Taxol (Paclitaxel)

TAXOL™

Bristol-Myers Squibb

Paclitaxel

Antineoplastic Agent

Caution: Paclitaxel should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.

Patients receiving paclitaxel should be pretreated with corticosteroids, antihistamines, and H 2 antagonists (such as dexamethasone, diphenhydramine and cimetidine or ranitidine) to minimize hypersensitivity reactions (see Dosage). 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.

Action and Clinical Uses:

Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization.:

In vitro, paclitaxel exhibits cytotoxic activity against a wide variety of both human and rodent tumor cell lines including leukemia, non-small cell lung carcinoma, small cell lung carcinoma, colon carcinoma, CNS carcinoma, melanoma, renal carcinoma, ovarian carcinoma and breast carcinoma.

Pharmacokinetics: The pharmacokinetics of paclitaxel have been evaluated over a wide range of doses, up to 300 mg/m

Following 3 hour infusions of 175 mg/m

Variability in systemic paclitaxel exposure, as measured by AUC 0ƒ for successive treatment courses was minimal; there was no evidence of accumulation of paclitaxel with multiple treatment courses.

The pharmacokinetics of paclitaxel have been shown to be nonlinear. There is a disproportionately large increase in C max and AUC with increasing dose, accompanied by an apparent dose-related decrease in total body clearance. These findings are most readily observed in patients in whom high plasma concentrations of paclitaxel are achieved. Saturable processes in distribution and elimination/metabolism may account for these findings.

In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 g/mL, indicated that on average 89% of drug 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. After i.v. administration of paclitaxel, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3 to 12.7% of the dose, indicating extensive nonrenal clearance. Hydroxylated metabolites isolated in bile have been demonstrated to be the principal metabolites. In 1 patient, approximately 20% of an administered dose of paclitaxel was recovered in bile as the parent compound and metabolites, in the 24-hour period following treatment. Hepatic metabolism and biliary clearance may be the principal mechanism for disposition of paclitaxel. The effect of renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated.

The effect of cimetidine premedication on the metabolism of paclitaxel has been investigated; the clearance of paclitaxel was not affected by cimetidine pretreatment.

Preliminary animal/ex vivo data indicate that ketoconazole may inhibit the metabolism of paclitaxel. Likewise, preliminary reports suggest that plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when paclitaxel and doxorubicin are used in combination. The mechanism for this interaction is unknown. The pharmacodynamic consequences of this interaction are unclear (see Precautions, Drug Interactions).

Indications And Clinical Uses :

Alone or in combination, for the treatment of carcinoma of the ovary or breast or lung.

Ovarian Carcinoma: First-line therapy in combination with other chemotherapeutic agents. Second-line treatment of metastatic carcinoma of the ovary after failure of standard therapy.

Breast Carcinoma: Second-line treatment of metastatic carcinoma of the breast after failure of standard therapy.

Lung Carcinoma: First-line treatment of advanced non-small cell lung cancer.

Contra-Indications:

In patients who have a history of severe hypersensitivity reactions to paclitaxel or other drugs formulated in Cremophor EL (polyethoxylated castor oil).

Warnings in Clinical States:

Paclitaxel should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.

Paclitaxel should be administered as a diluted infusion. Patients receiving paclitaxel should be pretreated with corticosteroids, antihistamines, and H 2 antagonists (such as dexamethasone, diphenhydramine and cimetidine or ranitidine) to minimize hypersensitivity reactions (see Dosage). Severe hypersensitivity reactions characterized by dyspnea, flushing, chest pain, tachycardia, 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. In case of a severe hypersensitivity reaction, infusion should be discontinued immediately and the patient should not be rechallenged with the drug.

Paclitaxel should not be administered to patients with baseline neutrophil counts of less than 1 500 cells/mm

Severe cardiac conduction abnormalities have been reported rarely during paclitaxel therapy. If patients develop significant conduction abnormalities during administration, appropriate therapy should be administered and continuous electrocardiographic monitoring should be performed during subsequent therapy with paclitaxel (see Adverse Effects).

Pregnancy: Paclitaxel may cause fetal harm when administered to a pregnant woman. Paclitaxel has been shown to be embryotoxic and fetotoxic in rabbits and to decrease fertility in rats. There are no studies in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with paclitaxel.

Lactation: Paclitaxel should not be administered to nursing mothers.

Precautions:

Drug Interactions: In a Phase 1 trial in which paclitaxel was administered as a 24-hour infusion and cisplatin was administered as a 1 mg/min infusion, myelosuppression was more profound when paclitaxel was given after cisplatin than with the alternate sequence (i.e., paclitaxel before cisplatin). When paclitaxel is given before cisplatin, the safety profile of paclitaxel is consistent with that reported for single-agent use. Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when paclitaxel was administered following cisplatin. Therefore, paclitaxel should be given before cisplatin when used in combination.

