PACLITAXEL injection, powder, lyophilized, for suspension

Paclitaxel by

Drug Labeling and Warnings

Paclitaxel by is a Prescription medication manufactured, distributed, or labeled by Sandoz Inc. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • SPL UNCLASSIFIED SECTION

    Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound)

  • BOXED WARNING (What is this?)

    WARNING: NEUTROPENIA

    • Do not administer paclitaxel protein-bound particles for injectable suspension (albumin-bound) therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm 3[see Contraindications (4)].
    • Monitor for neutropenia, which may be severe and result in infection or sepsis, it is recommended that frequent [see Warnings and Precautions (5.1, 5.3)].
    • Perform frequent complete blood cell counts on all patients receiving paclitaxel protein-bound particles for injectable suspension (albumin-bound)  [see Contraindications (4),  Warnings and Precautions (5.1, 5.3)].
  • 3 DOSAGE FORMS AND STRENGTHS

    For injectable suspension, for intravenous use: white to yellow, sterile lyophilized powder containing 100 mg of paclitaxel formulated as albumin-bound particles in single-dose vial for reconstitution.

  • 4 CONTRAINDICATIONS

    Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is contraindicated in patients with:

  • 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 (≥ 20%) of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.1)]. The most common serious adverse reactions of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). 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%).

    In a randomized open-label trial of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of paclitaxel protein-bound particles for injectable suspension (albumin-bound) are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration [see Adverse Reactions (6.1)]. 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%).

    6.1 Clinical Trials Experience

    Metastatic Breast Cancer

    Table 6 shows 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
    < 2.0 x 10 9/L 8082
    < 0.5 x 10 9/L 922
    Thrombocytopenia
    < 100 x 10 9/L 23
    < 50 x 10 9/L <1<1
    Anemia
    < 11 g/dL3325
    < 8 g/dL1<1
    Infections2420
    Febrile Neutropenia21
    Neutropenic Sepsis<1<1
    Bleeding22
    Hypersensitivity Reaction b
    All412
    Severe c02
    Cardiovascular
    Vital Sign Changes During Administration
    Bradycardia<1<1
    Hypotension55
    Severe Cardiovascular Events c34
    Abnormal ECG
    All Patients6052
    Patients with Normal Baseline3530
    Respiratory
    Cough76
    Dyspnea129
    Sensory Neuropathy
    Any Symptoms7156
    Severe Symptoms c102
    Myalgia / Arthralgia
    Any Symptoms4449
    Severe Symptoms c84
    Asthenia
    Any Symptoms4739
    Severe Symptoms c83
    Fluid Retention/Edema
    Any Symptoms108
    Severe Symptoms c0<1
    Gastrointestinal
    Nausea
    Any Symptoms3022
    Severe Symptoms c3<1
    Vomiting
    Any Symptoms1810
    Severe Symptoms c41
    Diarrhea
    Any Symptoms2715
    Severe Symptoms c<11
    Mucositis
    Any Symptoms76
    Severe Symptoms c<10
    Alopecia9094
    Hepatic(Patients with Normal Baseline)
    Bilirubin Elevations77
    Alkaline Phosphatase Elevations3631
    AST (SGOT) Elevations3932
    Injection Site Reaction<11

    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.

    Non-Small Cell Lung Cancer

    Adverse reactions were assessed in 514 paclitaxel protein-bound particles for injectable suspension (albumin-bound)/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. Paclitaxel protein-bound particles for injectable suspension (albumin-bound) was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m 2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m 2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mgmin/mL was administered intravenously on Day 1 of each 21-day cycle after completion of paclitaxel protein-bound particles for injectable suspension (albumin-bound)/paclitaxel infusion.

    The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose-and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment.

    The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in paclitaxel protein-bound particles for injectable suspension (albumin-bound) plus carboplatintreated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the paclitaxel protein-bound particles for injectable suspension (albumin-bound) plus carboplatin treatment group).

    Table 7 provides the frequency and severity of laboratory-detected abnormalities which occurred with a difference of ≥5% for all grades (1-4) or≥2% for Grade 3-4 toxicity between paclitaxel protein-bound particles for injectable suspension (albumin-bound) plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.

    Table 7: Selected Hematologic Laboratory-Detected Abnormalities with a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups
    Paclitaxel protein-bound particles for injectable suspension (albumin-bound) (100 mg/m 2 weekly) plus carboplatin Paclitaxel Injection (200 mg/m 2 every 3 weeks) plus carboplatin
    Grades 1-4 (%)Grade 3-4 (%)Grades 1-4 (%)Grade 3-4 (%)

    Anemia 1,2

    		9828917
    Neutropenia 1,385478358
    Thrombocytopenia 1,36818559

    1 508 patients assessed in Paclitaxel protein-bound particles for injectable suspension (albumin-bound)/carboplatin-treated group.

    2 514 patients assessed in paclitaxel injection/carboplatin-treated group.

    3 513 patients assessed in paclitaxel injection/carboplatin-treated group.

    Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 Paclitaxel protein-bound particles for injectable suspension (albumin-bound) plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.

    Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups
    System Organ ClassAdverse ReactionPaclitaxel protein-bound particles for injectable suspension (albumin-bound) (100 mg/m 2 weekly) + carboplatin (N=514) Paclitaxel Injection (200 mg/m 2 every 3 weeks) + carboplatin (N=524)
    Grade 1-4 Toxicity (%)Grade 3-4 Toxicity (%)Grades 1-4 Toxicity (%)Grade 3-4 Toxicity (%)
    Nervous system disordersPeripheral neuropathy a4836412
    General disorders and administration site conditionsEdema peripheral1004<1
    Respiratory thoracic and mediastinal disordersEpistaxis7020
    Musculoskeletal and connective tissue disordersArthralgia13<1252
    Myalgia10<1192
    a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).

    For the Paclitaxel protein-bound particles for injectable suspension (albumin-bound) plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of Paclitaxel protein-bound particles for injectable suspension (albumin-bound).

    Adenocarcinoma of the Pancreas

    Adverse reactions were assessed in 421 patients who received Paclitaxel protein-bound particles for injectable suspension (albumin-bound) plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the Paclitaxel protein-bound particles for injectable suspension (albumin-bound)/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the Paclitaxel protein-bound particles for injectable suspension (albumin-bound)/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of Paclitaxel protein-bound particles for injectable suspension (albumin-bound) was 81%.

    Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 14 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in Paclitaxel protein-bound particles for injectable suspension (albumin-bound) plus gemcitabine-treated patients.

    Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or≥ 2% for Grades 3-4 Events) in the Paclitaxel protein-bound particles for injectable suspension (albumin-bound)/Gemcitabine Arm
    Paclitaxel protein-bound particles for injectable suspension (albumin-bound) (125 mg/m 2)/Gemcitabine dGemcitabine
    Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)
    Neutropenia a,b73385827
    Thrombocytopenia b,c7413709

    a 405 patients assessed in Paclitaxel protein-bound particles for injectable suspension (albumin-bound)/gemcitabine-treated group.

    b 388 patients assessed in gemcitabine-treated group.
    c 404 patients assessed in Paclitaxel protein-bound particles for injectable suspension (albumin-bound)/gemcitabine-treated group.
    d Neutrophil growth factors were administered to 26% of patients in the Paclitaxel protein-bound particles for injectable suspension (albumin-bound)/gemcitabine group.

    Table10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the Paclitaxel protein-bound particles for injectable suspension (albumin-bound) plus gemcitabine-treated group compared to the gemcitabine group.

    Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the Paclitaxel protein-bound particles for injectable suspension (albumin-bound)/Gemcitabine Arm
    System Organ ClassAdverse ReactionPaclitaxel protein-bound particles for injectable suspension (albumin-bound) (125 mg/m 2) and gemcitabine (N=421) Gemcitabine (N=402)
    All GradesGrade 3 or HigherAll GradesGrade 3 or Higher
    General disorders and administration site conditionsFatigue248 (59%)77 (18%)183 (46%)37 (9%)
    Peripheral edema194 (46%)13 (3%)122 (30%)12 (3%)
    Pyrexia171 (41%)12 (3%)114 (28%)4 (1%)
    Asthenia79 (19%)29 (7%)54 (13%)17 (4%)
    Mucositis42 (10%)6 (1%)16 (4%)1 (<1%)
    Gastrointestinal disordersNausea228 (54%)27 (6%)192 (48%)14 (3%)
    Diarrhea184 (44%)26 (6%)95 (24%)6 (1%)
    Vomiting151 (36%)25 (6%)113 (28%)15 (4%)
    Alopecia212 (50%)6 (1%)21 (5%)0
    Skin and subcutaneous tissue disordersRash128 (30%)8 (2%)45 (11%)2 (<1%)
    Nervous system disordersPeripheral neuropathya227 (54%)70 (17%)51 (13%)3 (1%)
    Dysgeusia68 (16%)033 (8%)0
    Headache60 (14%)1 (<1%)38 (9%)1 (<1%)
    Metabolism and nutrition disordersDecreased appetite152 (36%)23 (5%)104 (26%)8 (2%)
    Dehydration87 (21%)31 (7%)45 (11%)10 (2%)
    Hypokalemia52 (12%)18 (4%)28 (7%)6 (1%)
    Respiratory, thoracic and mediastinal disordersCough72 (17%)030 (7%)0
    Epistaxis64 (15%)1 (<1%)14 (3%)1 (<1%)
    Infections and infestationsUrinary tract infections b47 (11%)10 (2%)20 (5%)1 (<1%)
    Musculoskeletal and connective tissue disordersPain in extremity48 (11%)3 (1%)24 (6%)3 (1%)
    Arthralgia47 (11%)3 (1%)13 (3%)1 (<1%)
    Myalgia44 (10%)4 (1%)15 (4%)0
    Psychiatric disordersDepression51 (12%)1 (<1%)24 (6%)0

    a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope).

    b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococcal.

    Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received paclitaxel protein-bound particles for injectable suspension (albumin-bound)/gemcitabine included:

    Infections & infestations: oral candidiasis, pneumonia

    Vascular disorders: hypertension

    Cardiac disorders: tachycardia, congestive cardiac failure

    Eye disorders: cystoid macular edema

    Peripheral Neuropathy

    Grade 3 peripheral neuropathy occurred in 17% of patients who received paclitaxel protein-bound particles for injectable suspension (albumin-bound)/gemcitabine compared to 1% of patients who received gemcitabine only; no patients developed Grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the paclitaxel protein-bound particles for injectable suspension (albumin-bound) arm was 140 days. Upon suspension of paclitaxel protein-bound particles for injectable suspension (albumin-bound) dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of paclitaxel protein-bound particles for injectable suspension (albumin-bound)-treated patients with Grade 3 peripheral neuropathy, 44% resumed paclitaxel protein-bound particles for injectable suspension (albumin-bound) at a reduced dose.

