Approval date: June 30, 2008
Revision date: December 10, 2009
September 29, 2010
August 03, 2011
January 28, 2013
September 22, 2013
January 15, 2014
February 03, 2015
April 14, 2016
Prescription Drugs
Paclitaxel for Injection (Albumin Bound) Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
Paclitaxel (albumin-bound) for Injection should be used under the supervision of a physician experienced in chemotherapy. Complications that occur during treatment can only be managed appropriately if there are well established diagnostic and treatment facilities.
The drug should not be administered if the patient’s peripheral blood neutrophil count is below 1500/mm3 prior to treatment. Severe neutropenia can lead to infection. To enable monitoring of patients for possible myelosuppression (mainly neutropenia), periodic peripheral blood counts are recommended for all patients treated with this product.
Note: The pharmacodynamic properties of Paclitaxel for Injection (albumin-bound) are different from those of other formulations of Paclitaxel, please do not interchange or mix this product with other formulations of Paclitaxel. Drug Name
Generic name: Paclitaxel for Injection (Albumin-bound)
English trade name: Abraxane®
English name: Paclitaxel for Injection (Albumin Bound)
Hanyu Pinyin: Zhusheyong Zishanchun (Baidanbai Jiehexing)
Ingredients
Each vial contains 100mg of paclitaxel and 900mg of human albumin. paclitaxel is the active ingredient of this product, and human albumin plays the role of dispersing, stabilizing and transporting the main drug.
The chemical name of Paclitaxel: 5β, 20-epoxy-1,2α, 4,7β,10β, 13α-hexahydroxy-paclitaxel-11-en-9-one -4,10-diacetate-2-benzoate 13-(2R,3S)-N-benzoyl-3-phenylisoserine ester.
The chemical structure formula of paclitaxel.
Molecular formula: C47H51NO14
Molecular weight: 853.91
【Properties】.
This product is white to light yellow sterile lyophilized block or powder.
Indications]
It is indicated for the treatment of metastatic breast cancer that has failed combination chemotherapy or breast cancer that has recurred within 6 months after adjuvant chemotherapy. Unless there is clinical contraindication, previous chemotherapy should include an anthracycline anticancer agent.
Specification】100mg
Dosage]
For patients with metastatic breast cancer that has failed combination chemotherapy or breast cancer that has recurred after adjuvant chemotherapy, the recommended dose is 260mg/m2 administered intravenously over 30 minutes every 3 weeks.
Abnormal liver function.
Regardless of indication, no dose adjustment is required for patients with mild hepatic abnormalities (total bilirubin greater than ULN and less than or equal to 1.5 x ULN and aspartate aminotransferase [AST] less than or equal to 10 x ULN). Use the same dose as in patients with normal liver function.
For the treatment of patients with metastatic breast cancer with moderate to severe abnormal liver function (total bilirubin >1.5 to ≤5 x ULN and AST ≤10 x ULN), a dose reduction is recommended
If the patient tolerates at least 2 subsequent courses of therapy, the reduced dose may be increased to the dose used in breast cancer patients with normal liver function.
In patients with total bilirubin > 5 x ULN or AST > 10 x ULN, ABRAXANE is contraindicated in patients regardless of indication due to lack of sufficient data.
For the adjustment of the initial dose the following table 1 is recommended.
Table 1: Recommended initial doses for patients with abnormal liver function AST (SGOT ) levels Bilirubin levels Paclitaxel for injection (albumin-bound)a Mild <10 x ULN >ULN to ≤1.5 x ULN 260 mg/m2 Moderate <10 x ULN and >1.5 to 3 x ULN 200 mg/m2b Severe <10 x ULN & gt;3 to ≤5.0×ULN200 mg/m2b >10×ULN or>5.0×ULN not recommendeda Recommended dose is for the first course only. The need for dose adjustment for subsequent courses of therapy should refer to the degree of individual tolerance.
b If the patient tolerates the lower dose for two courses, an increase in dose to 260 mg/m2 may be considered for patients with metastatic breast cancer in subsequent courses. abnormal renal function: No initial dose adjustment of ABRAXANE is required for patients with mild to moderate abnormal renal function (estimated creatinine clearance ≥30 ml/min to <90 ml/min). In patients with severe renal abnormalities or end-stage renal disease (creatinine clearance estimates <30 ml/min), there are insufficient data to recommend dosing (see [Pharmacokinetics]). In randomized controlled trials, patients with blood creatinine >2 mg/dL were excluded.
Dose reduction: If patients develop severe neutropenia (ANC<500/mm3 for 1 week or more) or severe sensory neurotoxicity during treatment, the subsequent dose should be reduced to 220 mg/m2. If severe neutropenia or severe sensory neurotoxicity occurs again as described above, the subsequent dose should be further reduced to 180 mg/m2. Patients with grade 3 sensory neurotoxicity should be suspended and treatment should not be continued until neurotoxicity has returned to ≤ grade 2, with subsequent dose reductions required for subsequent treatment.
