Mayne Standard

Solution for Injection, 6 mg/mL Sterile ANTINEOPLASTIC Hospira Healthcare Corporation 1111 Dr. Frederik-Philips Suite 600 Saint-Laurent, QC H4M 2X6 Date of Preparation: June 25, 2007 Control #: 097503

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 15 DOSAGE AND ADMINISTRATION 17 OVERDOSAGE 19 ACTION AND CLINICAL PHARMACOLOGY 19 STORAGE AND STABILITY 22 SPECIAL HANDLING INSTRUCTIONS 22 DOSAGE FORMS, COMPOSITION AND PACKAGING 23

PART II: SCIENTIFIC INFORMATION 24

PHARMACEUTICAL INFORMATION 24 CLINICAL TRIALS 25 DETAILED PHARMACOLOGY 29 TOXICOLOGY 31 MUTAGENICITY & GENOTOXICITY 38 REFERENCES 39

PART III: CONSUMER INFORMATION 44

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PACLITAXEL FOR INJECTION

Mayne Standard

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Patients who have a history of severe hypersensitivity reactions to paclitaxel or other drugs formulated in Cremophor(r) EL (polyethoxylated castor oil). Patients with severe baseline neutropenia (< 1,500 cells/mm3).

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• Should only be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents (see INDICATIONS AND CLINICAL USE).

• Paclitaxel for Injection should be administered as diluted infusion.

• Patients should be pre-treated with corticosteroids, antihistamines, and H2 antagonist (see

Sensitivity/Resistance

section below).

Should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3 (see Hematologic section below).

General

Paclitaxel should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. 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 for Injection solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

Carcinogenesis and Mutagenesis

See section TOXICOLOGY under SCIENTIFIC INFORMATION.

Cardiovascular

Hypotension, hypertension and bradycardia have been observed during paclitaxel administration; patients are usually asymptomatic and generally do not require treatment. In severe cases, paclitaxel infusions may need to be interrupted or discontinued at the discretion of the treating physician. 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 ADVERSE REACTIONS). Severe cardiac conduction abnormalities have been reported in < 1% of patients 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 for Injection.

Driving/Operating Machinery

Since Paclitaxel for Injection contains ethanol (absolute alcohol), consideration should be given to the possibility of CNS and other effects.

Hematologic

Paclitaxel for Injection should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3 (see CONTRAINDICATIONS). Bone marrow suppression (primarily neutropenia) is dose and schedule dependent and is the dose-limiting toxicity within a regimen. Neutrophil nadirs occurred at a median of 11 days. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Paclitaxel for Injection. Patients should not be re-treated with subsequent cycles of Paclitaxel for Injection 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 for Injection therapy, a 20% reduction in dose for subsequent courses of therapy is recommended (see DOSAGE AND ADMINISTRATION).

Hepatic/Biliary/Pancreatic

There is evidence that the toxicity of paclitaxel is enhanced in patients with elevated liver enzymes. Caution should be exercised when administering Paclitaxel for Injection to patients with moderate to severe hepatic impairment and dose adjustments should be considered (see ADVERSE REACTIONS).

Injection Site Reaction

Injection site reactions, including reactions secondary to 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 three-hour infusion. 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. Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis and fibrosis have been received as part of the continuing surveillance of paclitaxel safety. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days. A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Neurologic

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 Injection for severe neuropathy (see ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION). Paclitaxel for Injection contains ethanol (absolute alcohol), 396 mg/mL; consideration should be given to possible CNS and other effects of ethanol (absolute alcohol). Children may be more sensitive than the adults to the effects of ethanol (absolute alcohol); see Special Populations - Pediatrics.

Sensitivity/Resistance

Paclitaxel for Injection should be administered as a diluted infusion. Patients receiving Paclitaxel for Injection should be pre-treated with corticosteroids, antihistamines, and H2 antagonists (such as dexamethasone, diphenhydramine and cimetidine or ranitidine) to minimize hypersensitivity reactions (see DOSAGE AND ADMINISTRATION).

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, or generalized urticaria have occurred in approximately 2% of patients receiving Paclitaxel for Injection. These reactions are probably histamine-mediated. Rare fatal reactions have occurred in patients despite pre- treatment. In case of a severe hypersensitivity reaction, paclitaxel infusion should be discontinued immediately and the patient should not be rechallenged with the drug (see ADVERSE REACTIONS).