    Sepsis

    Sepsis occurred in 5% of patients who received paclitaxel protein-bound particles for injectable suspension (albumin-bound)/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent.

    Pneumonitis

    Pneumonitis occurred in 4% of patients who received paclitaxel protein-bound particles for injectable suspension (albumin-bound)/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the paclitaxel protein-bound particles for injectable suspension (albumin-bound) arm with pneumonitis died.

    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.

  • 7 DRUG INTERACTIONS

    The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. Caution should be exercised when administering paclitaxel protein-bound particles for injectable suspension (albumin-bound) concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4.

  • 8 USE IN SPECIFIC POPULATIONS

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Based on its 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 [see Clinical Pharmacology (12.1)] . There are no available human data on paclitaxel protein-bound particles for injectable suspension (albumin-bound) use in pregnant women to inform the drug-associated risk.

    In animal reproduction studies, administration of paclitaxel formulated as albumin-bound particles to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity at doses approximately 2% of the daily maximum recommended human dose on a mg/m 2basis (see Data). Advise females of reproductive potential of the potential risk to a fetus.

    The background rate of major birth defects and miscarriage is unknown for the indicated population. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

    Data

    Animal Data

    In embryo-fetal development studies, intravenous administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m 2(approximately 2% of the daily maximum recommended human dose on a mg/m 2basis) caused embryo-fetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight, and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles.

    8.2 Lactation

    Risk Summary

    There are no data on the presence of paclitaxel in human milk, or its effect on the breastfed child or on milk production. In animal studies, paclitaxel and/or its metabolites were excreted into the milk of lactating rats (see Data). Because of the potential for serious adverse reactions in a breastfed child from paclitaxel protein-bound particles for injectable suspension (albumin-bound), advise lactating women not to breastfeed during treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and for two weeks after the last dose.

    Data

    Animal Data

    Following intravenous administration of radiolabeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations.

    8.3 Females and Males of Reproductive Potential

    Based on animal studies and mechanism of action, paclitaxel protein-bound particles for injectable suspension (albumin-bound) can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

    Pregnancy Testing

    Verify the pregnancy status of females of reproductive potential prior to starting treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound).

    Contraception

    Females

    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).

    Males

    Based on findings in genetic toxicity and animal reproduction studies, advise males 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)and Nonclinical Toxicology (13.1)].

    Infertility

    Females and Males

    Based on findings in animals, paclitaxel protein-bound particles for injectable suspension (albumin-bound) may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)] .

    8.4 Pediatric Use

    Safety and effectiveness in pediatric patients have not been established. Pharmacokinetics, safety, and antitumor activity of paclitaxel protein-bound particles for injectable suspension (albumin-bound) were assessed in an open-label, dose escalation, dose expansion study ( NCT01962103) in 96 pediatric patients aged 1.4 to < 17 years with recurrent or refractory pediatric solid tumors. The maximum tolerated dose (MTD) normalized for body surface area (BSA) was lower in pediatric patients compared to adults. No new safety signals were observed in pediatric patients across these studies.

    Paclitaxel protein-bound exposures normalized by dose were higher in 96 pediatric patients (aged 1.4 to < 17 years) as compared to those in adults.

    8.5 Geriatric Use

    Of the 229 patients in the randomized study who received paclitaxel protein-bound particles for injectable suspension (albumin-bound) for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. This study of paclitaxel protein-bound particles for injectable suspension (albumin-bound) did not include a sufficient number of patients with metastatic breast cancer who were 65 years and older to determine whether they respond differently from younger patients.

    A subsequent pooled analysis was conducted in 981 patients receiving paclitaxel protein-bound particles for injectable suspension (albumin-bound) monotherapy for metastatic breast cancer, of which 15% were 65 years of age or older and 2% were 75 years of age or older. A higher incidence of epistaxis, diarrhea, dehydration, fatigue, and peripheral edema was found in patients 65 years of age or older.

    Of the 514 patients in the randomized study who received paclitaxel protein-bound particles for injectable suspension (albumin-bound) and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old.

    Of the 431 patients in the randomized study who received paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of paclitaxel protein-bound particles for injectable suspension (albumin-bound) did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients.

    8.6 Renal Impairment

    No adjustment of the starting paclitaxel protein-bound particles for injectable suspension (albumin-bound) dose is required for patients with mild to moderate renal impairment (estimated creatinine clearance 30 to <90 mL/min) [see Clinical Pharmacology (12.3)]. There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 mL/min).

    8.7 Hepatic Impairment

    No adjustment of the starting paclitaxel protein-bound particles for injectable suspension (albumin-bound) dose is required for patients with mild hepatic impairment (total bilirubin > ULN and ≤ 1.5 x ULN and aspartate aminotransferase [AST] ≤ 10 x ULN). Reduce paclitaxel protein-bound particles for injectable suspension (albumin-bound) starting dose in patients with moderate to severe hepatic impairment [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)] . Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is not recommended for use in patients with total bilirubin > 5 x ULN or AST > 10 x ULN [see Dosage and Administration (2.5), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)] . Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is not recommended for use in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment [see Dosage and Administration (2.5)].

