Beizray Prescribing Information
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BEIZRAY administered at 100 mg/m2was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients dosed at 60 mg/m2, mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function. Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths.
BEIZRAY administered at a dose of 100 mg/m2in 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/m2dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m2dose level, 3 of 5 patients had an ECOG PS of 2 at study entry
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
For patients with isolated elevations of transaminase >1.5 × ULN, consider BEIZRAY dose modifications
Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of BEIZRAY therapy.
3. Monitor blood counts frequently as neutropenia may be severe and result in infection.
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/mm3
A 25% reduction in the dose of BEIZRAY is recommended during subsequent cycles following severe neutropenia (<500 cells/mm3) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a BEIZRAY cycle
Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 mg/m2to 100 mg/m2of BEIZRAY and grade 4 neutropenia (<500 cells/mm3) occurs in 85% of patients given 100 mg/m2and 75% of patients given 60 mg/m2. 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/mm3.
Febrile neutropenia occurred in about 12% of patients given 100 mg/m2but was very uncommon in patients given 60 mg/m2. Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related
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
BEIZRAY is contraindicated in patients with:
• neutrophil counts of <1500 cells/mm3
• a history of severe hypersensitivity reactions to docetaxel. Severe reactions, including anaphylaxis, have occurred
- Hypersensitivity to docetaxel
- Neutrophil counts of <1500 cells/mm3
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
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.
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
When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg.
Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m2. Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention. The median cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m2. Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of 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).
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).
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).
BEIZRAY (docetaxel) injection is a clear, colorless liquid supplied as follows:
BEIZRAY 80 mg kit consisting of the following:
- One single-dose vial of BEIZRAY: 80 mg/4 mL
- One single-dose vial of IV Solution Stabilizer: 50 mL of 25% Albumin Human USP solution for infusion; a clear and slightly viscous solution
BEIZRAY 160 mg kit consisting of the following:
- Two single-dose vials of BEIZRAY: 80 mg/4 mL each
- One single-dose vial of IV Solution Stabilizer: 50 mL of 25% Albumin Human USP solution for infusion; a clear and slightly viscous solution
BEIZRAY carton containing one single-dose vial:
- 80 mg/4 mL
Avoid BEIZRAY in patients with bilirubin >ULN and patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN
Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death.
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
For patients with isolated elevations of transaminase >1.5 × ULN, consider BEIZRAY dose modifications
Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of BEIZRAY therapy.
The pharmacokinetics of docetaxel has been evaluated in cancer patients after administration of 20 mg/m2to 115 mg/m2in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m2to 115 mg/m2with 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.
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.
With extended plasma sampling up to 8 to 22 days post infusion, the estimated mean total body clearance was 18 L/h/m2(range of means: 14 to 23) and mean terminal elimination half-life was 116 hours (range of means: 92 to 135).
Docetaxel is metabolized by the CYP3A4 isoenzyme in vitro
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.
Effect of Age: A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m2. 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
Effect of Race: Mean total body clearance for Japanese patients dosed at the range of 10 mg/m2to 90 mg/m2was similar to that of European/American populations dosed at 100 mg/m2, suggesting no significant difference in the elimination of docetaxel in the two populations.
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/m2intravenous) alone or docetaxel (10 mg/m2intravenous) 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
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/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) 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.
The alcohol content of BEIZRAY Injection should be taken into account when given to patients with hepatic impairment
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/m2delivers 4.0 g/m2of ethanol. For a patient with a BSA of 2.0 m2, this would deliver 8.0 grams of ethanol
BEIZRAY is contraindicated in patients with:
• neutrophil counts of <1500 cells/mm
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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/mm3
A 25% reduction in the dose of BEIZRAY is recommended during subsequent cycles following severe neutropenia (<500 cells/mm3) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a BEIZRAY cycle
Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 mg/m2to 100 mg/m2of BEIZRAY and grade 4 neutropenia (<500 cells/mm3) occurs in 85% of patients given 100 mg/m2and 75% of patients given 60 mg/m2. 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/mm3.
Febrile neutropenia occurred in about 12% of patients given 100 mg/m2but was very uncommon in patients given 60 mg/m2. Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related
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
• a history of severe hypersensitivity reactions to docetaxel. Severe reactions, including anaphylaxis, have occurred
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
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.