Paclitaxel Protein Bound Drug Information

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. Consider premedication in patients who have had prior hypersensitivity reactions to paclitaxel protein-bound particles for injectable suspension (albumin-bound). Administer gemcitabine immediately after paclitaxel protein-bound particles for injectable suspension (albumin-bound) on Days 1, 8, and 15 of each 28-day cycle.

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 s Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophils less than 500 cells/mm 3 for 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 2 for 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). Upon resumption of dosing, permanently reduce paclitaxel protein-bound particles for injectable suspension (albumin-bound) and carboplatin doses as outlined in Table 2. Withhold paclitaxel protein-bound particles for injectable suspension (albumin-bound) for Grade 3-4 peripheral neuropathy.

Resume paclitaxel protein-bound particles for injectable suspension (albumin-bound) and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves. Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3 Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4. Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Recommended dose modifications for other adverse reactions in patients with adenocarcinoma of the pancreas are provided in Table 5.

Preparation for Intravenous Administration Paclitaxel is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 The 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. 1. Avoid generation of foam. 6. 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 gently inverted 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.

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. Image

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 20ºC to 25ºC (68ºF to 77ºF) 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 2ºC to 8ºC (36ºF to 46ºF) 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.

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 s Hematologic Disorders Neutropenia was dose dependent and reversible. 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 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 mg•min/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.

Patients in both treatment arms received a median of 6 cycles of treatment. 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. 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: 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)/ 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)/ 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. 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. Two of 17 patients in the paclitaxel protein-bound particles for injectable suspension (albumin-bound) arm with pneumonitis died.

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.

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.

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. Use caution when concomitantly administering paclitaxel protein-bound particles for injectable suspension (albumin-bound) with inhibitors or inducers of either CYP2C8 or CYP3A4.

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. There are no available human data on paclitaxel 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 2 basis. (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 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 2 basis) 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.

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.

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is contraindicated in patients with: Baseline neutrophil counts of < 1,500 cells/mm 3 A history of severe hypersensitivity reactions to paclitaxel protein-bound particles for injectable suspension (albumin-bound). Severe hypersensitivity reactions to paclitaxel.

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.