  • 10 OVERDOSAGE

    There is no known antidote for paclitaxel protein-bound particles for injectable suspension (albumin-bound) overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

  • 11 DESCRIPTION

    Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is paclitaxel formulated as albumin-bound nanoparticles with a mean particle size of approximately 130 nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous state. Paclitaxel is a microtubule inhibitor. The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2 R,3 S)- N-benzoyl-3-phenylisoserine. The empirical formula is C 47H 51NO 14and the molecular weight is 853.92. Paclitaxel has the following structural formula:

    structure

    Paclitaxel is a white to off-white crystalline powder. It is highly lipophilic, insoluble in water, and melts at approximately 213°C to 216°C.

    Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single‑dose vial contains 100 mg of paclitaxel (bound to human albumin) and approximately 900 mg of human albumin (containing sodium caprylate and sodium acetyltryptophanate). Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel formulated as albumin‑bound particles. Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is free of solvents.

  • 12 CLINICAL PHARMACOLOGY

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is a microtubule inhibitor that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

    12.3 Pharmacokinetics

    The pharmacokinetics of total paclitaxel following 30- and 180-minute infusions of paclitaxel protein-bound particles for injectable suspension (albumin-bound) at dose levels of 80 to 375 mg/m 2(0.31 to 1.15 times the maximum approved recommended dosage) were determined in clinical studies. Dose levels of mg/m 2refer to mg of paclitaxel in paclitaxel protein-bound particles for injectable suspension (albumin-bound). Following intravenous administration of paclitaxel protein-bound particles for injectable suspension (albumin-bound) to patients with solid tumors, paclitaxel plasma concentrations declined in a biphasic manner, the initial rapid decline representing distribution to the peripheral compartment and the slower second phase representing drug elimination.

    Following paclitaxel protein-bound particles for injectable suspension (albumin-bound) infusion, paclitaxel exhibited linear drug exposure (AUC) across clinical doses ranging from 80 to 300 mg/m 2(0.31 to 1.15 times the maximum approved recommended dosage). The pharmacokinetics of paclitaxel in paclitaxel protein-bound particles for injectable suspension (albumin-bound) were independent of the duration of intravenous administration.

    The pharmacokinetic data of 260 mg/m 2 paclitaxel protein-bound particles for injectable suspension (albumin-bound) administered over a 30-minute infusion was compared to the pharmacokinetics of 175 mg/m 2paclitaxel injection over a 3-hour infusion. Clearance was larger (43%) and the volume of distribution was higher (53%) for paclitaxel protein-bound particles for injectable suspension (albumin-bound) than for paclitaxel injection. There were no differences in terminal half-lives.

    Distribution

    Following paclitaxel protein-bound particles for injectable suspension (albumin-bound) administration to patients with solid tumors, paclitaxel is evenly distributed into blood cells and plasma and is highly bound to plasma proteins (94%). The total volume of distribution is approximately 1741 L; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel.

    In a within-patient comparison study, the fraction of unbound paclitaxel in plasma was significantly higher with paclitaxel protein-bound particles for injectable suspension (albumin-bound) (6.2%) than with solvent-based paclitaxel (2.3%). This contributes to significantly higher exposure to unbound paclitaxel with paclitaxel protein-bound particles for injectable suspension (albumin-bound) compared with solvent-based paclitaxel, when the total exposure is comparable. In vitrostudies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 µg/mL, indicated that the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

    Elimination
    At the clinical dose range of 80 to 300 mg/m 2(0.31 to 1.15 times the maximum approved recommended dosage), the mean total clearance of paclitaxel ranges from 13 to 30 L/h/m 2and the mean terminal half-life ranges from 13 to 27 hours.

    Metabolism
    In vitrostudies with human liver microsomes and tissue slices showed that paclitaxel in paclitaxel protein-bound particles for injectable suspension (albumin-bound) was metabolized primarily to 6α-hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3'- p-hydroxypaclitaxel and 6α, 3'- p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivofollowing normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivoas a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4 [see Drug Interactions (7)] .

    Excretion
    After a 30-minute infusion of 260 mg/m 2doses of paclitaxel protein-bound particles for injectable suspension (albumin-bound), the mean values for cumulative urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1% of the total administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and 3'- p-hydroxypaclitaxel. Fecal excretion was approximately 20% of the total dose administered.

    Specific Populations

    No clinically meaningful differences in the pharmacokinetics of paclitaxel in paclitaxel protein-bound particles for injectable suspension (albumin-bound) were observed based on body weight (40 to 143 kg), body surface area (1.3 to 2.4 m 2), sex, race (Asian vs. White), age (24 to 85 years), type of solid tumors, mild to moderate renal impairment (creatinine clearance 30 to <90 mL/min), and mild hepatic impairment (total bilirubin >1 to ≤1.5 x ULN and AST ≤10 x ULN).

    Patients with moderate (total bilirubin >1.5 to 3 x ULN and AST ≤10 x ULN) or severe (total bilirubin >3 to 5 x ULN) hepatic impairment had a 22% to 26% decrease in the maximum elimination rate of paclitaxel and approximately 20% increase in mean paclitaxel AUC compared with patients with normal hepatic function (total bilirubin ≤ULN and AST ≤ULN) [see Dosage and Administration (2.5)and Use in Specific Populations (8.7)] .