Precautions for drug formulation and administration: This product is a cytotoxic anticancer drug and, like other potentially toxic paclitaxel-like compounds, should be handled with care and gloves are recommended for handling. In case of skin contact with this product (lyophilized powder or dissolved suspension), it should be rinsed immediately and thoroughly with soap and water. Symptoms following local contact may include stinging, burning sensation and redness. If mucous membranes come in contact with this product, they should be rinsed thoroughly with running water.
Close observation of the injection site during the intravenous drip is recommended to be alert for any possible vascular leakage. As required, the drip time should be limited to 30 minutes to minimize local reactions associated with the drip. (See [Precautions])
Pretreatment: No antiallergic pretreatment of the patient is required prior to administration of this product.
Drug preparation prior to intravenous drip: This product is a sterile lyophilized block or powder prior to dispersion and dissolution. To avoid errors, please read the following drug preparation instructions carefully prior to dispersion and dissolution.
Disperse and dissolve each vial with 20ml of 0.9% sodium chloride injection under aseptic operation.
Use a sterile syringe to slowly inject 20ml of 0.9% Sodium Chloride Injection along the inner wall of the bottle for no less than 1 minute.
Do not inject 0.9% Sodium Chloride Injection directly onto the lyophilized block/powder to avoid foam formation.
After the injection is completed, allow the vial to stand for at least 5 minutes to ensure that the lyophilized block/powder is completely saturated.
Gently shake the vial or slowly invert the vial up and down for at least 2 minutes to allow all lyophilized blocks/powder in the vial to completely disperse and dissolve to avoid foam formation.
If foam is formed, leave for 15 minutes until the foam subsides.
After dispersion and dissolution, each ml of suspension contains 5 mg of paclitaxel.
Accurately calculate the total dosing volume for each patient and slowly draw the desired dosing volume from the vial of compounded ABRAXABE suspension into the syringe.
Total dosing volume (ml) = total dose (mg) ÷ 5 (mg/ml)
The solution in the bottle after dispersion and dissolution should be a homogeneous liquid that is milky white and free of visible particles. If particulate matter can be observed then the vial should be gently inverted up and down again to ensure complete dispersion and dissolution without visible particulate matter prior to dosing. If precipitation is observed then the drug solution should be discarded.
The required amount of suspension should be accurately drawn into a new, sterile polyvinyl chloride (PVC) or non-PVC infusion bag for intravenous infusion according to the calculated volume of administration.
It is not necessary to use special di-(2-ethylhexyl) phthalate-free (DEHP) infusion devices for the preparation and drip administration of this product. The use of medical devices containing silicone oil as a lubricant (i.e. syringes and infusion bags) for re-dissolution and injection of ABRAXANE may result in protein precipitation from the drug solution.
Visually inspect the compounded ABRAXANE suspension in the IV bag prior to administration. If protein precipitation is observed, filter the reconstituted ABRAXANE suspension through a 15 μm filter. Filters with pore sizes smaller than 15 μm should not be used.
Any drug used transvascularly should be carefully inspected by the naked eye for visible particulate matter and color changes in the solution before use under conditions where the solution and container are observable.
Stability: The product is stable when stored unopened in its original packaging in the temperature range of 20°C to 30°C until the date indicated on the label. Neither freezing nor refrigeration will have an adverse effect on the stability of the product.
Stability of suspension in the bottle after dispersion and dissolution: The product should be used immediately after dispersion and dissolution, but if necessary and not used immediately, the bottle containing the suspension should be returned to the original packaging to avoid light and stored in a refrigerator at 2°C to 8°C for up to 8 hours.
Stability of the suspension in the infusion bag after dispersion and dissolution: the suspension prepared as required should be used immediately after transfer from the vial to the infusion bag. The suspension in the infusion bag can be stored for 8 hours at room temperature (20°C to 25°C) and under room light conditions.
Discard any unused solution.
[Adverse Reactions].
Due to the widely varying conditions under which clinical trials are conducted, the incidence of adverse drug reactions observed in trials cannot be directly compared with the incidence of adverse reactions seen in clinical trials of other drugs and may not reflect the incidence of adverse reactions in actual therapy.
The most common adverse reactions (≥20%) were alopecia, neutropenia, sensory neurotoxicity, ECG abnormalities, fatigue/weakness, muscle pain/arthralgia, elevated AST levels, elevated alkaline phosphatase levels, anemia, nausea, infection, and diarrhea.
Summary of safety in clinical trials
The important adverse events that occurred in randomized controlled clinical trials with this product or paclitaxel injection in patients with metastatic breast cancer in Europe, the United States and China are shown in Table 2.
