxel monotherapy.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with docetaxel have not been performed.

Docetaxel was genotoxic by an aneugenic mechanism in the in vitro chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60th to 1/15th the recommended human dose on a mg/m 2basis). Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays. Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50th the recommended human dose on a mg/m 2basis), but decreased testicular weights were reported. This correlates with findings of a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3rd and 1/15th the recommended human dose on a mg/m 2basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.

14.1 Locally Advanced or Metastatic Breast Cancer

The efficacy and safety of docetaxel have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent–containing regimens or anthracycline-containing regimens).

Randomized Trials
In one randomized trial, patients with a history of prior treatment with an anthracyclinecontaining regimen were assigned to treatment with docetaxel (100 mg/m 2every 3 weeks) or the combination of mitomycin (12 mg/m 2every 6 weeks) and vinblastine (6 mg/m 2every 3 weeks). Two hundred three patients were randomized to docetaxel and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the docetaxel arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The following table summarizes the study results. (See Table 13.)

In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m 2) or doxorubicin (75 mg/m 2) every 3 weeks. One hundred sixty-one patients were randomized to docetaxel and 165 patients to doxorubicin.  Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The study results are summarized below. (See Table 14.)

In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive docetaxel monotherapy 60 mg/m 2(n=151), 75 mg/m 2(n=188) or 100 mg/m 2(n=188). In this trial, 94% of patients had metastatic disease and 79% had received prior anthracycline therapy. Response rate was the primary endpoint. Response rates increased with docetaxel dose: 19.9% for the 60 mg/m 2group compared to 22.3% for the 75 mg/m 2and 29.8% for the 100 mg/m 2group; pair-wise comparison between the 60 mg/m 2and 100 mg/m 2groups was statistically significant (p=0.037).

Single Arm Studies

Docetaxel at a dose of 100 mg/m 2was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an
anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% CI: 31.0-44.8) and the complete response rate was 2.1%.
Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m 2, in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% CI: 17.2-55.7), similar to the response rate in single arm studies of 100 mg/m 2.

14.2 Adjuvant Treatment of Breast Cancer

A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of docetaxel for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m 2administered 1-hour after doxorubicin 50 mg/m 2and cyclophosphamide 500 mg/m 2(TAC arm), or doxorubicin 50 mg/m 2followed by fluorouracil 500 mg/m 2and cyclophosphamide 500 mg/m 2 (FAC arm). Both regimens were administered every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion; all other drugs were given  as intravenous bolus on day 1. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC. Results from a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio=0.74; 2-sided 95% CI=0.60, 0.92, stratified log rank p=0.0047). The primary endpoint, disease-free survival, included local and distant recurrences, contralateral breast cancer and deaths from any cause. The overall reduction in risk of relapse was 25.7% for TAC-treated patients. (See Figure 1.) At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio=0.69, 2-sided 95% CI=0.53, 0.90). (See Figure 2.) There will be further analysis at the time survival data mature.

Figure 1: TAX316 Disease Free Survival K-M curve

Figure 2: TAX316 Overall Survival K-M Curve

The following table describes the results of subgroup analyses for DFS and OS (see Table 15).

14.3 Non-small Cell Lung Cancer (NSCLC)

The efficacy and safety of docetaxel has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy naive.

Monotherapy with docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy

Two randomized, controlled trials established that a docetaxel dose of 75 mg/m 2was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel at a dose of 100 mg/m 2, however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used [see Boxed Warning, Dosage and Administration ( 2.7), Warnings and Precautions ( 5.3)] .

One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status ≤2 to docetaxel or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to docetaxel 100 mg/m 2or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m 2. A total of 104 patients were randomized in this amended study to either docetaxel 75 mg/m 2or best supportive care.

In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic nonsmall cell lung cancer, a history of prior platinum based chemotherapy, and an ECOG performance status ≤2 were randomized to docetaxel 75 mg/m 2, docetaxel 100 mg/m 2and a treatment in which the investigator chose either vinorelbine 30 mg/m 2days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m 2days 1-3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was survival in both trials. The efficacy data for the docetaxel 75 mg/m 2arm and the comparator arms are summarized in Table 16and Figures 3and 4showing the survival curves for the two studies.

Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored docetaxel 75 mg/m 2. 

Figure 3: TAX317 Survival K-M Curves - Docetaxel 75 mg/m 2Versus Best Supportive Care

Figure 4: TAX320 Survival K-M Curves - Docetaxel 75 mg/m 2Versus Vinorelbine or Ifosfamide Control

Patients treated with docetaxel at a dose of 75 mg/m 2experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.

Combination Therapy with docetaxel for Chemotherapy-Naive NSCLC

In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: docetaxel 75 mg/m 2as a 1 hour infusion immediately followed by cisplatin 75 mg/m 2over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m 2administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m 2administered on day 1 of cycles repeated every 4 weeks; or a combination of docetaxel and carboplatin.