    The effect of severe renal impairment or end stage renal disease (creatinine clearance < 30 mL/min) on the pharmacokinetics of paclitaxel in paclitaxel protein-bound particles for injectable suspension (albumin-bound) is unknown.

    Drug Interaction Studies

    Carboplatin: Administration of carboplatin immediately after the completion of the paclitaxel protein-bound particles for injectable suspension (albumin-bound) infusion to patients with NSCLC did not cause clinically meaningful changes in paclitaxel exposure. The observed mean AUC inf of free carboplatin was approximately 23% higher than the targeted value (6 min*mg/mL), but its mean half-life and clearance were consistent with those reported in the absence of paclitaxel.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    The carcinogenic potential of paclitaxel protein-bound particles for injectable suspension (albumin-bound) has not been studied.

    Paclitaxel was clastogenic in vitro(chromosome aberrations in human lymphocytes) and in vivo(micronucleus test in mice). Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.

    Administration of paclitaxel formulated as albumin-bound particles to male rats at 42 mg/m 2on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a body surface area basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A dose of 42 mg/m 2also reduced male reproductive organ weights, mating performance, and sperm production. Testicular atrophy/degeneration was observed in single-dose toxicology studies in animals administered paclitaxel formulated as albumin-bound particles at doses lower than the recommended human dose; doses were 54 mg/m 2in rodents and 175 mg/m 2in dogs. Similar testicular degeneration was seen in monkeys administered three weekly doses of 108 mg/m 2paclitaxel formulated as albumin bound particles.

    Administration of paclitaxel prior to and during mating produced impairment of fertility in male and female rats. Paclitaxel caused reduced fertility and reproductive indices, and increased embryo-fetal toxicity.

  • 14 CLINICAL STUDIES

    14 CLINICAL STUDIES

    14.1 Metastatic Breast Cancer

    Data from 106 patients accrued in two single arm open label studies and from 460 patients enrolled in a randomized comparative study were available to support the use of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in metastatic breast cancer.

    Single Arm Open Label Studies
    In one study, paclitaxel protein-bound particles for injectable suspension (albumin-bound) was administered as a 30-minute infusion at a dose of 175 mg/m 2to 43 patients with metastatic breast cancer. The second trial utilized a dose of 300 mg/m 2as a 30-minute infusion in 63 patients with metastatic breast cancer. Cycles were administered at 3-week intervals. Objective responses were observed in both studies.

    Randomized Comparative Study
    This multicenter trial was conducted in 460 patients with metastatic breast cancer. Patients were randomized to receive paclitaxel protein-bound particles for injectable suspension (albumin-bound) at a dose of 260 mg/m 2given as a 30-minute infusion, or paclitaxel injection at 175 mg/m 2given as a 3-hour infusion. Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant setting, 40% in the metastatic setting and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study drug as second or greater than second-line therapy. Seventy-seven percent of the patients had been previously exposed to anthracyclines.

    In this trial, patients in the paclitaxel protein-bound particles for injectable suspension (albumin-bound) treatment arm had a statistically significantly higher reconciled target lesion response rate (the trial primary endpoint) of 21.5% (95% CI: 16.2% to 26.7%), compared to 11.1% (95% CI: 6.9% to 15.1%) for patients in the paclitaxel injection treatment arm. See Table 11. There was no statistically significant difference in overall survival between the two study arms.

    Table 11: Efficacy Results from Randomized Metastatic Breast Cancer Trial
    aReconciled Target Lesion Response Rate (TLRR) was the prospectively defined protocol specific endpoint, based on independent radiologic assessment of tumor responses reconciled with investigator responses (which also included clinical information) for the first 6 cycles of therapy. The reconciled TLRR was lower than the investigator Reported Response Rates, which are based on all cycles of therapy.
    bFrom Cochran-Mantel-Haenszel test stratified by 1 stline vs. > 1 stline therapy.
    cPrior therapy included an anthracycline unless clinically contraindicated.
    Paclitaxel Protein-bound Particles for Injectable Suspension (albumin-bound)
    260 mg/m 2    		Paclitaxel Injectionn
    175 mg/m 2
    Reconciled Target Lesion Response Rate (primary endpoint) a
    All randomized patientsResponse Rate
    [95% CI]     		50/233 (21.5%)
    [16.19% to 26.73%]     		25/227 (11.1%)
    [6.94% to 15.09%]
    p-value b0.003
    Patients who had failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapy cResponse Rate
    [95% CI]     		20/129 (15.5%)
    [9.26% to 21.75%]     		12/143 (8.4%)
    [3.85% to 12.94%]

    14.2 Non-Small Cell Lung Cancer

    A multicenter, randomized, open-label study was conducted in 1052 chemotherapy naive patients with Stage IIIb/IV non-small cell lung cancer to compare Paclitaxel Protein-bound Particles for Injectable Suspension (albumin-bound) in combination with carboplatin to paclitaxel injection in combination with carboplatin as first-line treatment in patients with advanced non-small cell lung cancer. Paclitaxel Protein-bound Particles for Injectable Suspension (albumin-bound) was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m 2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mgmin/mL was administered intravenously on Day 1 of each 21-day cycle after completion of Paclitaxel Protein-bound Particles for Injectable Suspension (albumin-bound)/paclitaxel infusion. Treatment was administered until disease progression or development of an unacceptable toxicity. The major efficacy outcome measure was overall response rate as determined by a central independent review committee using RECIST guidelines (Version 1.0).
    In the intent-to-treat (all-randomized) population, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1, and 73% were current or former smokers. Patients received a median of 6 cycles of treatment in both study arms.
    Patients in the Paclitaxel Protein-bound Particles for Injectable Suspension (albumin-bound)/carboplatin arm had a statistically significantly higher overall response rate compared to patients in the paclitaxel injection/carboplatin arm [(33% versus 25%) see Table 12]. There was no statistically significant difference in overall survival between the two study arms.