Patients with a history of severe hypersensitivity reactions to products containing Cremophor(r) EL should not be treated with Paclitaxel for Injection (see 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 for Injection and aggressive symptomatic therapy.

Special Populations

Pregnant Women:

Paclitaxel for Injection 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 for Injection. If Paclitaxel for Injection is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard.

Nursing Women:

It is not known whether paclitaxel is excreted in human milk. Breast feeding should be discontinued for the duration of paclitaxel therapy.

Pediatrics: The safety and effectiveness of paclitaxel in pediatric patients have not been established. There have been reports of central nervous system (CNS) toxicity (rarely associated with death) in a clinical trial in pediatric patients in which paclitaxel was infused intravenously over three hours at doses ranging from 350 mg/m2 to 420 mg/m2 . The toxicity is most likely attributable to the high dose of the ethanol component of the paclitaxel vehicle given over a short infusion time. The use of concomitant antihistamines may intensify this effect. Although a direct effect of the paclitaxel itself cannot be discounted, the high doses used in this study (over twice the recommended adult dosage) must be considered in assessing the safety of paclitaxel for use in this population.

DRUG INTERACTIONS

Serious Drug Interactions

Should be given before cisplatin when used in combination (see Drug-Drug Interactions). Caution should be exercised when administering concomitantly with known substrates, inducers or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4 (see Drug-Drug Interactions).

Overview

Cisplatin

In a Phase I 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 for Injection should be given before cisplatin when used in combination.

Cimetidine

The effect of cimetidine pre-medication on the metabolism of paclitaxel has been investigated; the clearance of paclitaxel was not affected by cimetidine pre-treatment.

Substrates, Inducers, Inhibitors of Cytochrome P450 2C8 and 3A4

The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when administering Paclitaxel for Injection concomitantly with known substrates, inducers or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. In vitro, the metabolism of paclitaxel to 6"-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporine, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17"-ethinyl estradiol, retinoic acid, montelukast and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6"-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials. Caution and close monitoring of liver function is required; further, no unapproved (e.g., investigational) protease inhibitor should be administered with Paclitaxel for Injection.

Doxorubicin

Sequence effects characterized by more profound neutropenic and stomatitis episodes, have been observed with combination use of paclitaxel and doxorubicin when paclitaxel was administered BEFORE doxorubicin and using longer than recommended infusion times (paclitaxel administered over 24 hours; doxorubicin administered over 48 hours). Plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when Paclitaxel for Injection and doxorubicin are used in combination. However, data from a trial using bolus doxorubicin and three-hour paclitaxel infusion found no sequence effects on the pattern of toxicity.

Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 2 - Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Metastatic carcinoma of the ovary

The administration of Paclitaxel for Injection at a dose of 175 mg/m2 over three hours in combination with cisplatin 75 mg/m2 every three weeks is recommended for the primary treatment of patients with advanced carcinoma of the ovary. Paclitaxel for Injection should be given before cisplatin when used in combination. In patients previously treated with chemotherapy, the recommended regimen is 175 mg/m2 administered intravenously over three hours every three weeks.

Carcinoma of the breast

For the adjuvant treatment of node-positive breast cancer, the recommended regimen is Paclitaxel for Injection, at a dose of 175 mg/m2 intravenously over three hours every three weeks for four courses administered sequentially to standard combination therapy. After failure of initial chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy, Paclitaxel for Injection at a dose of 175 mg/m2 administered intravenously over three hours every three weeks has been shown to be effective.

Non-small cell lung carcinoma

The recommended regimen, given every three weeks, is Paclitaxel for Injection administered intravenously over three hours at a dose of 175 mg/m2 followed by cisplatin. Single courses of Paclitaxel for Injection should not be repeated until the neutrophil count is at least 1,500 cells/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 for Injection therapy should have the dosage reduced by 20% for subsequent courses of Paclitaxel for Injection.

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 for Injection solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

Paclitaxel for Injection 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(r) filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

All patients should be pre-medicated prior to Paclitaxel for Injection administration in order to reduce the risk of severe hypersensitivity reactions.

Such pre-medication may consist of dexamethasone 20 mg orally (or its equivalent) approximately 12 and six hours before Paclitaxel for Injection, diphenhydramine 50 mg IV (or its equivalent), 30 to 60 minutes prior to Paclitaxel for Injection, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before Paclitaxel for Injection.

Preparation Precautions

Paclitaxel for Injection is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised in handling Paclitaxel for Injection. The use of gloves is recommended. Following topical exposure, tingling, burning, redness have been observed. If Paclitaxel for Injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Paclitaxel for Injection 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. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration (see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).

