Paxus PM

Paclitaxel.

Each vial of PAXUS PM for injection 30 mg or 100 mg includes Paclitaxel (USP) 30 mg or 100 mg.

Pharmacology: Pharmacodynamics: PAXUS PM for injection is polymeric micelle formulation of Paclitaxel. Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimmers 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. In additional, Paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Pharmacokinetics: The pharmacokinetics of total Paclitaxel following infusion of PAXUS PM over 3 hours at doses of 135, 175, 230, 300 and 390 mg/m² were determined in clinical study. The pharmacokinetic parameters of Paclitaxel from PAXUS PM studies demonstrated a low degree of variability and increased dose proportionally over the dose range tested.
The mean Paclitaxel concentration-time profiles following an infusion of PAXUS PM were characterized by a pronounced distribution phase followed by the terminal elimination phase. Within 5 to 15 minutes of the end of the infusion, Paclitaxel concentrations dropped to one-half or one-third of the peak level. With the constant­-rate infusion of PAXUS PM, maximum plasma Paclitaxel concentrations were observed between 1.45 and 3.22 hours after the start of the infusion. Mean values of Cmax of Paclitaxel ranged from 714 ng/mL (at the dose of 85 mg/mm²) to 6,567 ng/mL (at the dose of 390 mg/m² in PAXUS PM infusion).
At the recommended clinical dose of PAXUS PM, 300 mg/m², the mean maximum concentration of Paclitaxel was 3,107 ng/mL, which is a little lower than the value reported for the patients received 3-hour infusion of Paclitaxel 175 mg/m². Mean values of the Paclitaxel half-life after the administration of PAXUS PM ranged from 11.0 to 17.9 hours which were consistent with the values reported in the product label for Paclitaxel (13.1 hours for 135 mg/m² and 20.2 hours for 175 mg/mm²).
Mean values of the total area under the curve (AUC_inf) ranged from 2,790 to 27,491 ng-hr/mL in the dose range tested. Considering the mean AUC values, greater systemic exposures were inferred after Paclitaxel infusion than after comparable dosing regimens of PAXUS PM. At 175 mg/m² dose levels, the AUC values obtained after Paclitaxel infusion were 2.6 times greater than that obtained after PAXUS PM infusion. The mean values of total systemic clearance of Paclitaxel following 3-hour infusions of PAXUS PM were 12.1-33.3 l/hr/m. The mean V_d of Paclitaxel in the terminal elimination phase following PAXUS PM infusion ranged from 328 to 897 l/m², which is significantly greater than the V_d of Paclitaxel estimated in Paclitaxel infusion (67 to 182 l/m²: calculated from the mean values of CL and T_½ reported), suggesting that the PAXUS PM formulation produces greater distribution to the periphery compared to Paclitaxel.
No drug interaction studies have been conducted with PAXUS PM. However, it is known that the metabolism of Paclitaxel is catalyzed by CYP2C8 and CYP3A4. Thus, caution should be exercised when administering PAXUS PM concomitantly with known substrates or inhibitors of CYP2C8 and CYP3A4. Potential interactions between Paclitaxel, a substrate of CYP3A4 and protease inhibitors (such as Ritonavir, Saquinavir, lndinavir, and Nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials.

First-line treatment of metastatic or recurrent breast cancer.
First-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC).

Breast Cancer: The recommend regimen for PAXUS PM is 300 mg/m² administered by intravenous infusion over 3 hours every 3 weeks.
Premedication: PAXUS PM therapy does not require premedication to prevent hypersensitivity reactions. However, premedication may be given approximately 30 minutes prior to PAXUS PM administration, depending on the judgment of physicians in order to minimize the possibility of severe hypersensitivity reactions. Such premedication may consist of hydrocortisone 100 mg IV (or its equivalent), pheniramine maleate 45.5 mg IV (or its equivalent), and cimetidine 300 mg or ranitidine 300 mg or ranitidine 50 mg IV (or its equivalent).
Dose Adjustment: Dose can be reduced to Level-2 based upon the degree of toxicities experienced by patients who receive PAXUS PM therapy. If patients are not tolerant at a reduced dose of Level-2, discontinuation of this drug should be considered. (See Table 1.)