Table 2: Incidence of important adverse events in randomized controlled clinical trials with every three-week dosinga
Percentage of patients Paclitaxel for injection
(Albumin-bound)
260 mg/m2 /IV 30 minb Paclitaxel injection
175mg/m2 /IV 3 hoursc,d European and American patients
(N=229) Chinese patients
(N=104) European and American patients
(N=225)Chinese patients
(N=106) Bone marrow Neutropenia
< 2.0×109/L
< 0.5×109/L
80
9
92
7
82
22
75
7 Thrombocytopenia
< 100×109/L
< 50×109/L
2
<1
21
5
3
<1
16
<1 Anemia
< 11g/dL
< 8g/dL
33
1
71
10
25
<1
57
9 infection 24520<1 neutropenia with fever2<110 bleeding2<120 allergic reactionse all 43126 severe f0020 cardiovascular system altered vital signsg bradycardia<1<1<10 hypotension 5758 severe cardiovascular events f3<140 electrocardiogram abnormal all 60ND52ND Normal baseline values 35ND30ND Respiratory Cough 7262 dyspnea 1229<1 sensory neuropathy Any symptom 71765674 severe symptom f10726 muscle pain/arthralgia Any symptom 44494947 severe symptom f8242 weakness Any symptom 47173922 severe symptom f8<132 fluid retention Any symptom 1008<1 severe symptoms f00<10 gastrointestinal nausea any symptom 30232219 severe symptoms f30<1<1 vomiting any symptom 18141013 severe symptoms f401<1 diarrhea any symptom 27151515 severe symptoms f<1<110 mucositis any symptom 7865 severe symptoms f <1<100 alopecia 90769481 rash any symptom 82668 severe symptom f0001 pruritus 62139 abnormal liver function (those with normal baseline) elevated bilirubin 7378 elevated alkaline phosphatase 36123114 elevated AST (SGOT) 39243221 injection site reaction<101<1a: based on worst Situation analysis
b: Paclitaxel for injection (albumin-bound) 260 mg/m2 /IV 30 min dosing
c: Paclitaxel injection 175mg/m2 /intravenous 3 hours dosing
d: Anti-allergic pretreatment in the paclitaxel injection group before administration
e: including treatment-related allergic reactions such as facial flushing, dyspnea, chest pain, hypotension, rash on the day of administration
f: Serious adverse events of at least grade 3
g: Occurring at the time of dosing
ND/No information available
Adverse events occurring in systemic systems.
Hematologic: Anemia, myelosuppression, thrombocytopenia, neutropenia, and neutropenia with fever have been reported in clinical trials of this product. Neutropenia was dose dependent and returned to normal. In a randomized controlled clinical trial in patients with metastatic breast cancer, paclitaxel (albumin-bound) was administered at a dose of 260 mg/m2 every 3 weeks in the injectable group and 175 mg/m2 every 3 weeks in the paclitaxel injection group. The incidence of neutrophil count below 500/mm3 (grade 4) was 9% in European and American patients after this product treatment, and the incidence of grade 4 neutropenia was 22% in the paclitaxel injection group after treatment. The incidence of grade 4 neutropenia was 7% in Chinese patients both after this product and after paclitaxel injection treatment.
Infections: Candida infection, injection site infection, oral Candida infection, respiratory tract infection and pneumonia were the most common infectious complications. Sepsis and neutropenic sepsis occurred in <1% of patients.
Allergic reactions: Allergic reactions have been reported in clinical trials of this product. In randomized controlled clinical trials conducted in patients in Europe and the United States, grade 1 or 2 anaphylactic reactions were reported in patients on the day of administration, manifesting as dyspnea (incidence 1%), skin flushing, hypotension, chest pain, and arrhythmia (both incidence <1%). In a randomized controlled clinical trial conducted in China, 3% of patients experienced grade 1 or 2 skin reactions on the day of administration of this product, manifesting as pruritus and rash. There is no study data on the use of this product in patients with a history of hypersensitivity to paclitaxel or human albumin.
Cardiovascular system: Arrhythmias, bradycardia, cardiac arrest, congestive heart failure, edema, left ventricular insufficiency, supraventricular tachycardia, tachycardia, flushing, hypotension, hypertension, and atrioventricular block have been reported in clinical trials. In randomized controlled clinical trials in European and American patients with metastatic breast cancer, 5% of patients experienced a decrease in blood pressure during 30 minutes of dosing,<1% experienced bradycardia. In Chinese patients 7% of patients experienced a drop in blood pressure during dosing,<1% experienced bradycardia. These changes in vital signs are usually asymptomatic and do not require either special management or discontinuation of therapy.
Serious cardiovascular adverse events potentially associated with monotherapy with this product, including myocardial ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary infarction, and hypertension, occurred in approximately 3% of patients in Europe and the United States. Cerebrovascular accidents (strokes) and transient ischemic attacks have also been reported. Chinese patients with severe cardiovascular events after treatment with this product<1%.
Pre-treatment ECG abnormalities are common in European and American patients. ECG abnormalities during treatment were usually asymptomatic, independent of the dose administered, and had no effect on treatment. ECG abnormalities were observed in 60% of all patients. Thirty-five percent of patients with normal ECGs prior to treatment developed ECG changes during treatment. The most frequently reported ECG changes were nonspecific depolarization abnormalities, sinus bradycardia, and sinus tachycardia. The occurrence of atrioventricular block has been reported rarely in clinical trials of this product as monotherapy in metastatic breast cancer.