The primary efficacy endpoint was overall survival. Treatment with docetaxel+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin (see table below). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of docetaxel to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The efficacy data for the docetaxel+cisplatin arm and the comparator arm are summarized in Table 17

The second comparison in the same three-arm study, vinorelbine+cisplatin versus docetaxel+carboplatin, did not demonstrate superior survival associated with the docetaxel arm (Kaplan-Meier estimate of median survival was 9.1 months for docetaxel+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the docetaxel+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between docetaxel+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 18).

14.4 Castration-Resistant Prostate Cancer

The safety and efficacy of docetaxel in combination with prednisone in patients with metastatic castration-resistant prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) ≥60 were randomized to the following treatment groups: Docetaxel 75 mg/m 2every 3 weeks for 10 cycles. Docetaxel 30 mg/m 2administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles. Mitoxantrone 12 mg/m 2every 3 weeks for 10 cycles.All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously.In the docetaxel every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the docetaxel every 3 week arm versus the control arm are summarized in Table 19and Figure 5.

Figure 5 - TAX327 Survival K-M Curves

14.5 Gastric Adenocarcinoma

A multicenter, open-label, randomized trial was conducted to evaluate the safety and efficacy of docetaxelfor the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for advanced disease. A total of 445 patients with KPS >70 were treated with either docetaxel (T) (75 mg/m 2on day 1) in combination with cisplatin (C) (75 mg/m 2on day 1) and fluorouracil (F) (750 mg/m 2per day for 5 days) or cisplatin (100 mg/m 2on day 1) and fluorouracil (1000 mg/m 2 per day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF arm. The demographic characteristics were balanced between the two treatment arms. The median age was 55 years, 71% were male, 71% were Caucasian, 24% were 65 years of age or older, 19% had a prior curative surgery and 12% had palliative surgery. The median number of cycles administered per patient was 6 (with a range of 1-16) for the TCF arm compared to 4 (with a range of 1-12) for the CF arm. Time to progression (TTP) was the primary endpoint and was defined as time from randomization to disease progression or death from any cause within 12 weeks of the last evaluable tumor assessment or within 12 weeks of the first infusion of study drugs for patients with no evaluable tumor assessment after randomization. The hazard ratio (HR) for TTP was 1.47 (CF/TCF, 95% CI: 1.19-1.83) with a significantly longer TTP (p=0.0004) in the TCF arm. Approximately 75% of patients had died at the time of this analysis. Overall survival was significantly longer (p=0.0201) in the TCF arm with a HR of 1.29 (95% CI: 1.04-1.61). Efficacy results are summarized in Table 20and Figures 6and 7.

Subgroup analyses were consistent with the overall results across age, gender and race.

Figure 6: Gastric Cancer Study (TAX325) Time to Progression K-M Curve

Figure 7: Gastric Cancer Study (TAX325) Survival K-M Curve

14.6 Head and Neck Cancer

Induction Chemotherapy Followed by Radiotherapy (TAX323) 

The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, were randomized to one of two treatment arms.
Patients on the docetaxel arm received docetaxel (T) 75 mg/m 2followed by cisplatin (P) 75 mg/m 2on Day 1, followed by fluorouracil (F) 750 mg/m 2per day as a continuous infusion on Days 1-5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m 2on Day 1, followed by fluorouracil (F) 1000 mg/m 2/day as a continuous infusion on Days 1-5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with a conventional fraction regimen (1.8 Gy-2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week, for a total dose of 70 to 74 Gy, respectively). Surgical resection was allowed following chemotherapy, before or after radiotherapy.
The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p=0.0077 (median PFS: 11.4 vs 8.3 months, respectively) with an overall median follow-up time of 33.7 months. Median overall survival with a median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs 14.2 months, respectively). Efficacy results are presented in Table 21and Figure 8and 9.

Figure 8 - TAX323 Progression-Free Survival K-M Curve

Figure 9: TAX323 Overall Survival K-M Curve

Induction Chemotherapy Followed by Chemoradiotherapy (TAX324) The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m 2by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m 2administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m 2/day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on the comparator arm received cisplatin (P) 100 mg/m 2as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m 2/day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles.

All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70-72 Gy). Surgery on the primary site of disease and/or neck could be considered at any time following completion of CRT.

The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p=0.0058) with the docetaxel-containing regimen compared to PF (median OS: 70.6 vs 30.1 months, respectively, hazard ratio [HR]=0.70, 95% confidence interval [CI]=0.54-0.90). Overall survival results are presented in Table 22and Figure 10.

Figure 10: TAX324 Overall Survival K-M Curve

16.1 How Supplied

BEIZRAY is packaged as a kit in a carton (NDC 83513-010-01) that contains the following in a tray:

• Two single-dose vials of BEIZRAY Injection: 80 mg/4 mL each; a clear, colorless liquid. (NDC 83513-009-01)
• One single-dose vial of IV Solution Stabilizer: 50 mL of 25% Human Albumin solution for infusion; a clear and slightly viscous solution. (NDC 67467-643-01)

16.2 Storage

BEIZRAY Injection and IV Solution Stabilizer (25% Human Albumin):
Store at 20°C to 25°C (68°F to 77°F). Excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Retain in the original package to protect from light. Protect from freezing.

16.3 Handling and Disposal

BEIZRAY is a hazardous drug. Follow applicable special handling and disposal procedures.