Click on icon to see table/diagram/image

First dose adjustment (240 mg/m²): For patients who experience febrile neutropenia or who experience severe neutropenia (<500 cells/mm³) or thrombocytopenia (<50,000 cells/mm³) for more than one week, dose reduction to Level-1 should be considered. For patients with Grade 3 neurological toxicities, dose reduction to the Level-1 should be considered. For patients with Grade 4 neurological toxicities, discontinuation of this drug should be considered.
Second dose adjustment (190 mg/m²): If patients experience the recurrence of above toxicities after administration of Level-1 dose, additional dose reduction should be made to Level-2. For Grade 3/4 non-hematologic toxicities (except nausea, vomiting, and alopecia), the administration of this drug should be held till the recovery for up to 3 weeks, otherwise dose reduction or discontinuation of this drug should be considered. For Grade 1 or more increase/decrease in body weight, dosage may be recalculated based upon body surface and adjusted in the range of ±5 mg of recalculated dose.
After discontinuation of this drug due to hypersensitivity reactions, the therapy can be resumed by the judgment of physician. At resumption, patients should receive premedication and the same dosage of PAXUS PM as the previous therapy before discontinuation (the reduced dose in case of a dose reduction due to toxicities). When this resumption shows a tolerable result, premedication can be given afterwards.
Non-small Cell Lung Cancer: PAXUS PM is administered by intravenous infusion over 3 hours according to the following dose instructions, followed by cisplatin 60 mg/m² intravenous infusion every 3 weeks.
Premedication: All patients should be premedicated approximately 30 minutes prior to PAXUS PM administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of hydrocortisone 100 mg IV (or its equivalent), pheniramine maleate 45.5 mg IV (or its equivalent), and cimetidine 300 mg or ranitidine 50 mg IV (or its equivalent). Ondansetron 8 mg IV (or its equivalent) may be administered as prophylactic anti-emetics prior to cisplatin administration.
Dose Adjustment: The recommended initial dose of PAXUS PM is 230 mg/m². Dose adjustment for the subsequent courses PAXUS PM should be decided with consideration of dose increase/reduction conditions according to the following table. For patients with toxicities corresponding to dose reduction conditions, dose should be reduced to the Level -1, and -2. For patients who are not tolerant to the lowest dose level (Level-2, 145 mg/m²), discontinuation of this drug should be considered. (See Table 2.)

Click on icon to see table/diagram/image

Dose can be increased when all of the following conditions are fulfilled after the first administration of drug: In hematological analysis at the first and second week of the first cycle, absolute neutrophil count = 1.0 x 10⁹/L and thrombocyte count = 100 x 10⁹/L.
In hematological analysis prior to subsequent cycles of PAXUS PM, recovery of hematogenetic function, absolute neutrophil count = 1.0 x 10⁹/L and thrombocyte count 100 x 10⁹/L .
Dose can be increased in Grade 2 or lower non-hematological toxicities, but should be maintained in Grade 2 non-hematological toxicities related to this drug (in Grade 1, 2 or 3 nausea, vomiting, alopecia, myalgia and arthralgia, dose can be increased).
Dose should be reduced when one of the following conditions is observed after each cycle: In febrile neutropenia, severe neutropenia (<500 cells/mm³) or thrombocytopenia (<50,000 cells/mm³) more than one week, dose should be reduced to a lower dose level.
In Grade 2 neurological toxicities, dose should be reduced to a lower level. In Grade 3 or higher neurological toxicities, discontinuation of therapy should be considered.
In Grade 2 hepatic toxicities related abnormal bilirubin or ALP, SGOT, and SGPT, dose should be reduced to a lower dose level, in Grade 3 hepatic toxicities related abnormal bilirubin or ALP, SGOT, and SGPT elevations and discontinuation of therapy should be considered.
In order non-hematological toxicities, dose should be reduced to a lower dose level at Grade 2 and discontinuation of therapy should be considered at Grade 4 (except nausea, vomiting, alopecia, myalgia, and arthralgia). Once dose is reduced due to toxicities, the dose should not be increased (except the recovery of liver function).
Preparation of Solution for Infusion: Preparation of Pre-Mix Solution (Paclitaxel 6 mg/mL): PAXUS PM should be reconstituted by injection 5 ml of 0.9% Sodium Chloride Injection to each vial of PAXUS PM with aseptic syringe and a needle and swirling gently to dissolve.
The reconstituted solution is a colorless to bluish solution. If foaming are visible due to a solubilizing ingredient of drug, it is recommended to wait the disappearance of foaming up to 5 minutes and use it at once, but not required to wait until the complete disappearance of forming.
Preparation of Solution for Infusion: The reconstituted solution should be taken with a calibrated syringe and diluted with 0.9% Sodium Chloride Injection or 5% Dextrose injection to a final concentration of 0.6-3.0 mg/mL and swirled gently for complete mixing. It should be inspected visually prior to administration. If particular matters are observed, discard the solution.
The physical and chemical stability of the solution for infusion is as follows; See Table 3.