Respiratory: Cough, dyspnea, interstitial pneumonia, pleural effusion, pulmonary embolism, pulmonary thromboembolism, and radiation pneumonia have been reported in clinical trials. In randomized controlled clinical trials of patients with metastatic breast cancer in Europe and the United States, dyspnea was reported in 12%, cough in 7%, and the occurrence of pneumothorax <1%. In randomized controlled clinical trials in Chinese patients with metastatic breast cancer, 2% of patients developed cough or dyspnea after treatment with this product.
Neurological: Sensory neuropathy and sensory peripheral neuropathy have been reported in clinical trials. The frequency of sensory neuropathy was positively correlated with the cumulative dose administered. Treatment was discontinued due to sensory neurotoxicity in 3% of all patients (7/229). Of the 24 patients (10%) who developed grade 3 peripheral sensory neurotoxicity, 14 had symptomatic improvement after 22 days (median), of which 10 patients continued treatment after dose reduction and 2 withdrew from treatment. Of the 10 patients without documented symptom improvement, 4 discontinued treatment due to sensory neuropathy.
In a randomized controlled clinical trial of metastatic breast cancer conducted in China, 76% of patients in the paclitaxel (albumin-bound) for injection group developed sensory neurotoxicity, of which 7% (7/104) were grade 3. In the control group receiving paclitaxel injection, 74% of patients developed sensory neurotoxicity, 6% of which were grade 3. The seven patients in the paclitaxel (albumin-bound) injection group who developed grade 3 sensory neurotoxicity had remission times ranging from 8 to 33 days, including one patient who withdrew from treatment due to sensory neurotoxicity and four patients who required dose reduction.
No grade 4 sensory neurotoxicity was observed in either European or American patients or in Chinese patients. Only one grade 2 motor neurotoxicity was reported in each of the two treatment groups of the controlled trial in Europe and the United States.
Eye/eye disorders and visual disturbances: Blurred vision, conjunctivitis, increased tear production, keratitis, and eye/vision disturbances were reported in clinical trials of this product. In clinical studies conducted in European and American patients, ocular/visual adverse reactions accounted for 13% of all patients (N = 366) and 1% of severe cases, with symptoms including keratitis and blurred vision, seen in patients receiving doses beyond clinical recommendations (patients at 300 mg/m2 or 375 mg/m2), and were usually reversible.
In a phase I clinical study of this product in Chinese patients, one patient receiving a dose of 350 mg/m2 developed transient grade 3 blurred/reversible vision after treatment; in a randomized controlled clinical trial in Chinese patients with metastatic breast cancer, four patients (4%) reported mild blurred vision, all with transient symptom presentation that resolved spontaneously.
Muscle pain/arthralgia: Arthralgia, musculoskeletal pain and muscle pain have been reported in clinical trials of this product. They are usually transient, appear 2 to 3 days after administration, and recover after a few days.
Skin reactions: Alopecia, generalized rash, nail changes, nail pigmentation/discoloration, and pruritus have been reported in clinical trials of this product. In randomized controlled clinical trials in Europe, the United States and China, 8% of European and American patients and 26% of Chinese patients reported rash after treatment with this product; 6% of European and American patients and 21% of Chinese patients reported pruritus. Skin symptoms most often appeared 2 to 3 days after the first few courses of drug administration and usually resolved spontaneously or required only symptomatic treatment after several days.
Liver function: Elevated alkaline phosphatase, elevated aspartate aminotransferase, and elevated bilirubin have been reported in clinical trials of this product.
Elevated GGT levels of grade 3 or 4 were reported in 14% of patients in the treatment arm of this product and in 10% of patients in the paclitaxel injection arm.
Renal function: Elevated creatinine has been reported in clinical trials of this product. Elevated creatinine was seen in 11% of European and American patients (1% were severe) after treatment with this product. Mild creatinine elevations were seen in <1% of Chinese patients following administration. Discontinuation of therapy, dose reduction, or delayed dosing due to nephrotoxicity did not occur.
Gastrointestinal: Nausea/vomiting, diarrhea, and oral mucositis have been reported in clinical trials of this product.
Other clinical events: Metabolic/nutritional adverse reactions of dehydration, fluid retention; systemic adverse reactions of malaise, chest pain, edema, fatigue, injection site reactions, drowsiness, fever and general malaise have also been reported in clinical trials of this product. About 10% of European and American patients developed edema after treatment with this product, and no severe edema was reported. No cases of edema have been reported in Chinese patients.
A follow-up analysis was conducted in 981 patients treated with Abraxane monotherapy for metastatic breast cancer, 15% of whom were ≥65 years of age and 2% ≥75 years of age. The incidence of epistaxis, diarrhea, dehydration, fatigue, and peripheral edema was higher in patients ≥65 years of age.
Postmarketing Safety Summary for this and other paclitaxel formulations
Unless otherwise stated, the following refers to adverse reactions that have occurred after the approval of this product for marketing. Because these adverse reactions were reported spontaneously and the number of populations from which they were reported is unknown, it is not possible to reliably speculate on the incidence of these adverse reactions or to determine a causal relationship with drug exposure. In some cases, severe adverse events seen when receiving paclitaxel injection may also occur in patients treated with this product.
Hematologic: Whole blood cytopenia has been reported with the administration of this product.
