Korea United Pharma


Full Prescribing Info
Each mL contains Paclitaxel, USP 6 mg.
Pharmacology: Pharmacodynamics: Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Pharmacokinetics: Following intravenous administration, paclitaxel exhibits a biphasic decline in plasma concentrations. The pharmacokinetics of paclitaxel were determined following 3 and 24 hour infusions at doses of 135 and 175 mg/m2. Mean terminal half-life estimates ranged from 3.0 to 52.7 hours, and mean, non-compartmentally derived, values for total body clearance ranged from 11.6 to 24.0 l/hr/m2; total body clearance appeared to decrease with higher plasma concentrations of paclitaxel. Mean steady-state volume of distribution ranged from 198 to 688 l/m2, indicating extensive extravascular distribution and/or tissue binding. With the 3-hour infusion, increasing doses result in non-linear pharmacokinetics. For the 30% increase in dose from 135 mg/m2 to 175 mg/m2, the Cmax and AUC→∞ values increased 75% and 81%, respectively.
Following an intravenous dose of 100 mg/m2 given as a 3-hour infusion to 19 KS patients, the mean Cmax was 1,530 ng/ml (range 761-2,860 ng/ml) and the mean AUC 5,619 ng.hr/ml (range 2,609-9,428 ng.hr/ml). Clearance was 20.6 l/h/m2 (range 11-38) and the volume of distribution was 291 l/m2 (range 121-638). The terminal elimination half-life averaged 23.7 hours (range 12-33).
Intrapatient variability in systemic paclitaxel exposure was minimal. There was no evidence for accumulation of paclitaxel with multiple treatment courses.
In vitro studies of binding to human serum proteins indicate that 89-98% of medicinal product is bound. The presence of cimetidine, ranitidine, dexamethasone or diphenhydramine did not affect protein binding of paclitaxel.
The disposition of paclitaxel has not been fully elucidated in humans. Mean values for cumulative urinary recovery of unchanged drug have ranged from 1.3 to 12.6% of the dose, indicating extensive non-renal clearance. Hepatic metabolism and biliary clearance may be the principal mechanism for disposition of paclitaxel. Paclitaxel appears to be metabolised primarily by cytochrome P450 enzymes. Following administration of a radiolabelled paclitaxel, an average of 26, 2 and 6% of the radioactivity was excreted in the faeces as 6α-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel, and 6α-3'-p-dihydroxy-paclitaxel, respectively. The formation of these hydroxylated metabolites is catalysed by CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4 respectively. The effect of renal or hepatic dysfunction on the disposition of paclitaxel following a 3-hour infusion has not been investigated formally. Pharmacokinetic parameters obtained from one patient undergoing haemodialysis who received a 3-hour infusion of paclitaxel 135 mg/m2 were within the range of those defined in non-dialysis patients.
In clinical trials where paclitaxel and doxorubicin were administered concomitantly, the distribution and elimination of doxorubicin and its metabolites were prolonged. Total plasma exposure to doxorubicin was 30% higher when paclitaxel immediately followed doxorubicin than when there was a 24-hour interval between medicinal product.
For use of paclitaxel in combination with other therapies, please consult the Summary of Product Characteristics of cisplatin, doxorubicin or trastuzumab for information on the use of these medicinal products.
Paclitaxel is indicated for the treatment of metastatic carcinoma of the ovary or breast, after failure of standard therapy.
Dosage/Direction for Use
All patients should be premedicated prior to paclitaxel administration in order to minimize severe hypersensitivity reaction. Such premedication may consist of dexamethasone 20 mg orally approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before paclitaxel.
Paclitaxel at a dose of 175 mg/m2 administered intravenously over 3 hours every three weeks has been shown to be effective in patients with metastatic carcinoma of the ovary or breast who have failed standard therapy. Single courses of paclitaxel should not be repeated until the neutrophil count is at least 1,500 cell/mm3 and the platelet count is at least 100,000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3) or severe peripheral neuropathy during PACLITAXEL therapy should have the dosage reduced by 20% for subsequent courses of paclitaxel. Or as prescribed by the physician.