    Table 12: Efficacy Results from Randomized Non-Small Cell Lung Cancer Trial (Intent-to-Treat Population)
    Paclitaxel Protein-bound Particles for Injectable Suspension (albumin-bound) (100 mg/m 2 weekly) + carboplatin (N=521) Paclitaxel Injection
    (200 mg/m 2 every 3 weeks) + carboplatin
    (N=531)
    Overall Response Rate (ORR)
    Confirmed complete or partial overall response, n (%)170 (33%)132 (25%)
    95% CI28.6, 36.721.2, 28.5
    P-value (Chi-Square test)0.005
    Median DoR in months (95% CI)6.9 (5.6, 8.0)6.0 (5.6, 7.1)
    Overall Response Rate by Histology
    Carcinoma/Adenocarcinoma66/254 (26%)71/264 (27%)
    Squamous Cell Carcinoma94/229 (41%)54/221 (24%)
    Large Cell Carcinoma3/9 (33%)2/13 (15%)
    Other7/29 (24%)5/33 (15%)

    14.3 Adenocarcinoma of the Pancreas

    A multicenter, multinational, randomized, open-label study was conducted in 861 patients comparing Paclitaxel protein-bound particles for injectable suspension (albumin-bound) plus gemcitabine versus gemcitabine monotherapy as first-line treatment of metastatic adenocarcinoma of the pancreas. Key eligibility criteria were Karnofsky Performance Status (KPS) ≥70, normal bilirubin level, transaminase levels ≤ 2.5 times the upper limit of normal (ULN) or ≤ 5 times the ULN for patients with liver metastasis, no prior cytotoxic chemotherapy in the adjuvant setting or for metastatic disease, no ongoing active infection requiring systemic therapy, and no history of interstitial lung disease. Patients with rapid decline in KPS (≥10%) or serum albumin (≥20%) during the 14 day screening period prior to study randomization were ineligible.
    A total of 861 patients were randomized (1:1) to the Paclitaxel protein-bound particles for injectable suspension (albumin-bound)/gemcitabine arm (N=431) or to the gemcitabine arm (N=430).
    Randomization was stratified by geographic region (Australia, Western Europe, Eastern Europe, or North America), KPS (70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no). Patients randomized to Paclitaxel protein-bound particles for injectable suspension (albumin-bound)/gemcitabine received Paclitaxel protein-bound particles for injectable suspension (albumin-bound) 125 mg/m 2 as an intravenous infusion over 30-40 minutes followed by gemcitabine 1000 mg/m2 as an intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-day cycle. Patients randomized to gemcitabine received 1000 mg/m 2 as an intravenous infusion over 30-40 minutes weekly for 7 weeks followed by a 1-week rest period in Cycle 1 then as 1000 mg/m 2 on Days 1, 8, and 15 of each subsequent 28-day cycle. Patients in both arms received treatment until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall survival (OS). Additional outcome measures were progression-free survival (PFS) and overall response rate (ORR), both assessed by independent, central, blinded radiological review using RECIST (version 1.0).
    In the intent-to-treat (all randomized) population, the median age was 63 years (range 27-88 years) with 42% ≥ 65 years of age; 58% were men; 93% were White and KPS was 90-100 in 60%. Disease characteristics included 46% of patients with 3 or more metastatic sites; 84% of patients had liver metastasis; and the location of the primary pancreatic lesion was in the head of pancreas (43%), body (31%), or tail (25%).
    Results for overall survival, progression-free survival, and overall response rate are shown in Table 13.

    Table 13: Efficacy Results from Randomized Study in Patients with Adenocarcinoma of the Pancreas (ITT Population)
    Paclitaxel Protein-bound Particles for Injectable Suspension (albumin-bound) (125 mg/m 2) and gemcitabine (N = 431) Gemcitabine
    (N = 430)
    Overall Survival
    Number of deaths, n (%)333 (77)359 (83)
    Median Overall Survival (months)8.56.7
    95% CI7.9, 9.56.0, 7.2
    HR (95% CI) a0.72 (0.62, 0.83)
    P-value b<0.0001
    Progression-free Survival c
    Death or progression, n (%)277 (64)265 (62)
    Median Progression-free Survival (months)5.53.7
    95% CI4.5, 5.93.6, 4.0
    HR (95% CI) a0.69 (0.58, 0.82)
    P-value b<0.0001
    Overall Response Rate c
    Confirmed complete or partial overall response, n (%)99 (23)31 (7)
    95% CI19.1, 27.25.0, 10.1
    P-value d<0.0001

    CI = confidence interval, HR = hazard ratio of Paclitaxel Protein-bound Particles for Injectable Suspension (albumin-bound) plus gemcitabine / gemcitabine, ITT = intent-to-treat population.
    a Stratified Cox proportional hazard model.
    b Stratified log-rank test stratified by geographic region (North America versus Others), Karnofsky performance score (70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no).
    c Based on Independent Radiological Reviewer Assessment.
    d Chi-square test.
    In exploratory analyses conducted in clinically relevant subgroups with a sufficient number of subjects, the treatment effects on overall survival were similar to that observed in the overall study population.

