Paclitaxel Dailymed

1 Indications And Usage

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is a microtubule inhibitor indicated for the treatment of:

• Metastatic breast cancer, after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. ( 1.1)

1.1 Metastatic Breast Cancer

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

2 Dosage And Administration

• Do not substitute paclitaxel protein-bound particles for injectable suspension (albumin-bound) for other paclitaxel products. (2.1)
• Extravasation: Closely monitor the infusion site for extravasation and infiltration. ( 2.1)
• Metastatic Breast Cancer (MBC): Recommended dosage of paclitaxel protein-bound particles for injectable suspension (albumin-bound) is 260 mg/m ²intravenously over 30 minutes every 3 weeks. ( 2. 2)
• Use in Patients with Hepatic Impairment: Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is not recommended for use in patients with AST > 10 × ULN; or bilirubin > 5 × ULN. For MBC, reduce starting dose in patients with moderate to severe hepatic impairment. ( 2.5)
• Dose Reductions for Adverse Reactions: Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicities. ( 2.6)

2.1 Important Administration Instructions

DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. Paclitaxel protein-bound particles for injectable suspension (albumin-bound) has different dosage and administration instructions from other paclitaxel products.

Closely monitor the infusion site for extravasation or drug infiltration during administration. Limiting the infusion of paclitaxel protein-bound particles for injectable suspension (albumin-bound) to 30 minutes may reduce the risk of infusion-related reactions [see Adverse Reactions (6.2)] .

Consider premedication in patients who have had prior hypersensitivity reactions to paclitaxel protein-bound particles for injectable suspension (albumin-bound). Do not re-challenge patients who experience a severe hypersensitivity reaction to paclitaxel protein-bound particles for injectable suspension (albumin-bound)  [see Contraindications (4)and Warnings and Precautions (5.5)] .

2.2 Recommended Dosage for Metastatic Breast Cancer

After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for paclitaxel protein-bound particles for injectable suspension (albumin-bound) is 260 mg/m ²administered intravenously over 30 minutes every 3 weeks.

2.5 Dosage Modifications for Hepatic Impairment

For patients with moderate or severe hepatic impairment, reduce the starting dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) as shown in Table 1.

Table 1: Recommendations for Starting Dose in Patients with Moderate and Severe Hepatic Impairment

AST = Aspartate Aminotransferase; MBC = Metastatic Breast Cancer; ULN = Upper limit of normal.
aDosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance.
bA dose increase to 260 mg/m 2for patients with metastatic breast cancer in subsequent courses should be considered if the patient tolerates the reduced dose for two cycles.
	AST Levels		Bilirubin Levels	Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) Dose a
				MBC
Moderate	< 10 x ULN	AND	> 1.5 to ≤ 3 x ULN	200 mg/m 2 b
Severe	< 10 x ULN	AND	> 3 to ≤ 5 x ULN	200 mg/m 2 b
	> 10 x ULN	OR	> 5 x ULN	not recommendedÂ

2.6 Dosage Modifications for Adverse Reactions

Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophils less than 500 cells/mm ³for a week or longer) or severe sensory neuropathy during paclitaxel protein-bound particles for injectable suspension (albumin-bound) therapy should have dosage reduced to 220 mg/m ²for subsequent courses of paclitaxel protein-bound particles for injectable suspension (albumin-bound). For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m ². For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of paclitaxel protein-bound particles for injectable suspension (albumin-bound)  [see Contraindications (4), Warnings and Precautions (5.1, 5.2)and Adverse Reactions (6.1)].

2.7 Preparation for Intravenous Administration

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is a cytotoxic drug. Follow applicable special handling and disposal procedures. ¹The use of gloves is recommended. If paclitaxel protein-bound particles for injectable suspension (albumin-bound) (lyophilized cake or reconstituted suspension) contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure to paclitaxel, events may include tingling, burning, and redness. If paclitaxel protein-bound particles for injectable suspension (albumin-bound) contacts mucous membranes, the membranes should be flushed thoroughly with water.

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is supplied as a sterile lyophilized powder for reconstitution before use.

Read the entire preparation instructions prior to reconstitution.

Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized cake as this will result in foaming. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized cake/powder. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any cake/powder occurs. Avoid generation of foam. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides.

Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel.

The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be gentlyinverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion.

Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient and slowly withdraw the dosing volume of the reconstituted suspension from the vial(s) into a syringe: Dosing volume (mL)=Total dose (mg)/5 (mg/mL).

Inject the appropriate amount of reconstituted paclitaxel protein-bound particles for injectable suspension (albumin-bound) into an empty, sterile intravenous bag [plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type intravenous bag]. The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer paclitaxel protein-bound particles for injectable suspension (albumin-bound) infusions. The use of medical devices containing silicone oil as a lubricant (i.e., syringes and intravenous bags) to reconstitute and administer paclitaxel protein-bound particles for injectable suspension (albumin-bound) may result in the formation of proteinaceous strands.

Visually inspect the reconstituted paclitaxel protein-bound particles for injectable suspension (albumin-bound) suspension in the intravenous bag prior to administration. Discard the reconstituted suspension if proteinaceous strands, particulate matter, or discoloration are observed.

2.8 Stability

Unopened vials of paclitaxel protein-bound particles for injectable suspension (albumin-bound) are stable until the date indicated on the package when stored between 20°C to 25°C (68°F to 77°F) in the original package. Neither freezing nor refrigeration adversely affects the stability of the product.

Stability of Reconstituted Suspension in the Vial Reconstituted paclitaxel protein-bound particles for injectable suspension (albumin-bound) in the vial should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 24 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original carton to protect it from bright light. Discard any unused portion.

Stability of Reconstituted Suspension in the Infusion Bag The suspension for infusion when prepared as recommended in an infusion bag should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) and protected from bright light for a maximum of 24 hours.

The total combined refrigerated storage time of reconstituted paclitaxel protein-bound particles for injectable suspension (albumin-bound) in the vial and in the infusion bag is 24 hours. This may be followed by storage in the infusion bag at ambient temperature (approximately 25°C) and lighting conditions for a maximum of 4 hours.

Discard any unused portion.

• Sensory neuropathy occurs frequently and may require dose reduction or treatment interruption. ( 5.2)
• Sepsis occurred in patients with or without neutropenia who received paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine; interrupt paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine until sepsis resolves, and if neutropenia, until neutrophils are at least 1500 cells/mm3, then resume treatment at reduced dose levels. ( 5.3)
• Pneumonitis occurred with the use of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine; permanently discontinue treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine. ( 5.4)
• Severe hypersensitivity reactions with fatal outcome have been reported. Do not rechallenge with this drug. ( 4, 5.5)
• Exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, consider dose reduction and closely monitor patients with hepatic impairment. ( 2.5, 5.6)
• Paclitaxel protein-bound particles for injectable suspension (albumin-bound)contains albumin derived from human blood, which has a theoretical risk of viral transmission. ( 5.7)
• Paclitaxel protein-bound particles for injectable suspension (albumin-bound)can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.8, 8.1, 8.3)

5.1 Severe Myelosuppression

Severe myelosuppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of paclitaxel protein-bound particles for injectable suspension (albumin-bound). In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC).

Monitor for severe neutropenia and thrombocytopenia by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC). Do not administer paclitaxel protein-bound particles for injectable suspension (albumin-bound) to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm ³ [see Contraindications (4)] .

In the case of severe neutropenia (<500 cells/mm ³for seven days or more) during a course of paclitaxel protein-bound particles for injectable suspension (albumin-bound) therapy, reduce the dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in subsequent courses in patients with MBC.

In patients with MBC, resume treatment with every-3-week cycles of paclitaxel protein-bound particles for injectable suspension (albumin-bound) after ANC recovers to a level >1,500 cells/mm ³and platelets recover to a level >100,000 cells/mm ³ [see Dosage and Administration (2.6)].