Preparation for Intravenous Administration: Paclitaxel for Injection must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% Sodium chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, or 5% Dextrose in Ringer's Injection to a final concentration of 0.3 to 1.2 mg/mL. The solutions are physically and chemically stable for up to 27 hours at ambient temperature (15-30°C).
Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant loss in potency has been noted following simulated delivery of the solution through IV tubing containing an in-line (0.22 micron) filter.
Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl) phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC containers and administration sets is not recommended. Paclitaxel solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.
Pharmaceutical Precautions: Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP di-(2-ethylhexyl)phthalate, which may be leached from PVC infusion bags or sets, diluted paclitaxel solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.
Paclitaxel should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2 filter which incorporate short inlet and outlet PCV-coated tubing has not resulted in significant leaching of DEHP.
Paclitaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised in handling paclitaxel. The use of gloves is recommended. If paclitaxel solution comes in contact with the skin, wash the skin immediately and thoroughly with soap and water. If paclitaxel contacts mucous membranes flush thoroughly with water.
There is no known antidote for paclitaxel overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis.
Paclitaxel is contraindicated in patients who have a history of severe hypersensitivity reactions to paclitaxel or other drugs formulated in Cremophor + EL (polyethoxylated castor oil).
Paclitaxel should not be used in patients with severe baseline neutropenia (<1,500 cells/mm3).
Special Precautions
Paclitaxel should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.
Patients receiving the drug should be pretreated with corticosteroids, antihistamines, and H2 antagonists (such as dexamethasone, diphenhydramine and cimetidine or ranitidine) to minimize hypersensitivity reactions. Severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in patients receiving paclitaxel. These reactions are probably histamine mediated. One of these reactions was fatal in a patient treated without premedication in a Phase I study. Patients who experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with the drug.
Hematology: Paclitaxel should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Paclitaxel. Patients should not be retreated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (>500 cells/mm3) during a course of paclitaxel therapy, a 20% reduction in dose for subsequent courses of therapy is recommended.
Hypersensitivity Reactions: Patients with a history of severe hypersensitivity reaction to products containing Cremophor+ EL should not be treated with paclitaxel. Minor symptoms such as flushing, skin reactions, dyspnea, hypotension or tachycardia do not require interruption of therapy.
However, severe reaction, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema or generalized urticaria require immediate discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with paclitaxel.
Cardiovascular: Hypotension and bradycardia have been observed during administration of paclitaxel, but generally do not require treatment. Frequent vital sign monitoring particularly during the first hour of paclitaxel infusion, is recommended. Continuous cardiac monitoring is not required except for patients who develop serious conduction abnormalities.
Nervous System: Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of paclitaxel.
Hepatic: There is no evidence that the toxicity of paclitaxel is enhanced in patients with abnormal liver function, but no data are available for patients with severe baseline cholestasis.
Use in Pregnancy & Lactation: There are no studies in pregnant women. Paclitaxel has been shown to be embryo and feto-toxic in rabbits and to decrease fertility in rats. Paclitaxel should not be administered to nursing mothers.
Use In Pregnancy & Lactation
There are no studies in pregnant women. Paclitaxel has been shown to be embryo and feto-toxic in rabbits and to decrease fertility in rats. Paclitaxel should not be administered to nursing mothers.
Adverse Reactions
The incidences of adverse reactions in the table as follows are derived from ten clinical trials in carcinoma of the ovary and schedules of 3 or 24 hours (see table).

Click on icon to see table/diagram/image

Summary of 3 hour infusion data at dose of 175 mg/m2: Unless otherwise stated, the following safety data relate to 62 patients with ovarian cancer and 119 patients with breast cancer treated at a dose of 175 mg/m2 and a 3 hour infusion schedule, in phase III clinical trials. All patients were premedicated to minimize hypersensitivity reactions. Data from these clinical trials demonstrate that paclitaxel given at this dose and schedule is well tolerated. Myelosuppression, in particular, is less frequent and less severe than with a 24 hour infusion schedule. Moreover, as compared to a 24 hour infusion schedule, the incidence of hypersensitivity reaction, peripheral neuropathy or other significant undesirable effects was not increased when paclitaxel was administered at this dose and schedule.