Allergic reactions: Severe allergic reactions have been reported following administration of this product. There is no study data on the use of this product in patients with a history of hypersensitivity to paclitaxel or human albumin.
Cardiovascular system: Congestive heart failure, left ventricular dysfunction and atrioventricular block have been reported after administration of this product. Most of these cases had previous use of cardiotoxic drugs, such as anthracyclines, or a history of underlying cardiac disease.
Respiratory: Pneumonia, interstitial pneumonia and pulmonary embolism have been reported in patients treated with this product, and radiation pneumonia has been reported in patients receiving concurrent radiotherapy. Pulmonary fibrosis has been reported during ongoing monitoring of the safety of paclitaxel injection and may be seen with treatment with this product.
Neurological: Cranial nerve palsy, vocal cord palsy, and paralytic bowel obstruction due to autonomic neuropathy have been reported.
Visual disturbances: Abnormal visual evoked potentials due to paclitaxel injection have been reported in the literature, suggesting that the drug may cause persistent damage to the optic nerve. This abnormality may also be seen with the treatment of this product.
Cystoid macular edema: Reduced visual acuity due to cystoid macular edema (CME) has been reported rarely (<1/1000 cases) in patients treated with this product as well as other paclitaxel analogues. CME should recover after cessation of treatment.
Liver function: Reports of liver necrosis and death from hepatic encephalopathy received during continuous monitoring of the safety of paclitaxel injection may likewise be seen with the treatment of this product.
Gastrointestinal: Intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis have been reported following treatment with this product. Small bowel colitis (appendicitis) due to neutropenia has been reported in patients treated with paclitaxel injection as monotherapy or in combination with chemotherapy, even when concomitantly supplemented with G-CSF.
Injection site reactions: Leakage of this product has been reported. Considering the possible leakage of the drug, it is recommended to closely observe the injection site reaction during the administration.
Severe adverse events such as phlebitis, cellulitis, skin sclerosis, epidermal peeling, necrosis and fibrosis have been reported during continuous monitoring of the safety of Paclitaxel Injection. Injection site reactions may occur during prolonged titration or may be delayed until 1 week to 10 days after administration. The reoccurrence of vascular leakage at the original injection site after changing the site of paclitaxel injection due to vascular leakage at the injection site (i.e., “relapse”) has also been reported.
Other clinical events: Patients have reported skin reactions after administration of this product, including generalized rash, papular rash, and erythema. In addition, patients have reported photosensitivity reactions, recall of radiation therapy, and painful palmoplantar erythema in some patients who had previously used capecitabine. Stevens-Johnson syndrome and toxic epidermolysis bullosa have also been reported.
Conjunctivitis and increased tear production have also been reported in the ongoing safety monitoring of paclitaxel injection.
Accidental Exposure
Accidental exposure to this product has not been reported. However, respiratory distress, chest pain, burning eye pain, sore throat, and nausea following inhalation of paclitaxel have been reported in the literature. Local exposure may cause tingling, burning sensation and local redness and swelling.
[Contraindication].
This product should not be given if the patient’s peripheral blood neutrophil count is below 1500/mm3 prior to treatment.
This product is contraindicated in patients who are hypersensitive to paclitaxel or human albumin.
[Precautions].
Hematology: Bone marrow suppression (mainly neutropenia) is dose-dependent and dose-limiting toxic. Patients should not be administered if their peripheral blood neutrophil count is below 1500/mm3 prior to treatment. To monitor patients for possible myelotoxicity during dosing, peripheral blood counts should be performed periodically. Dosing may be continued when the patient’s neutrophil count returns to >1,500/mm3 and platelet count >100,000/mm3. If severe neutropenia (below 500/mm3 for 7 days or longer) occurs during treatment, the dose administered should be reduced with subsequent therapy (see [DOSAGE AND ADMINISTRATION]).
Nervous System: Peripheral neurotoxicity may occur with the use of this product. Generally, grade 1 or 2 peripheral neurotoxicity does not require dose adjustment, while grade 3 peripheral neurotoxicity requires discontinuation of therapy until recovery to grade 2 or less, and dose reduction in subsequent therapy (see [DOSAGE AND ADMINISTRATION]).
Hepatic abnormalities: Because paclitaxel exposure and toxicity can be increased by abnormal liver function, caution should be exercised when administering this product to patients with abnormal liver function. (See [Dosage] [Precautions] and [Pharmacokinetics]).
Patients with abnormal liver function may be at increased risk of toxicity (especially the development of myelosuppression); these patients should be monitored closely to prevent the development of severe myelosuppression. ABRAXANE is not recommended for patients with total bilirubin > 5 x ULN or AST > 10 x ULN.
Severe hypersensitivity reactions: The occurrence of severe hypersensitivity reactions is rare, including very rare fatal anaphylactic events. If a patient has had a severe hypersensitivity reaction to treatment with this product, the product should not be used again.
Use in male patients: Male patients who are treated with this product are advised to use contraception during treatment.