5.2 Severe Neuropathy

Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1)] . If ≥ Grade 3 sensory neuropathy develops, withhold paclitaxel protein-bound particles for injectable suspension (albumin-bound) treatment until resolution to Grade 1 or 2 for metastatic breast cancer followed by a dose reduction for all subsequent courses of paclitaxel protein-bound particles for injectable suspension (albumin-bound)  [see Dosage and Administration (2.6)] .

5.3Sepsis

Sepsis occurred in 5% of patients with or without neutropenia who received paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis.

If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine until fever resolves and ANC ≥ 1,500, then resume treatment at reduced dose levels [see Dosage and Administration (2.6)] .

5.4 Pneumonitis

Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine.

Monitor patients for signs and symptoms of pneumonitis and interrupt paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine.

5.5 Severe Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Do not rechallenge patients who experience a severe hypersensitivity reaction to paclitaxel protein-bound particles for injectable suspension (albumin-bound) with this drug [see Contraindications (4)] .

Cross-hypersensitivity between paclitaxel protein-bound particles for injectable suspension (albumin-bound) and other taxane products has been reported and may include severe reactions such as anaphylaxis. Closely monitor patients with a previous history of hypersensitivity to other taxanes during initiation of paclitaxel protein-bound particles for injectable suspension (albumin-bound) therapy.

5.6 Use in Patients with Hepatic Impairment

The exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment. Closely monitor patients with hepatic impairment for severe myelosuppression.

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is not recommended in patients who have total bilirubin >5 x ULN or AST >10 x ULN. Reduce the starting dose for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.5), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] .

5.7 Albumin (Human)

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) contains albumin (human), 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.

5.8 Embryo-Fetal Toxicity

Based on mechanism of action and findings in animals, paclitaxel protein-bound particles for injectable suspension (albumin-bound) can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.

Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and for at least six months after the last dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound)  [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and for at least three months after the last dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound)  [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

6 Adverse Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions (≥ 20%) with single-agent use of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)] .

The most common adverse reactions resulting in permanent discontinuation of paclitaxel protein-bound particles for injectable suspension (albumin-bound) are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of paclitaxel protein-bound particles for injectable suspension (albumin-bound) are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in paclitaxel protein-bound particles for injectable suspension (albumin-bound) dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%).

The most common serious adverse reactions of paclitaxel protein-bound particles for injectable suspension (albumin-bound) (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of paclitaxel protein-bound particles for injectable suspension (albumin-bound) are peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of paclitaxel protein-bound particles for injectable suspension (albumin-bound) are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in paclitaxel protein-bound particles for injectable suspension (albumin-bound) dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%).

• The most common adverse reactions (≥ 20%) in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Metastatic Breast Cancer

Table 6shows the frequency of important adverse reactions in the randomized comparative trial for the patients who received either single-agent paclitaxel protein-bound particles for injectable suspension (albumin-bound) or paclitaxel injection for the treatment of metastatic breast cancer.

Table 6: Adverse Reactions in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule

aPaclitaxel injection patients received premedication.
bIncludes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing.
cSevere events are defined as at least Grade 3 toxicity.
	Percent of Patients
	Paclitaxel Protein-bound Particles for Injectable Suspension (albumin-bound) 260 mg/m 2over 30 min (n=229)	Paclitaxel Injection 175 mg/m 2over 3 h a (n=225)
Bone Marrow
 Neutropenia
   < 2 x 10 9/L	80	82
   < 0.5 x 10 9/L	9	22
 Thrombocytopenia
   < 100 x 10 9/L	2	3
   < 50 x 10 9/L	<1	<1
 Anemia
   < 11 g/dL	33	25
   < 8 g/dL	1	<1
 Infections	24	20
 Febrile Neutropenia	2	1
 Neutropenic Sepsis	<1	<1
 Bleeding	2	2
Hypersensitivity Reaction b
 All	4	12
 Severe c	0	2
Cardiovascular
 Vital Sign Changes During Administration
   Bradycardia	<1	<1
   Hypotension	5	5
 Severe Cardiovascular Events c	3	4
Abnormal ECG
 All Patients	60	52
 Patients with Normal Baseline	35	30
Respiratory
 Cough	7	6
 Dyspnea	12	9
Sensory Neuropathy
 Any Symptoms	71	56
 Severe Symptoms c	10	2
Myalgia / Arthralgia
 Any Symptoms	44	49
 Severe Symptoms c	8	4
Asthenia
 Any Symptoms	47	39
 Severe Symptoms c	8	3
Fluid Retention/Edema
 Any Symptoms	10	8
 Severe Symptoms c	0	<1
Gastrointestinal
 Nausea
   Any Symptoms	30	22
   Severe Symptoms c	3	<1
 Vomiting
   Any Symptoms	18	10
   Severe Symptoms c	4	1
 Diarrhea
   Any Symptoms	27	15
   Severe Symptoms c	<1	1
  Mucositis
   Any Symptoms	7	6
   Severe Symptoms c	<1	0
Alopecia	90	94
Hepatic(Patients with Normal Baseline)
 Bilirubin Elevations	7	7
 Alkaline Phosphatase Elevations	36	31
 AST (SGOT) Elevations	39	32
Injection Site Reaction	<1	1