None of the observed toxicities were influenced by age.
Hematologic: The most frequent significant undesirable effect of Paclitaxel was bone marrow suppression. Severe neutropenia (<500 cells/mm3) occurred in 27% of the patients, but was not associated with febrile episodes. Only 1% of the patients experienced severe neutropenia for 7 days or more.
Eighteen percent of the patients had an infectious episode. Although severe septic episodes associated with severe neutropenia attributable to Paclitaxel were reported in early clinical trials, no severe infections or septic episodes were seen at the recommended dose and infusion schedule.
Thrombocytopenia was reported in 6% of the patients. One percent of the patients had a platelet nadir count 50,000 cells/mm3 at least once while on study.
Anemia was observed in 62% of the patients, but was severe (Hb<8 g/dL) in only 6% of the patients.
Incidence and severity of anemia are related to baseline hemoglobin status.
Hypersensitivity Reactions: A significant hypersensitivity reaction (defined as hypotension requiring therapy, angioedema, respiratory distress requiring bronchodilator therapy or generalized urticaria) occurred in 2 patients. Thirty-nine percent of the patients (20% of all courses) experienced minor hypersensitivity reaction. These minor reaction, mainly flushing and rash did not require therapeutic intervention nor did they prevent continuation of Paclitaxel therapy.
Cardiovascular: Hypotension and bradycardia were experienced by 22% and 3% of the patients, respectively, and were asymptomatic in all cases.
One patient experienced transient hypertension during the second Paclitaxel cycle. In addition, 2 patients presented severe cardiovascular events (tachycardia and thrombophlebitis), but these were considered unrelated to Paclitaxel. In the same studies at a lower dose or longer infusion, 3 severe cardiovascular events (atrioventricular (AV) block, syncope and hypotension associated with coronary stenosis resulting in death) possibly related to Paclitaxel administration were reported. In early clinical studies, conducted with varying dosage and infusion schedules, 4(2%) patients experienced severe cardiovascular events possibly related to Paclitaxel which included asymptomatic ventricular tachycardia, tachycardia with bigeminy, AV block and syncope.
Neurologic: Peripheral neuropathy, mainly manifested by paresthesia, affected 64% of the patients, but was severe in only 4% of the patients. Peripheral neuropathy can occur following the first course and can worsen with increasing exposure to Paclitaxel. Sensory symptoms have usually improved or resolved within several months of Paclitaxel discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contraindication for Paclitaxel therapy.
Arthralgia/Myalgia: Arthralgia or myalgia affected 54% of the patients and was severe in 12% of the patients.
Alopecia: Alopecia was observed in almost all patients.
Gastrointestinal: Gastrointestinal side effects were usually mild to moderate: nausea/vomiting, diarrhea and mucositis were reported by 44%, 25% and 20% of the patients, respectively. Other gastrointestinal events included anorexia (25% of patients), constipation (18%) and intestinal obstruction (4%).
Hepatic: Severe elevations (>5 x normal values) in AST (SGOT), alkaline phosphatase or bilirubin were seen in 5%, 5% and 1% of patients, respectively.
Drug Interactions
In a phase 1 trial using escalating doses of paclitaxel (110-200 mg/m2) and cisplatin (50 or 75 mg/m2) given as sequential infusions, myelosuppression was more profound when paclitaxel was given after cisplatin than with the alternate sequence (i.e. paclitaxel before cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when paclitaxel was administered following cisplatin.
Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.
Store at temperatures not exceeding 25°C. Protect from light.
ATC Classification
L01CD01 - paclitaxel ; Belongs to the class of plant alkaloids and other natural products, taxanes. Used in the treatment of cancer.
Inj (colorless to pale yellow viscous liquid in vial) 150 mg/25 mL x 1's. 300 mg/50 mL x 1's.
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