    04

  • 15 REFERENCES

    1. OSHA Hazardous Drugs. OSHA http://www.osha.gov/SLTC/hazardousdrugs/index.html

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is a white to yellow, sterile lyophilized powder supplied as:

    NDC: 0781-3531-91 100 mg of paclitaxel in a single-dose vial, individually packaged in a carton.

    Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light.

    Discard unused portion.

    Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the approved patient labeling (Patient Information).

    Severe Myelosuppression

    • Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their healthcare provider immediately for fever or evidence of infection [see Warnings and Precautions (5.1), (5.3)].

    Severe Neuropathy

    • Patients must be informed that sensory neuropathy occurs frequently with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and patients should advise their healthcare providers of numbness, tingling, pain, or weakness involving the extremities [see Warnings and Precautions (5.2)].

    Pneumonitis

    • Instruct patients to contact their healthcare provider immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)] .

    Severe Hypersensitivity

    • Instruct patients to contact their healthcare provider for signs of an allergic reaction, which could be severe and sometimes fatal [see Warnings and Precautions (5.5)].

    Common Adverse Reactions

    • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with paclitaxel protein-bound particles for injectable suspension (albumin-bound).
    • Instruct patients to contact their healthcare providers for persistent vomiting, diarrhea, or signs of dehydration [see Adverse Reactions (6)] .

    Embryo-Fetal Toxicity

    • Paclitaxel protein-bound particles for injectable suspension (albumin-bound) injection can cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Females of reproductive potential should use effective contraception 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 Warnings and Precautions (5.8)and Use in Specific Populations (8.1, 8.3)].
    • 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 (8.3)].

    Lactation

    • Advise patients not to breastfeed while taking paclitaxel protein-bound particles for injectable suspension (albumin-bound) and for two weeks after receiving the last dose [see Use in Specific Populations (8.2)] .

    Infertility

    • Advise males and females of reproductive potential that paclitaxel protein-bound particles for injectable suspension (albumin-bound) may impair fertility [see Use in Specific Populations (8.3)].
  • SPL UNCLASSIFIED SECTION

    Manufactured by Jiangsu Hengrui Pharmaceuticals Co., Ltd.,

    Lianyungang, Jiangsu 222069, China for

    Sandoz Inc., Princeton, NJ 08540

    Revised: May 2025

    25AUF03

  • PATIENT PACKAGE INSERT

    This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 05/2025
    Patient Information
    Paclitaxel (pak-li-TAX-el) Protein-Bound Particles for Injectable Suspension
    (Albumin-Bound)
    What is paclitaxel protein-bound particles for injectable suspension (albumin-bound)?
    Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is a prescription medicine used to treat:
    • advanced breast cancer in people who have already received certain other medicines for their cancer.
    • advanced non-small cell lung cancer (NSCLC), in combination with carboplatin in people who cannot be treated with surgery or radiation.
    • advanced pancreatic cancer, when used in combination with gemcitabine as the first medicine for advanced pancreatic cancer
    It is not known if paclitaxel protein-bound particles for injectable suspension (albumin-bound) is safe or effective in children.
    Do not receive paclitaxel protein-bound particles for injectable suspension (albumin-bound) if:
    • your white blood cell count is below 1,500 cells/ mm 3.
    • you have had a severe allergic reaction to paclitaxel protein-bound particles for injectable suspension (albumin-bound).
    Before you receive paclitaxel protein-bound particles for injectable suspension (albumin-bound), tell your healthcare provider about all of your medical conditions, including if you:
    • have liver or kidney problems.
    • had a prior allergic reaction to a taxane.
    • are pregnant or plan to become pregnant. Paclitaxel protein-bound particles for injectable suspension (albumin-bound) can harm your unborn baby.
      Females who are able to become pregnant:
      • Your healthcare provider will check to see if you are pregnant before you start treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound).
      • You should not become pregnant during your treatment and for at least six months after the last dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound).
      • You should use effective birth control (contraception) during your treatment and for at least six months after the last dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound). Talk to your healthcare provider about birth control methods you can use during this time.