Other Adverse Reactions

Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm ³(Grade 4) in 9% of the patients treated with a dose of 260 mg/m ²compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m ². Pancytopenia has been observed in clinical trials.

Infections Infectious episodes were reported in 24% of the patients treated with paclitaxel protein-bound particles for injectable suspension (albumin-bound). Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.

Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of paclitaxel protein-bound particles for injectable suspension (albumin-bound) administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation.

Severe cardiovascular events possibly related to single-agent paclitaxel protein-bound particles for injectable suspension (albumin-bound) occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported.

Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia.

Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound).

Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of paclitaxel protein-bound particles for injectable suspension (albumin-bound) discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with paclitaxel protein-bound particles for injectable suspension (albumin-bound) developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy.

No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial.

Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m ²). These effects generally have been reversible.

Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after paclitaxel protein-bound particles for injectable suspension (albumin-bound) administration, and resolved within a few days.

Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and 10% of patients treated with paclitaxel injection in the randomized trial.

Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities.

Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of paclitaxel protein-bound particles for injectable suspension (albumin-bound) or with paclitaxel injection and may be expected to occur with paclitaxel protein-bound particles for injectable suspension (albumin-bound). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity Reactions

Severe and sometimes fatal hypersensitivity reactions. Cross-hypersensitivity between paclitaxel protein-bound particles for injectable suspension (albumin-bound) and other taxanes has been reported.

Cardiovascular

Congestive heart failure, left ventricular dysfunction, and atrioventricular block. Most patients were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory

Pneumonitis, interstitial pneumonia, and pulmonary embolism

Radiation pneumonitis in patients receiving concurrent radiotherapy.

Lung fibrosis has been reported with paclitaxel injection.

Neurologic

Cranial nerve palsies and vocal cord paresis, as well as autonomic neuropathy resulting in paralytic ileus.

Vision Disorders

Reduced visual acuity due to cystoid macular edema (CME). After cessation of treatment, CME may improve, and visual acuity may return to baseline. Abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage.

Hepatic

Hepatic necrosis and hepatic encephalopathy leading to death in patients treated with paclitaxel injection.

Gastrointestinal (GI)

Intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis. In patients treated with paclitaxel injection, neutropenic enterocolitis (typhlitis) despite the coadministration of G-CSF, alone and in combination with other chemotherapeutic agents.

Injection Site Reaction

Extravasation. Closely monitor the paclitaxel protein-bound particles for injectable suspension (albumin-bound) infusion site for possible infiltration during drug administration [see Dosage and Administration 2.1)] .

Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported with paclitaxel injection. In some cases, the onset of the injection site reaction occurred during a prolonged infusion or was delayed up to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site has been reported.

Metabolic and Nutritional Disorders

Tumor lysis syndrome

Other Clinical Events

Skin reactions including generalized or maculopapular rash, erythema, and pruritus

Photosensitivity reactions, radiation recall phenomenon, scleroderma, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

Conjunctivitis, cellulitis, and increased lacrimation have been reported with paclitaxel injection.

Accidental Exposure

Upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.

Following topical exposure, tingling, burning, and redness have been reported.