Preliminary animal/ex vivo data indicate that ketoconazole may inhibit the metabolism of paclitaxel; caution should be exercised when treating patients with paclitaxel if they are receiving ketoconazole.

Preliminary reports suggest that plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when paclitaxel and doxorubicin are used in combination.

Hematology: Paclitaxel should not be administered to patients with baseline neutrophil counts of less than 1 500 cells/mm

Hypersensitivity Reactions: Patients with a history of severe hypersensitivity reactions to products containing Cremophor EL should not be treated with paclitaxel (see Warnings and Contraindications). 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 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; patients are usually asymptomatic and generally do not require treatment. Frequent monitoring of vital signs, particularly during the first hour of paclitaxel infusion, is recommended. Continuous cardiac monitoring is not required except for patients who develop serious conduction abnormalities (see Warnings and Adverse Effects).

Nervous System: Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual. A dose reduction of 20% is recommended for all subsequent courses of paclitaxel for moderate to severe neuropathy (see Adverse Effects and Dosage).

Paclitaxel contains dehydrated alcohol, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol.

Hepatic: There is no evidence that the toxicity of paclitaxel is increased when given as a 3-hour infusion to patients with mildly abnormal liver function. No data are available for patients with severe baseline cholestasis (see Adverse Effects).

When paclitaxel is given as a 24-hour infusion to patients with moderate to severe hepatic impairment, increased myelosuppression may be seen as compared to patients with mildly elevated liver function tests given 24-hour infusions.

Adverse Reactions:

The incidences of adverse reactions are derived from 10 clinical trials in carcinoma of the ovary and of the breast involving 812 patients treated at doses ranging from 135 to 300 mg/mSupplied 2/day and schedules of 3 or 24 hours. In addition, toxicities that were observed in non-small cell lung carcinoma patients or were noted to have occurred with greater severity in this population are also described.

Hematologic: The most frequent significant undesirable effect of paclitaxel was bone marrow suppression.

Thrombocytopenia with platelet counts below 100 000 cells/mm

Anemia was observed in 62% of patients, but was severe (Hb<8 g/dL) in only 6% of patients. Incidence and severity of anemia are related to baseline hemoglobin status. Red cell transfusions were required in 13% of patients (6% of those with normal baseline hemoglobin levels).

When paclitaxel was administered in combination with cisplatin to patients with advanced NSCLC in the ECOG study, the incidence of neutropenia (Grade IV) was 74% (paclitaxel 135 mg/m

Hypersensitivity Reactions: Despite premedication, severe hypersensitivity reactions occurred in 1% of patients. These reactions generally occurred in early treatment courses and within the first hour of infusion. Dyspnea, flushing, chest pain and tachycardia were the most frequent manifestations.

Paclitaxel dosage or schedule had no effect on the frequency of hypersensitivity reactions. In patients who received the recommended dose of paclitaxel at the recommended schedule, 21% of courses were associated with hypersensitivity reactions. The majority of reactions were of minor significance. The most frequent manifestations were flushing (28%), rash (14%) and hypotension (3%).

Cardiovascular: During paclitaxel infusion, hypotension or bradycardia were experienced by 24% and 4% of patients, respectively. Bradycardia and hypotension did not usually occur during the same course and the majority of episodes were asymptomatic and did not require treatment.

One patient experienced transient hypertension during the second paclitaxel cycle. In addition, 2 patients presented severe cardiovascular events (tachycardia and thrombophlebitis), possibly related to paclitaxel. None of these patients required discontinuation of treatment. In the same studies at a lower dose or longer infusion, 3 severe cardiovascular events (AV block, syncope and hypotension associated with coronary stenosis resulting in death) possibly related to paclitaxel administration were reported. In the overall 812 patients experience, 10 severe cardiovascular events occurred, including cardiac rhythm disturbance and syncope (see Warnings).

Thirteen percent of patients had an abnormal ECG during the clinical trials utilizing 175 mg/m

Since the above summary, cases of myocardial infarction have been reported rarely. Congestive heart failure has been reported typically in patients who have received other chemotherapy, notably anthracyclines.