Human Albumin: This product contains serum albumin derived from human blood. However, due to strict screening of blood donors and stringent quality control during the manufacturing process, the risk of viral infection through treatment with this product is extremely low, and the theoretical risk of infection with Creutzfeldt-Jakob syndrome (CJD) is also extremely low. No cases of viral or Creutzfeldt-Jakob disease infection have been reported so far.
Effects on driving and machine operation ability: Adverse events such as fatigue, drowsiness and discomfort may affect driving and machine operation.
[Pregnant and lactating women medication].
Use in Pregnant Women: The risk to the fetus from use during pregnancy is category D. Adequate and sufficient clinical studies have not been conducted in pregnant women. The use of this product in pregnant women may cause serious damage to the fetus. The potential risk to the fetus should be weighed against the potential risk to the fetus if this product is used by a pregnant woman or if the patient becomes pregnant while taking the drug. Patients should be advised to avoid pregnancy if they are of childbearing age and receiving this product.
In a study of reproductive developmental toxicity in rats, female rats receiving 6 mg/m2 (2% of the maximum recommended human dose) on days 7-17 of conception experienced embryo-fetal toxicity, including intrauterine death, increased embryo uptake (up to 5-fold), decreased litter size/surviving litters in females, and reduced, malformed, or mutated litter weight. Fetal malformations include soft tissue and skeletal abnormalities such as protruding eyes, retinal folds, small eye fissures, and dilated ventricles. Soft tissue and skeletal abnormalities have also been observed in fetuses of pregnant rats receiving 3 mg/m2 (1% of the maximum recommended human dose).
Lactating women: It is not known whether paclitaxel is secreted into human milk. Paclitaxel and/or its metabolites can be secreted into rat milk. Because many drugs can be secreted into human milk, there is a potential risk of serious adverse reactions in infants, so women treated with this product should choose to stop breastfeeding or discontinue the drug.
Pediatric Use]
There is no information on the safety and efficacy of this product in pediatric patients.
Geriatric use]
In a multicenter randomized controlled clinical study in Europe and the United States, 13% of the 229 patients in the paclitaxel (albumin-bound) for injection group were older than 65 years of age and 2% were older than 75 years of age<2%; in a multicenter randomized controlled clinical study in China, 7% of the 104 patients in the paclitaxel (albumin-bound) for injection group were older than 65 years of age. There was no increase in the frequency of toxic reactions in elderly patients treated with this product.
[Drug Interactions].
No drug interaction studies have been conducted with this product.
Paclitaxel is metabolized by cytochrome CYP2C8 and CYP3A4. Because no drug interaction studies have been performed, caution should be exercised when combining paclitaxel with known cytochrome CYP2C8 and CYP3A4 inhibitors (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibezil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or inducers (e.g., rifampin, carbamazepine, phenytoin, efavirenz, nevirapine). Caution should be exercised when used in combination (see [Pharmacokinetics]).
Drug overdose
The main predictable complications of overdose include bone marrow suppression, peripheral neuropathy and mucositis.
Clinical trials
Metastatic breast cancer
Single-arm, open phase II clinical studies: Two phase II clinical trials were conducted with this product administered intravenously over 30 minutes and every 3 weeks. The two trials were similar in design, but the doses administered were different, with 43 cases in the 175 mg/m2 group and 63 cases in the 300 mg/m2 group, and objective efficacy was observed in both trials.
Randomized controlled clinical trials: Two randomized controlled clinical studies with paclitaxel injection were conducted, one in multiple countries in Europe and the United States, with a total of 460 patients with metastatic breast cancer participating in the study. The other was conducted in China, with a total of 210 patients with metastatic breast cancer enrolled. Patients were randomly assigned to either the paclitaxel (albumin-bound) for injection group, 260 mg/m2, 30-minute drip, administered every 3 weeks, or the paclitaxel injection group, 175 mg/m2, 3-hour drip, administered every 3 weeks. At the time of patient enrollment, 64% of European and American patients and 47% of Chinese patients had abnormal physical status scores (ECOG = 1 or 2); 79% of European and American patients and 70% of Chinese patients had organ metastases; 76% of European and American patients and 61% of Chinese patients had more than 3 metastases; 14% of European and American patients and 17% of Chinese patients had not received chemotherapy; 27% of European and American patients and 64% of Chinese patients had received adjuvant chemotherapy The study drug was used as first-line treatment for metastatic breast cancer in 42% of European, American and 59% of Chinese patients; 59% of European, American and 41% of Chinese patients used the study drug as first-line treatment or more; and 77% of European, American and 58% of Chinese patients had used an anthracycline anticancer drug.
In these two randomized controlled clinical studies, the confirmed remission rate of target lesions (the main efficacy index of the trial) was 21.5% (95% confidence interval: 16.2%-26.7%) in the paclitaxel (albumin-bound) group and 11.1% (95% confidence interval: 6.9%-15.1%) in the paclitaxel injection group in Europe and the United States; the remission rate in the paclitaxel (albumin-bound) group in Chinese patients was 11.1% (95% confidence interval: 6.9%-15.1%). The remission rate was 54% (95% confidence interval: 44.3%-63.4%) in the Chinese patients in the paclitaxel (albumin-bound) group and 29% (95% confidence interval: 20.6%-37.9%) in the paclitaxel injection group. The comparison of patient outcomes between the two studies is shown in Table 3. The difference in overall survival data between the two trial groups in the European and American patient trials was not statistically significant. No data on overall survival were available for the Chinese patient trial.