Reconstitution:

Parenteral Products:

Prior to the addition of drug, calculate the appropriate volume of diluent to be removed from packaging system to take into account the overage of diluent volume in the packaging system and the amount of drug to be added.

Paclitaxel for Injection must be diluted prior to infusion. Paclitaxel for Injection 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 - 25degC) and room lighting conditions; infusions should be completed within this timeframe. There have been rare reports of precipitation with longer than the recommended three-hour infusion schedules. Excessive agitation, vibration or shaking may induce precipitation and should be avoided. Infusion sets should be flushed thoroughly with a compatible diluent before use.

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 for Injection 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. Devices with spikes should not be used with vials of Paclitaxel for Injection since they can cause the stopper to collapse resulting in loss of sterile integrity of Paclitaxel for Injection solution.

OVERDOSAGE

There is no known antidote for paclitaxel overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Overdoses in pediatric patients may be associated with acute ethanol toxicity (see WARNINGS AND PRECAUTIONS).

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Paclitaxel is an antimicrotubule antineoplastic agent. It promotes microtubule assembly by enhancing the polymerisation of tubulin, the protein subunit of spindle microtubules, even in the absence of the mediators normally required for microtubule assembly (e.g. guanosine triphosphate [GTP]), thereby inducing the formation of stable, nonfunctional microtubules. While the precise mechanism of action of the drug is not completely known, paclitaxel disrupts the dynamic equilibrium within the microtubule system and blocks cells in the late G2 phase and M phase of the cell cycle, inhibiting cell replication and impairing function of nervous tissue. 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 (see DETAILED PHARMACOLOGY).

Pharmacokinetics

Table 3 - Summary of paclitaxel's pharmacokinetic parameters in patients given doses of 135 and 175 mg/m2 as three hour and 24 hours infusions.

Absorption: The pharmacokinetics of paclitaxel have been evaluated over a wide range of doses, up to 300 mg/m2, and infusion schedules ranging from three to 24 hours. Following intravenous administration of paclitaxel, the drug exhibited a biphasic decline in plasma concentrations. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment. In patients treated with doses of 135 and 175 mg/m2 given as three and 24 hour infusions, mean terminal half-life has ranged from 3.0 to 52.7 hours, and total body clearance has ranged from 11.6 to 24.0 L/h/m2. Mean steady state volume of distribution has ranged from 198 to 688 L/m2, indicating extensive extravascular distribution and/or tissue binding. Following three hour infusions of 175 mg/m2, mean terminal half-life was estimated to be 9.9 hours; mean total body clearance was 12.4 L/h/m2. Variability in systemic paclitaxel exposure, as measured by AUC0-% 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 non-linear. There is a disproportionately large increase in Cmax 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.

Distribution: In vitro

studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 ug/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.

Metabolism: In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6"-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3-p-hydroxypaclitaxel and 6", 3'-p-dihydroxypaclitaxel by CYP3A4. In vitro, the metabolism of paclitaxel to 6"-hydroxypaclitaxel was inhibited by a number of agents (see DRUG INTERACTIONS). The effect of renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated. Excretion: The disposition of paclitaxel has not been fully elucidated in humans. After intravenous administration of paclitaxel, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3 to 12.7% of the dose, indicating extensive non-renal clearance. In five patients administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a three-hour infusion, 14% of the radioactivity was recovered in the urine and 71 % was excreted in the feces in 120 hours. Total recovery of radioactivity ranged from 56% to 101 % of the dose. Paclitaxel represented a mean of 5% of the administered radioactivity recovered in the feces while metabolites, primarily 6"-hydroxypaclitaxel, accounted for the balance.

STORAGE AND STABILITY

Paclitaxel for Injection should be stored at room temperature (15 -25degC). Retain in the original package and protect from light. Once punctured, the 16.7 mL, 25 mL and 50 mL vials of Paclitaxel for Injection are stable for 28 days at room temperature (15 -25degC). These presentations are labeled as multi-dose vials. Unused portions of the 5 mL single dose format should be discarded. Solutions for infusion prepared as recommended may be stored at room temperature (15 - 25/C) only if necessary. However, the infusion should be initiated within 24 hours of reconstitution. If unopened vials are refrigerated, a precipitate may form which redissolves with little or no agitation upon reaching room temperature. Product quality is not affected. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded.

As with all parenteral drug products, injections/intravenous ad-mixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used. Discard unused portion.