Click on icon to see table/diagram/image

PAXUS PM should not be administered to patients who have a history of severe hypersensitivity reactions to paclitaxel.
PAXUS PM should not be used in patients with severe myelosuppression (baseline neutrophil counts <1,500 cells/mm³). (Myelosuppression is a dose-limiting toxicity and may accompany infection and become severe.)
PAXUS PM should not be used in patients who accompany infection. (Infection may be worsen by myelosuppression.)
PAXUS PM should not be used in pregnant women or child-bearing potential women.

PAXUS PM should be administered under the supervision of a physician with experiences of the use of chemotherapeutic agents.
PAXUS PM must be administered as a diluted solution.
Severe hypersensitivity reactions characterized by anaphylaxis, dyspnea, hypotension requiring treatment, angioedema, and generalized urticaria were observed in 4.9% of patients in clinical study for breast cancer. If severe hypersensitivity reactions occur, the discontinuation of drug and the following treatment should be given; IV infusion of pheniramine maleate 45.5 mg (or its equivalent).
Administration of epinephrine or its equivalent until the resolution of hypersensitivity reactions or total 6 doses, IV administration at hypotension which does not respond to epinephrine or its equivalent.
Spray of albuterol or its equivalent at stridor which does not respond to adrenaline or its equivalent.
Infusion of methylprednisolone 125 mg or its equivalent to prevent recurrent or advanced allergy.
When premedication is determined to be necessary to minimize the risk of severe hypersensitivity reactions in breast cancer, premedication may be given approximately 30 minutes prior to therapy, including hydrocortisone 100 mg IV (or its equivalent), pheniramine maleate 45.5 mg IV (or its equivalent) and cimetidine 300 mg or ranitidine 50 mg IV (or its equivalent).
PAXUS PM should not be administered to patients with baseline neutrophil counts of less than 1500 cells/mm³. Bone marrow suppression (primarily neutropenia) is a dose-dependent and a dose-limiting toxicity. Frequent monitoring of blood counts should be instituted during PAXUS PM treatment. Patients should not be re-treated with subsequent cycles of PAXUS PM until neutrophil counts recover to a level > 1500 cells/mm³ and platelet counts recover to a level >100,000 cells/mm³.

PAXUS PM should be given carefully in the following patients; Patients with myelosuppression. (The risk of myelosuppression may be increased.)
Patients with liver dysfunction. (As metabolism function may be decreased, severe adverse reactions may occur.)
Patients with renal dysfunction. (As renal dysfunction may be decreased, severe adverse events may occur.)
Patients with interstitial pneumonia or pulmonary fibrosis. (The risk of symptoms may be increased.)
General Precautions: The efficacy of PAXUS PM is based on the response rates of metastatic or recurrent breast cancer study and locally advanced or metastatic NSCLC study. No controlled randomized trial was reported proving clinical benefits such extension of the duration of overall survival.
As adverse events may occur even at the beginning or low-dose administration, patients should be fully aware of precautions.
Hematology: PAXUS PM therapy should not be administered to patients with baseline neutrophil counts less than 1,500 cells/mm³. In order to monitor the occurrence of myelotoxicity, it is recommended to check frequent peripheral blood cell counts for all patients receiving PAXUS PM. Patients should not be rechallenged with subsequent cycles of PAXUS PM until the recovery of neutrophils to a level of 1,500 cells/mm³ and platelets to a level of 100,000 cells/mm³. When severe neutropenia (<500 cells/mm³) occurs during PAXUS PM therapy, dose reduction by 20% is recommended for subsequent courses.
Hypersensitivity reactions: Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. However, severe reactions such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of PAXUS PM and aggressive symptomatic therapy, patients who have developed severe hypersensitivity reactions should not be rechallenged with drug.
Nervous system: Peripheral neuropathy was frequently observed, but was hardly developed to severe symptom. In moderate or severe toxicities, dose should be reduced by 20% for subsequent courses.
Hepatic system: Caution should be taken and dose reduction should be considered in patients with moderate or severe hepatic dysfunction.
Injection site reaction: Injection site reactions including extravasation were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of PAXUS PM at a different site (i.e., RECALL) has been reported rarely. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.
Use in Children: The safety in premature infant, newborn infant, infant, toddler, or pediatric patients has not been established.
Use in the Elderly: As decreased physiologic function and frequent myelosuppression is frequent in geriatric patients, dose and dosing interval should be careful and laboratory tests (e.g. blood test, hepatic function test, renal function test) should be frequently performed.