The incidence of Grade III or greater cardiovascular events was 13% (paclitaxel 135 mg/m

Neurologic: Peripheral neuropathy, mainly manifested by paresthesia, affected 64% of patients, but was severe in only 4% of patients. Neurologic symptoms may occur following the first course and the frequency of symptoms may increase with increasing exposure to paclitaxel. Peripheral neuropathy was the cause of paclitaxel discontinuation in 3 cases. 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. Rare neurologic events reported after paclitaxel administration include grand mal seizures and encephalopathy. Reports of motor neuropathy with resultant minor distal weakness and autonomic neuropathy resulting in paralytic ileus and orthostatic hypotension have also appeared. Optic nerve and/or visual disturbances (scintillation scotomata) have also been reported, particularly in patients who have received higher doses than recommended. These effects generally have been reversible.

The administration of paclitaxel in combination with cisplatin compared with single-agent paclitaxel, regardless of the infusion duration, resulted in greater incidence of neurotoxicity in patients with NSCLC.

Arthralgia/Myalgia: Arthralgia or myalgia usually consisting of pain in the large joints of the arms and legs occurred in 54% of patients; severe symptoms were seen in 12% of patients. The symptoms were usually transient occurring 2 to 3 days after paclitaxel administration and resolving within a few days.

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 patients, respectively. Other gastrointestinal events included anorexia (25% of patients), constipation (18%) and intestinal obstruction (4%). Neutropenic enterocolitis, bowel obstruction/perforation and ischemic colitis and pancreatitis have been reported.

The incidence of nausea and vomiting was greater when paclitaxel was administered with cisplatin as compared to single-agent paclitaxel.

Hepatic: In patients with normal baseline liver function, 4% experienced elevated bilirubin, 18% had elevated alkaline phosphatase, and 18% had elevated AST. Severe elevations (>5 x normal values) bilirubin, alkaline phosphatase or AST were seen in 1%, 5% and 5% of patients, respectively. Hepatic necrosis and hepatic encephalopathy leading to death have been reported rarely.

Injection Site Reactions: Phlebitis may occur following the i.v. administration of paclitaxel. Extravasation during i.v. administration may lead to edema, pain, erythema and induration; on occasion, extravasation can result in cellulitis. Skin discoloration may also occur. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e., recall, has been reported rarely. A specific treatment for extravasation reactions is unknown at this time, however treatment with a s.c. injection of hyaluronidase diluted in saline has been demonstrated to be effective in a mouse skin model.

Other: Transient and mild nail and skin changes have been observed. Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.

Symptoms And Treatment Of Overdose:

There is no known antidote for paclitaxel overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis.

Dosage And Administration: Note: Undiluted concentrate should not come in contact with plasticized PVC equipment. In order to minimize patients 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 filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

All patients should be premedicated prior to paclitaxel administration in order to minimize severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg orally (or its equivalent) approximately 12 and 6 hours before paclitaxel, diphenhydramine 50 mg (or its equivalent) i.v. 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) i.v. 30 to 60 minutes before paclitaxel.

Paclitaxel at a dose of 175 mg/m

Preparation and Administration Precautions: 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. Following topical exposure, tingling, burning, redness have been observed. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water.

If paclitaxel 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.

The administration of paclitaxel at a dose of 175 mg/m

Preparation for I.V. 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 to 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 i.v. 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.

As with all parenteral drug products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit.

Paclitaxel should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns.

Special Instructions: Preparation of paclitaxel should be done in a vertical laminar flow hood (Biological Safety Cabinet-Class II).

Personnel preparing paclitaxel should wear PVC gloves, safety glasses, disposable gowns and masks.

All needles, syringes, vials and other materials which have come in contact with paclitaxel should be segregated and incinerated at 1 000°C or more. Sealed containers may explode. Intact vials should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport.

Personnel regularly involved in the preparation and handling of paclitaxel should have biannual blood examinations.

Directions for Dispensing from Pharmacy Bulk Vial: The use of Pharmacy Bulk Vial is restricted to hospitals with a recognized i.v. admixture program. The Pharmacy Bulk Vial is intended for single puncture, multiple dispensing and for i.v. use only. Dispensing from the Pharmacy Bulk Vial should be completed within 24 hours after initial entry.

Solutions for infusion prepared as recommended may be stored at room temperature (15 to 30°C) only if necessary. However, the infusion should be initiated within 24 hours of reconstitution.

Availability And Storage: Each mL contains: paclitaxel 6 mg. Nonmedicinal ingredients: dehydrated alcool 49.7% v/v and polyethoxyethylated castor oil. Multidose vials of 5 and 16.7 mL and pharmacy bulk vials of 50 mL. Store at room temperature (15 to 30°C). Retain in the original package and protect from light. Once punctured, the 5 and 16.7 mL vials are stable for 28 days at room temperature. The 50 mL pharmacy bulk vial should be used within 24 hours after initial entry.

TAXOL™ Bristol-Myers Squibb Paclitaxel Antineoplastic Agent

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