SPECIAL HANDLING INSTRUCTIONS

Contact of undiluted Paclitaxel for Injection with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended (see DOSAGE AND ADMINISTRATION). Prior to infusion, Paclitaxel for Injection 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. As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit. Paclitaxel for Injection should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. Preparation of Paclitaxel for Injection should be done in a vertical laminar flow hood (Biological Safety Cabinet - Class II). Personnel preparing Paclitaxel for Injection should wear PVC gloves, safety glasses, disposable gowns and masks. All needles, syringes, vials and other materials which have come in contact with Paclitaxel for Injection should be segregated and incinerated at 1000degC 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 for Injection should have bi-annual blood examinations.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Paclitaxel for Injection is available in single dose vials of 5 mL and in multi-dose vials of 16.7 mL, 25 mL and 50 mL, containing 30 mg, 100 mg, 150 mg and 300 mg of paclitaxel, respectively at a concentration of 6 mg/mL. All presentations are available in single pack cartons. Each mL of Paclitaxel for Injection contains paclitaxel 6 mg, Cremophor(r) EL (polyethoxylated castor oil) 527 mg, Citric Acid (anhydrous) 2 mg and Absolute Alcohol 46.5% v/v.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Paclitaxel Chemical name: 5$,20-epoxy-1,2",4,7$,10$,13"-hexahydroxytax-11-en-9-one 4, 10-diacetate 2-benzoate 13-ester with (2R, 3S)-N-benzoyl-3- phenylisoserine or

[2aR-[2aa, 4b, 4ab, 6b, 9a(aR *,bS *), 11a, 12a, 12aa, 12ba]]-b- (Benzoylamino)-a- hydroxybenzenepropanoic acid 6, 12b-bis (acetyloxy)-12-(benzoyloxy)-2a, 3, 4, 4a, 5, 6, 9, 10, 11, 12, 12a, 12b-

dodecahydro-4,-11-dihydroxy-4a, 8, 13, 13-tetramethyl-5-oxo-7, 11-

methano-1H-cyclodeca-[3, 4] benz [1,2-b]oxet-9-yl ester

Structural formula: Molecular formula: C47H51NO14 Molecular mass: 853.9 Physicochemical properties: Paclitaxel is a white powder with a melting point of 214 - 230degC. Paclitaxel is not soluble in water, but is soluble to varying degrees in organic solvents.

CLINICAL TRIALS

Clinical Trials

Ovarian Carcinoma

First-Line data: The adverse event profile for patients receiving paclitaxel in combination with cisplatin was consistent with that seen in previous clinical studies (see ADVERSE REACTIONS). Second-Line data: In addition to the Phase III trial described above, data from five Phase I and II clinical studies as well as an interim analysis of data from more than 300 patients enrolled in a treatment referral center program were used in support of the use of paclitaxel in patients who have failed initial or subsequent chemotherapy for metastatic carcinoma of the ovary. Paclitaxel remained active in patients who had developed resistance to platinum-containing therapy (defined as tumor progression while on, or tumor relapse within six months from completion of, a platinum containing regimen) with response rates of 14% in the Phase III study and 31 % in the Phase I and II clinical studies. The adverse event profile in this Phase III study was consistent with that seen in previous clinical studies (see ADVERSE REACTIONS). The results of this randomized study support the use of paclitaxel at doses of 135 to 175 mg/m2 administered by a three-hour intravenous infusion. The same doses administered by 24-hour infusion were more toxic.

Breast Carcinoma

Breast Carcinoma (continued)

Adjuvant Breast Carcinoma Study: The adverse event profile for patients receiving paclitaxel subsequent to AC was consistent with that seen in previous clinical studies (see ADVERSE REACTIONS). After Failure of Initial Chemotherapy: In addition to the Phase III trial described above, data from three Phase II clinical studies were used in support of the use of paclitaxel in patients with metastatic breast carcinoma. The adverse event profile for patients receiving paclitaxel subsequent to AC was consistent with that seen in previous clinical studies (see ADVERSE REACTIONS).

Non-Small Cell Lung Carcinoma (NSCLC)

The adverse event profile for patients who received paclitaxel in combination with cisplatin was consistent with that seen in previous clinical studies (see ADVERSE REACTIONS).