Table 3: Comparison of efficacy in multicenter randomized controlled clinical trials
Paclitaxel for Injection
(albumin-bound)
(260 mg/m2) Paclitaxel injection
(175 mg/m2) Confirmed efficacy data for European and American patientsa All-case remission rate
95% confidence interval50/233 (21.5%)16.19%, 26.73%25/227 (11.1%)6.94%, 15.09%P valueb0.003 chemotherapy failure or after adjuvant chemotherapy
Cases with relapse at 6 monthsc Remission rate
95% confidence interval 20/129 (15.5%) 9.26%, 21.75% 12/143 (8.4%) 3.85%, 12.94% Confirmed efficacy data for Chinese patientsd All-case remission rate
95% confidence interval56/104 (54%) 44.3%, 63.4%31/106 (29%) 20.6%, 37.9%P valueb<0.001 Primary patients
(study drug as first-line treatment) Remission rate
95% confidence interval 34/61 (56%) 43.3%, 68.2% 17/64 (27%) 15.7%, 37.4% Retreatment patients
（Remission rate (study drug as first-line treatment or higher)
95% confidence interval22/43 (51%) 36.2%, 66.1%14/42 (33%) 19.1%, 47.6%a Target lesion remission rate (TLRR) confirmed after 6 courses of treatment was independently assessed by radiologic laboratory physicians according to clinical protocol provisions. The TLRR diagnosed by an independent radiology laboratory was lower than the remission rate reported by the investigator because the latter was based on the efficacy judgment made after the patient had received the full course of treatment.
b Using the Cochran-Mantel-Haenszel test, patients were stratified by first-line or more than first-line treatment
c Unless clinically contraindicated, previous chemotherapy should have included an anthracycline antitumor agent
d Clinical investigators combined with diagnostic radiologists’ diagnostic results
Pharmacology and Toxicology
It is an anti-microtubule drug that promotes microtubule aggregation in microtubule protein dimers and inhibits microtubule depolymerization to stabilize the microtubule system. This stabilizing effect can interfere with the normal kinetic rearrangement of microtubule bundles, thus blocking the critical interphase and mitotic processes. Paclitaxel induces abnormal arrangement or “clustering” of microtubules throughout the cell cycle and induces multiple stellate formation of microtubules during mitosis.
The potential carcinogenic effect of this product has not been studied. In vitro studies have shown that paclitaxel can cause chromosomal aberrations in human lymphocytes, and in vivo studies have shown that it can cause abnormal micronucleus assays in mice; Ames assay or CHO/HGPRT gene mutation assay showed no mutagenic effect.
In male rats given 42 mg/m2 per week (16% of the maximum recommended human dose in body surface area) for 11 weeks prior to mating with unadministered females, a decrease in male fertility was observed, as evidenced by a decrease in conception rate and an increase in the number of miscarriages in mated females. In a single dose toxicology test, testicular atrophy/degeneration was observed in rodents (54 mg/m2) and dogs (175 mg/m2) after administration of this product at a dose lower than the recommended human dose, respectively.
Pharmacokinetics]
Absorption
The clinical pharmacokinetic study showed that the plasma paclitaxel concentration decreased biphasically after 30 and 180 minutes of intravenous dosing in the dose range of 80 mg/m2 to 375 mg/m2 (the dose level expressed in mg/m2 is the amount of paclitaxel in this product), with the initial rapid decrease representing the rapid distribution of the drug into the peripheral compartment and the later slow decrease representing the clearance of the drug.
In the dose range of 80 mg/m2 to 300 mg/m2, the area under the curve (AUC) increased proportionally to the dose administered, but not to the duration of intravenous administration. The mean volume of distribution was 632 L/m2 (European and American patients) and 662.1 L/m2 (Chinese patients); this large volume of distribution indicates extensive extravascular distribution and/or binding of paclitaxel to tissues.
Pharmacokinetic data from a 30-minute intravenous dosing study with 260 mg/m2 of paclitaxel compared with a 3-hour intravenous dosing study with 175 mg/m2 of paclitaxel showed a higher total clearance of 43% (European and American patients) and 56% (Chinese patients) and a higher volume of distribution of 53% (European and American patients) and 112% (Chinese patients) compared with paclitaxel injection. The differences in peak blood concentrations and dose corrected peak blood concentrations were mainly due to the different doses and titration rates used for the two drugs. There was no significant difference in the terminal half-life between the two drugs.