Pregnancy: Paclitaxel may cause fetal harm when administered to pregnant woman. Paclitaxel has been shown to be embryo- and feto-toxic in rabbits and to decrease fertility in rats. No study involving paclitaxel therapy in pregnant women has been reported. Women of childbearing potential should be advised to avoid becoming pregnant.
Nursing mother: Paclitaxel should not be administered to nursing mothers and nursing should be discontinued during the therapy.

Adverse Events from Single Therapy in Breast Cancer: Adverse events in the following table are based on the experience of clinical study in 41 patients with metastatic breast cancer who received single therapy of PAXUS PM at an initial dose of 300 mg/m² over 3 hours. (See Table 4.)

Click on icon to see table/diagram/image

Adverse Events from First-line treatment for NSCLC combination therapy: The incidence rate of adverse events in the following table are based on the experienced of 69 patients with NSCLC enrolled in a phase II clinical study who received PAXUS PM in combination with cisplatin.
All 69 patients, who were enrolled in a phase II study and received PAXUS PM, experienced more than one adverse events. Gastrointestinal toxicities and dermatology/skin toxicities were most common by 87.0% (60/69) and 87.0% (60/69) among adverse events experienced by body system, followed by neurological toxicities (81.2%, 56/69), blood/bone marrow toxicities (78.3%, 54/69), and musculoskeletal toxicities (71.0%, 49/69). (See Table 5.)

Click on icon to see table/diagram/image

In a Phase I trial of PAXUS PM (110-220 mg/m²) and cisplatin (50 or 75 mg/m²) given as sequential infusions, myelosuppression was more profound when cisplatin was administered before PAXUS PM than the alternate sequence (i.e., PAXUS PM administration before cisplatin). Pharmacokinetics data from these patients demonstrated a decrease in paclitaxel clearance when cisplatin was administered before PAXUS PM. Peripheral neuropathy may increase by the concurrent therapy. When the concurrent therapy is given, dose adjustment or prolonged dose interval should be considered with the observation of patients.
The metabolism of drug is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. As there are no adequate clinical studies for drug interactions, caution should be taken when PAXUS PM is administered with known substrates or inhibitors (such as ritovanir, saquinavir, indinavir, and nelfinavir) of cytochrome P450 isoenzymes CYP2C8 and CYP3A4.
The metabolism of paclitaxel may be suppressed by Vitamin A, azole antifungal agents (e.g. ketoconazole, miconazole), macrolide hormones (e.g. ethinyl estradiol), dihydropyridine calcium channel inhibitor (e.g. nifedipine), terfenadine, cyclosporine, verapamil, quinidine, midazolam, phenacetin, ritonavir, saquinavir, indinavir and nelfinavir. At concurrent administration, dose adjustment or prolonged dosing interval should be considered with the observation of patients.
At the concurrent radiotherapy to the chest, severe esophagitis or lung enteritis was reported and myelosuppression may be increased.
The concurrent therapy with other antitumor drugs may increase the risk of myelosuppression.

Preparation and Administration Precautions: PAXUS PM is a cytotoxic anticancer drug and should be treated carefully as well as other potentially toxic compounds. The use of gloves is recommended. Following topical exposure, events have included tingling, burning, and redness. If PAXUS PM solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If the drug contacts mucous membranes, the membranes should be flushed thoroughly with water, upon inhalation, dyspnea, chest pain, burning eyes, sore throat and nausea have been reported.

Store the vial in original cartons at 2-25°C and retain in the original package to protect from light.
EXPIRATION DURATION: 24 months from manufacturing date.

Cytotoxic Chemotherapy

L01CD01 - paclitaxel ; Belongs to the class of taxanes from plant alkaloids and other natural products. Used in the treatment of cancer.

S