      Males with a female sexual partner who can become pregnant:
      • Paclitaxel protein-bound particles for injectable suspension (albumin-bound) can harm the unborn baby of your partner.
      • You should not father a child during your treatment and for at least three months after the last dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound).
      • You should use effective birth control (contraception) during your treatment and for at least three months after the last dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound).
    • are breastfeeding or plan to breastfeed. Do not breastfeed during your treatment and for two weeks after the last dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound).
    Tell your healthcare provider about all the medicines you take,including prescription and over-the-counter medicines, vitamins, and herbal supplements.
    Know the medicines you take. Keep a list to show your healthcare provider and pharmacist when you get a new medicine.
    How will I receive paclitaxel protein-bound particles for injectable suspension (albumin-bound)?
    • Your healthcare provider will prescribe paclitaxel protein-bound particles for injectable suspension (albumin-bound) in an amount that is right for you.
    • Your healthcare provider may give you certain medicines to help prevent allergic reactions if you have had an allergic reaction to paclitaxel protein-bound particles for injectable suspension (albumin-bound) in the past.
    • Paclitaxel protein-bound particles for injectable suspension (albumin-bound) will be given to you by intravenous (IV) infusion into your vein.
    • Your healthcare provider should do blood tests regularly during treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound).
    • Your healthcare provider may stop your treatment, delay your treatment, or change your dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) if you have certain side effects.
    What are the possible side effects of paclitaxel protein-bound particles for injectable suspension (albumin-bound)?
    Paclitaxel protein-bound particles for injectable suspension (albumin-bound) may cause serious side effects, including:
    • severe decreased blood cell counts. Paclitaxel protein-bound particles for injectable suspension (albumin-bound) can cause a severe decrease in neutrophils, a type of white blood cell which helps fight infections, and blood cells called platelets which help to clot blood. Your healthcare provider will check your blood cell count during your treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound).
    • severe nerve problems (neuropathy).Tell your healthcare provider if you have numbness, tingling, pain, or weakness in your hands or feet.
    • severe infection (sepsis).If you receive paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine, infections can be severe and lead to death. Tell your healthcare provider right away if you have a fever (temperature greater than 100.4° F) or develop signs of infection.
    • lung or breathing problems.If you receive paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine, lung or breathing problems may be severe and can lead to death. Tell your healthcare provider right away if you suddenly get a dry cough that will not go away or shortness of breath.
    • severe allergic reactions.Severe allergic reactions are medical emergencies that can happen in people who receive paclitaxel protein-bound particles for injectable suspension (albumin-bound) and can lead to death. You may have an increased risk of having an allergic reaction to paclitaxel protein-bound particles for injectable suspension (albumin-bound) if you are allergic to other taxane medicines. Your healthcare provider will monitor you closely for allergic reactions during your infusion of paclitaxel protein-bound particles for injectable suspension (albumin-bound). Tell your healthcare provider right away if you get any of these signs of a serious allergic reaction: trouble breathing, sudden swelling of your face, lips, tongue, throat, or trouble swallowing, hives (raised bumps), rash, or redness all over your body.
    The most common side effects of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in people with breast cancer include:
    • hair loss
    • numbness, tingling, pain, or weakness in the hands or feet
    • tiredness
    • changes in your liver function tests
    • nausea
    • diarrhea
    • infections
    • decreased white blood cell count
    • abnormal heartbeat
    • joint and muscle pain
    • low red blood cell count (anemia). Red blood cells carry oxygen to your body tissues. Tell your healthcare provider if you feel weak, tired, or short of breath.
    The most common side effects of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in people with non-small cell lung cancer include:
    • low red blood cell count (anemia)
    • decreased platelet cell count
    • numbness, tingling, pain, or weakness in the hands or feet
    • tiredness
    • decreased white blood cell count
    • hair loss
    • nausea
    The most common side effects of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in people with pancreatic cancer include:
    • decreased white bolld cell count
    • numbness, tingling, pain, or weakness in the hands or feet
    • hair loss
    • diarrhea
    • vomiting
    • rash
    • tiredness
    • nausea
    • swelling in the hands or feet
    • fever
    • decreased appetitie
    • signs of dehydration including thirst, dry mouth, dark yellow urine, decreased urine, headache, or muscle cramps

    Tell your healthcare provider if you have vomiting, diarrhea, or signs of dehydration that does not go away. Paclitaxel protein-bound particles for injectable suspension (albumin-bound) may cause fertility problems in males and females, which may affect your ability to have a child. Talk to your healthcare provider if this is a concern for you. These are not all of the possible side effects of paclitaxel protein-bound particles for injectable suspension (albumin-bound).

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
    General information about the safe and effective use of paclitaxel protein-bound particles for injectable suspension (albumin-bound).
    Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about paclitaxel protein-bound particles for injectable suspension (albumin-bound) that is written for health professionals.
    What are the ingredients in paclitaxel protein-bound particles for injectable suspension (albumin-bound)?
    Active ingredient:paclitaxel (bound to human albumin).
    Other ingredient:human albumin (containing sodium caprylate and sodium acetyltryptophanate).

    Manufactured by Jiangsu Hengrui Pharmaceuticals Co., Ltd.,

    Lianyungang, Jiangsu 222069, China for

    Sandoz Inc., Princeton, NJ 08540
    For more information, call 1-800-525-8747.

    25AUF03

  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL - 100 mg Vial

    NDC: 0781-3531-91

    Paclitaxel protein-bound particles for injectable suspension (albumin-bound)

    vial label

  • INGREDIENTS AND APPEARANCE
    PACLITAXEL 
    paclitaxel injection, powder, lyophilized, for suspension
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0781-3531
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    PACLITAXEL (UNII: P88XT4IS4D) (PACLITAXEL - UNII:P88XT4IS4D) PACLITAXEL100 mg  in 20 mL
    Inactive Ingredients
    Ingredient NameStrength
    ALBUMIN HUMAN (UNII: ZIF514RVZR)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0781-3531-911 in 1 CARTON10/09/2024
    120 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21270010/08/2024
    Labeler - Sandoz Inc (005387188)
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