Distribution
After administration of ABRAXANE in patients with solid tumors, paclitaxel was uniformly distributed in blood cells and plasma and was highly bound to plasma proteins (94%). A patient’s own comparative study showed that the proportion of unbound paclitaxel in plasma was significantly higher in patients after ABRAXANE administration (6.2%) than in the solution form of paclitaxel (2.3%). The reason for this phenomenon is that ABRAXANE has significantly more unbound paclitaxel compared to solution-based paclitaxel when the overall dose administered is comparable. In vitro experiments on the binding of human serum proteins to paclitaxel showed that cimetidine, ranitidine, dexamethasone or diphenhydramine did not affect paclitaxel binding to serum proteins at paclitaxel concentrations of 0.1 to 50 µg/ml. A population-based pharmacokinetic analysis showed a total volume of distribution of approximately 1741 L; the large volume of distribution suggests extensive extravascular distribution and/or tissue binding of paclitaxel.
Metabolism
In vitro experiments with human liver microsomes and tissue sections showed that paclitaxel was metabolized mainly by CYP2C8 to 6α-hydroxypaclitaxel and to a lesser extent by CYP3A4 to 3′-p-hydroxypaclitaxel and 6α-, 3′-p-bis-hydroxypaclitaxel. In vitro, metabolism of paclitaxel to 6α-hydroxypaclitaxel can be inhibited by certain drugs, such as ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporine, teniposide, etoposide, and vincristine, but the drug concentrations required to produce this inhibition need to exceed those found in vivo at normal therapeutic doses. Testosterone, 17α-ethinylestradiol, retinoic acid, and quercetin (a CYP2C8-specific inhibitor), also inhibit the formation of 6α-hydroxypaclitaxel in vitro. In vivo, certain substrates, inducers or inhibitors of CYP2C8 and/or CYP3A4 can also alter the pharmacokinetic parameters of paclitaxel.
The mean overall clearance of paclitaxel ranges from 13 L/h/m2 to 30 L/h/m2 over a clinical dose range of 80 mg/m2 to 300 mg/m2, with a mean terminal phase half-life of 13 hours to 27 hours.
Excretion
A 30-minute dose of 260 mg/m2 of this product resulted in 4% of the prototype paclitaxel recovered in cumulative urine, indicating that renal clearance is not the primary route of drug excretion. Less than 1% of the total dose administered was excreted via urine as metabolites, the metabolites of which were 6α-hydroxypaclitaxel and 3′-p-hydroxypaclitaxel. The fecal excretion of paclitaxel accounts for approximately 20% of the total administered dose.
Effect of abnormal liver function
The effect of abnormal liver function on the pharmacokinetics of paclitaxel after ABRAXANE administration was examined in patients with advanced solid tumors. The results of the study showed that mild abnormalities of liver function (total bilirubin>1×ULN to ≤1.5×ULN, AST ≤10×ULN, n=8) had no clinically significant effect on paclitaxel pharmacokinetics. The maximum elimination rate of paclitaxel in patients with moderate (total bilirubin>1.5×ULN to ≤3×ULN, AST ≤10×ULN, n=7) or severe (total bilirubin>3×ULN to ≤5×ULN, n=5) hepatic abnormalities was decreased by 22% to 26% compared to patients with normal liver function (total bilirubin ≤ULN, AST ≤ULN, n=130). The mean paclitaxel AUC was increased by approximately 20%. See [Dosage].
Elimination of paclitaxel was negatively correlated with total bilirubin and positively correlated with serum albumin. Pharmacokinetic/pharmacodynamic modeling suggests no association between liver function (as measured by baseline albumin or total bilirubin levels) and neutropenia after correction for ABRAXANE exposure. See [DOSAGE].
Effect of Renal Insufficiency
The effect of pre-existing mild (creatinine clearance ≥60 to <90 ml/min, n=61) or moderate (creatinine clearance ≥30 to <60 ml/min, n=23) renal dysfunction on the pharmacokinetics of paclitaxel was examined in patients with advanced solid tumors following ABRAXANE administration. There was no clinically significant effect of mild to moderate renal abnormalities on the maximum clearance and systemic exposure (AUC and Cmax) of paclitaxel.
There are insufficient data on the pharmacokinetics in patients with severe renal abnormalities, and no data are available for patients with end-stage renal disease.
Pharmacokinetics in Elderly Patients
The pharmacokinetics of ABRAXANE in humans aged 24-85 years were analyzed and showed that age did not significantly affect the maximum clearance rate and systemic exposure (AUC and Cmax) of paclitaxel.
Other intrinsic factors
Population pharmacokinetic analysis of ABRAXANE showed no clinically significant effects of body weight (40 kg to 143 kg), body surface area (1.3 m2 to 2.4 m2), sex, race (Asian vs. Caucasian), age (24 to 85 years), and solid tumor type on the maximum rate of elimination and systemic exposure (AUC and Cmax) of paclitaxel.
Storage】Store away from light at 20～30℃.
Package】In glass vials, one bottle per box.
Expiration date】36 months
Execution Standard】Imported drug registration standard JX20060230
Imported drug registration number】H20130650
【Manufacturing Company
Company Name: Celgene Corporation
Company Address: 86 Morris Ave, Summit, NJ 07901, USA (USA)
Plant Name: Fresenius Kabi USA, LLC.
Plant Address: Melrose Park, IL, 60160, USA (USA)
Domestic contact number: 021-61339333