DOCETAXEL ANHYDROUS Drug Interactions: What You Need to Know

INTERACTIONS Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4. In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of Docetaxel Injection and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In patients receiving treatment with Docetaxel Injection close monitoring for toxicity and a Docetaxel Injection dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided [ see Dosage and Administration ( 2.7 ), Clinical Pharmacology ( 12.3 ) ]. Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel metabolism. ( 7 )

Docetaxel Injection is contraindicated in patients with:

• neutrophil counts of <1500 cells/mm 3 [ see Warnings and Precautions (5.3) ].
• a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80. Severe reactions, including anaphylaxis, have occurred [ see Warnings and Precautions (5.5) ].
• Hypersensitivity to docetaxel or polysorbate 80 ( 4 )
• Neutrophil counts of <1500 cells/mm 3 ( 4 )

AND PRECAUTIONS Second primary malignancies: In patients treated with BEIZRAY- containing regimens, monitor for delayed AML, MDS, NHL, and renal cancer. ( 5.7 ) Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe cutaneous adverse reactions have been reported. Severe skin toxicity may require dose adjustment or permanent treatment discontinuation. ( 5.8 ) Neurologic reactions: Reactions including paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. ( 5.9 ) Eye disorders: Cystoid macular edema (CME) has been reported and requires treatment discontinuation. ( 5.10 ) Asthenia: Severe asthenia may occur and may require treatment discontinuation. ( 5.11 ) Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.12 , 8.1 , 8.3 ) Alcohol content: The alcohol content in a dose of BEIZRAY Injection may affect the central nervous system. This may include impairment of a patient’s ability to drive or use machines immediately after infusion. ( 5.13 ) Tumor lysis syndrome: Tumor lysis syndrome has been reported. Patients at risk should be well hydrated and closely monitored during treatment. ( 5.14 ) BEIZRAY final infusion solution contains albumin derived from human blood, which has a theoretical risk of viral transmission. ( 5.15 )

5.1 Toxic Deaths Breast Cancer BEIZRAY administered at 100 mg/m 2 was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT &gt;1.5 times ULN together with AP &gt;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 2 in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies). There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m 2 dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m 2 dose level, 3 of 5 patients had an ECOG PS of 2 at study entry <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Clinical Studies ( 14 )]</span> .

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 &gt; upper limit of normal (ULN), or to patients with AST and/or ALT &gt;1.5 × ULN concomitant with alkaline phosphatase &gt;2.5 × ULN <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . For patients with isolated elevations of transaminase &gt;1.5 × ULN, consider BEIZRAY dose modifications <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.7 )]</span> . 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 &gt;1500 cells/mm 3 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Avoid retreating patients until platelets recover to a level &gt;100,000 cells/mm 3 . A 25% reduction in the dose of BEIZRAY is recommended during subsequent cycles following severe neutropenia (&lt;500 cells/mm 3 ) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a BEIZRAY cycle <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.7 )]</span> . Neutropenia (&lt;2000 neutrophils/mm 3 ) occurs in virtually all patients given 60 mg/m 2 to 100 mg/m 2 of BEIZRAY and grade 4 neutropenia (&lt;500 cells/mm 3 ) occurs in 85% of patients given 100 mg/m 2 and 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 &lt;1500 cells/mm 3 . Febrile neutropenia occurred in about 12% of patients given 100 mg/m 2 but 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ), Clinical Studies ( 14 )]</span> . Three breast cancer patients with severe liver impairment (bilirubin &gt;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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.7 ), Adverse Reactions ( 6 )]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.2 )]</span> .

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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . 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. <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.2 )]</span> . In TAC-treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up. Monitor patients for second primary malignancies <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.7 )]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.7 )]</span> . 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 Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease.

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> .

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 2 delivers 4.0 g/m 2 of ethanol. For a patient with a BSA of 2.0 m 2 , this would deliver 8.0 grams of ethanol <span class="opacity-50 text-xs">[see Description ( 11 )]</span> . Other docetaxel products may have a different amount of alcohol.

5.14 Tumor Lysis Syndrome Tumor lysis syndrome has been reported with docetaxel <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . 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 Albumin Human USP, 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.

5.1 Toxic Deaths Breast Cancer BEIZRAY administered at 100 mg/m 2 was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT &gt;1.5 times ULN together with AP &gt;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 2 in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies). There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m 2 dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m 2 dose level, 3 of 5 patients had an ECOG PS of 2 at study entry <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Clinical Studies ( 14 )]</span> .

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 &gt; upper limit of normal (ULN), or to patients with AST and/or ALT &gt;1.5 × ULN concomitant with alkaline phosphatase &gt;2.5 × ULN <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . For patients with isolated elevations of transaminase &gt;1.5 × ULN, consider BEIZRAY dose modifications <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.7 )]</span> . 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 &gt;1500 cells/mm 3 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Avoid retreating patients until platelets recover to a level &gt;100,000 cells/mm 3 . A 25% reduction in the dose of BEIZRAY is recommended during subsequent cycles following severe neutropenia (&lt;500 cells/mm 3 ) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a BEIZRAY cycle <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.7 )]</span> . Neutropenia (&lt;2000 neutrophils/mm 3 ) occurs in virtually all patients given 60 mg/m 2 to 100 mg/m 2 of BEIZRAY and grade 4 neutropenia (&lt;500 cells/mm 3 ) occurs in 85% of patients given 100 mg/m 2 and 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 &lt;1500 cells/mm 3 . Febrile neutropenia occurred in about 12% of patients given 100 mg/m 2 but 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ), Clinical Studies ( 14 )]</span> . Three breast cancer patients with severe liver impairment (bilirubin &gt;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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.7 ), Adverse Reactions ( 6 )]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.2 )]</span> .

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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . 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. <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.2 )]</span> . In TAC-treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up. Monitor patients for second primary malignancies <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.7 )]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.7 )]</span> . 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 Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease.

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> .

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 2 delivers 4.0 g/m 2 of ethanol. For a patient with a BSA of 2.0 m 2 , this would deliver 8.0 grams of ethanol <span class="opacity-50 text-xs">[see Description ( 11 )]</span> . Other docetaxel products may have a different amount of alcohol.

5.14 Tumor Lysis Syndrome Tumor lysis syndrome has been reported with docetaxel <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . 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 Albumin Human USP, 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.