Beizray Dosage

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 .

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

See additional premedication recommendations for the indicated populations

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 .

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.

In patients previously treated with chemotherapy, a dosage of 100 mg/m 2is not recommended because this dosage was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized controlled trials.

For chemotherapy-naive patients, the recommended dosage 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.

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. Recommend concomitant use of 5 mg of prednisone orally twice daily continuously .

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.

Repeat treatment every three weeks. Must receive premedication with antiemetics and appropriate hydration for cisplatin administration .

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 .

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 .

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.
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.

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/m 2or 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 . Avoid retreating patients until platelets recover to a level >100,000 cells/mm 3. Discontinue treatment if these toxicities persist .

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 .

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 .

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.

Preparation and Administration

BEIZRAY is available in two packaging configurations:

• Co-packaged kit containing BEIZRAY vial(s) and IV Solution Stabilizer (25% Albumin Human USP)
• Carton containing one BEIZRAY vial only

Preparation

Read this entire section carefully before mixing and diluting.

• Inject 25% Albumin Human USP (IV Solution Stabilizer) directly into the 0.9% Sodium Chloride Injection bag. Do not use 25% Albumin Human USP (IV Solution Stabilizer) to dilute BEIZRAY.
• To prevent precipitation, BEIZRAY needs to be diluted with a prepared infusion bag containing Albumin Human USP and 0.9% Sodium Chloride Injection to ensure a final concentration between 0.14 mg/mL and 0.31 mg/mL.

Follow the preparation instructions provided below.

Step 1 Calculate the required amount of BEIZRAY

Calculate the required amount of BEIZRAY using the following formula:
Required amount of BEIZRAY (mL) = prescribed BEIZRAY dose (mg/m 2) × body surface area (m 2) ÷ 20 (mg/mL)

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

Based on the calculated amount of BEIZRAY from Step 1, determine the required amount of 0.9% Sodium Chloride Injection in Table 3.

Step 3 Calculate the required amount of 25% Albumin Human USP (IV Solution Stabilizer)

Calculate the required amount of 25% Albumin Human USP (IV Solution Stabilizer) using the following formula:
Required amount of 25% Albumin Human USP (IV Solution Stabilizer) (mL) = Required amount of BEIZRAY (mL) × 6

Step 4 Add 25% Albumin Human USP (IV Solution Stabilizer) to the infusion bag

1. Withdraw the calculated amount of 25% Albumin Human USP (IV Solution Stabilizer) from the vial and inject into a 0.9% Sodium Chloride Injection bag.
2. Thoroughly mix the diluted solution by gently inverting the bag for at least 5 times. Do not shake. This solution should be used immediately after preparation.

Step 5 Add BEIZRAY to the final infusion solution

1. Aseptically withdraw the calculated amount of BEIZRAY with a calibrated syringe and inject via a single injection into the infusion bag containing the initial diluted solution with 25% Albumin Human USP (IV Solution Stabilizer) to produce a final concentration between 0.14 mg/mL and 0.31 mg/mL.
2. After injection, remove the syringe and immediately thoroughly mix the final infusion solution by gently inverting the bag for at least 10 times. Do not shake.

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

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).