Bone Marrow Suppression

Advise patients that periodic assessment of their blood count will be performed to detect neutropenia, thrombocytopenia, and/ or anemia [see Contraindications ( 4), Warnings and Precautions ( 5.3)] . Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever.

Enterocolitis and Neutropenic Colitis

Advise patients of the symptoms of colitis, such as abdominal pain or tenderness, and/or diarrhea, with or without fever, and instruct patients to promptly contact their healthcare provider if they experience these symptoms [see Dosage and Administration ( 2.7) and Warnings and Precautions ( 5.4)] .

Hypersensitivity Reactions

Ask patients whether they have previously received paclitaxel therapy, and if they have experienced a hypersensitivity reaction to paclitaxel. Instruct patients to immediately report to their healthcare provider signs of a hypersensitivity reaction [see Contraindications ( 4), Warnings and Precautions ( 5.5)] .

Fluid Retention

Advise patients to report signs of fluid retention such as peripheral edema in the lower extremities, weight gain, and dyspnea immediately to their healthcare provider [see Warnings and Precautions ( 5.6)] .

Second Primary Malignancies

Advise patients on the risk of second primary malignancies during treatment with BEIZRAY [see Warnings and Precautions ( 5.7)] .

Cutaneous Reactions

Advise patients that localized erythema of the extremities and severe skin toxicities may occur. Instruct patients to immediately report severe cutaneous reactions to their healthcare provider [see Dosage and Administration ( 2.7) and Warnings and Precautions ( 5.8)] .

Neurologic Reactions

Advise patients that neurosensory symptoms or peripheral neuropathy may occur. Instruct patients to immediately report neurologic reactions to their healthcare provider [see Dosage and Administration ( 2.7) and Warnings and Precautions ( 5.9)] .

Eye Disorders

Advise patients that vision disturbances and excessive tearing are associated with BEIZRAY administration. Instruct patients to immediately report any vision changes to their healthcare provider [see Warnings and Precautions ( 5.10)] .

Gastrointestinal Reactions

Explain to patients that nausea, vomiting, diarrhea, and constipation are associated with BEIZRAY administration. Instruct patients to report any severe events to their healthcare provider [see Adverse Reactions ( 6)] .

Cardiac Disorders

Advise patients to report any irregular and/or rapid heartbeat, severe shortness of breath, dizziness, and/or fainting immediately to their healthcare provider [see Adverse Reactions ( 6)] .

Other Common Adverse Reactions

Advise patients that other common adverse reactions associated with BEIZRAY may include alopecia (cases of permanent hair loss have been reported), asthenia, anorexia, dysgeusia, mucositis, myalgia, nail disorders, or pain. Instruct patients to report these reactions to their healthcare provider if serious events occur [see Adverse Reactions ( 6)] .

Importance of Corticosteroids

Explain the significance of oral corticosteroids such as dexamethasone administration to the patient to help facilitate compliance. Instruct patients to report to their healthcare provider if they were not compliant with the oral corticosteroid regimen [see Dosage and Administration ( 2.6)] .

Embryo-Fetal Toxicity

BEIZRAY can cause fetal harm. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise patients to avoid becoming pregnant while receiving this drug. Advise female patients of reproductive potential to use effective contraceptives during treatment
and for 2 months after the last dose of BEIZRAY. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of BEIZRAY [see Warnings and Precautions ( 5.12), and Use in Specific Populations ( 8.1, 8.3)] .

Lactation

Advise women not to breastfeed during BEIZRAY treatment and for 1 week after the last dose [see Use in Specific Populations ( 8.2)] .

Infertility

Advise males of reproductive potential that BEIZRAY may impair fertility [see Nonclinical Toxicology ( 13.1)] .

Alcohol Content in BEIZRAY

Explain to patients the possible effects of the alcohol content in BEIZRAY, including possible effects on the central nervous system [see Warnings and Precautions ( 5.13)] .

Tumor Lysis Syndrome

Advise patients of the potential risk of tumor lysis syndrome and to immediately report any signs or symptoms associated with this event (nausea, vomiting, confusion, shortness of breath, seizure, irregular heartbeat, dark or cloudy urine, reduced amount of urine, unusual tiredness, muscle cramps) to their healthcare provider. Advise patients of the importance of keeping scheduled appointment for blood work or other laboratory tests and of drinking adequate fluids to avoid dehydration. [see Warnings and Precautions ( 5.14)] .

Ability to Drive or Operate Machines

Explain to patients that BEIZRAY may impair their ability to drive or operate machines due to its side effects [see Adverse Reactions ( 6) ] or due to the alcohol content of BEIZRAY [see Warnings and Precautions ( 5.13)] . Advise them not to drive or use machines if they experience these side effects during treatment.

Drug Interactions

Inform patients about the risk of drug interactions and the importance of providing a list of prescription and non-prescription drugs to their healthcare provider [see Drug Interactions ( 7)] .

Manufactured by:
Ningbo Shuangcheng Pharmaceutical Co., Ltd.
Ningbo, Zhejiang, 315336, China

Distributed by:
Zhuhai Beihai Biotech Co.,Ltd.
Zhuhai, Guangdong, 519090, China