DETAILED PHARMACOLOGY

In vitro

Paclitaxel exhibits cytotoxic activity against a wide variety of both human and rodent tumor cell lines in vitro including leukemia, non-small cell lung carcinoma, small cell lung carcinoma, colon carcinoma, CNS carcinoma, melanoma, renal carcinoma, ovarian carcinoma and breast carcinoma at IC50 concentration (defined as the concentration required to inhibit cell proliferation to 50% of that of untreated control cells) in the nM range. Paclitaxel blocks cell replication in the late G2 and/or M phases of the cell cycle. Additionally, paclitaxel produces unusual cytoskeletons characterized by discrete bundles or microtubules and the formation of abnormal spindle asters during mitosis. As a consequence of the disruption of the microtubule cytoskeleton, paclitaxel inhibits a variety of cell functions including chemotaxis, migration, cell spreading, polarization, generation of hydrogen peroxide and killing of phagocytosed microorganisms. In addition to its ability to induce microtubule polymerization, exposure of murine macrophages to paclitaxel results in the release of tumor necrosis factor-a (TNF-a) accompanied by down regulation of the receptor.

In vivo

Paclitaxel has shown antitumor activity against many tumor models including leukemias and solid tumors and human solid xenografts. The table that follows summarizes paclitaxel's activity.

Suspension in hydroxypropylcellulose

* * Paclitaxel , in ethanol/cremophor diluted with saline

TOXICOLOGY

ACUTE TOXICITY

a

Range-Finding phase

b

Lethality phase

Signs of toxicity in rats were lethargy, rough coat, thinness, hunched posture, neck abscesses, soft stool, decreased body weight, squinted eyes, alopecia. Signs of toxicity in dogs were decreased body weight. SUBACUTE TOXICITY

SUBACUTE TOXICITY (continued)

SUBACUTE TOXICITY (continued)

Range Finding phase

* *Lethality phase

a

Paclitaxel in Cremaphor EL (50%): ethanol (50%) and then diluted with saline to provide dosing solutions

b

Untreated

CHRONIC TOXICITY

CHRONIC TOXICITY (continued)

Paclitaxel in Cremophor EL: ethanol (50/50) diluted with saline for dosing solutions

REPRODUCTION AND TERATOLOGY

REPRODUCTION AND TERATOLOGY (continued)

Paclitaxel in Cremophor EL: ethanol (50/50) diluted with saline for dosing solutions

MUTAGENECITY AND GENOTOXICITY

Paclitaxel was not mutagenic in the Ames/Salmonella and Escherichia Coli WP2 reverse mutation assays but was found to be clastogenic, in the in vitro cytogenetics assay in primary human lymphocytes. Paclitaxel was genotoxic in vivo on the mouse erythropoietic system in the mouse bone marrow erythrocyte micronucleus assay.

REFERENCES

1. Berg S.L., Cowan K.H., Balis F.M., et al. Pharmacokinetics of Taxol and doxorubicin administered alone and in combination by continuous 72-hour infusion. J Nat Can Inst 1994; 86:143-145.

2. Brown T., Havlin K., Weiss G., Cagnola J., Kuhn J., Rizzo J., Craig J., Phillips J., and Van Hoff

D. A phase I trial of taxol given by a 6-hour intravenous infusion. J Clin Oncol 1991; 9: 1261- 1267. Cabral F.R., Wible L., Brenner S., and Brinkley B.R. Taxol-requiring mutant of Chinese hamster ovary cells with impaired mitotic spindle assembly. J Cell Biol 1983; 97: 30-39. Capri G., Munzone E., Tarenzi E., et al. Optic nerve disturbances: A new form of paclitaxel neurotoxicity. J Nat Cancer Inst. 1994; 86: 1099-1101. DeBrabander M. A model for the microtubule organizing activity of the centrosomes and kinetochores in mammalian cells. Cell Biol Int Rep 1982; 6: 901-915. Donehower R.C., Rowinsky E.K., Grochow L.B., et al. Phase I trial of taxol in patients with advanced cancer. Cancer Treat Reports 1987; 71(12): 1171-1177. Dorr R.T., Snead K., Liddil, J.D. Skin Ulceration Potential of Paclitaxel in a Mouse Skin Model In Vivo. Cancer 1996; 78(l): 152-156. Einzig A.I., Wiernik P.H., and Schwartz E.L. Taxol: A new agent active in melanoma and ovarian cancer. In New Drugs, Concepts and Results in Cancer Chemotherapy, FM Muggia (ed. ), pp. 89-100. Kluwer Academic Publishers, Inc. (1992). Gianni L., Kearns C.M., Giani A., et al. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 1995; 13: 180-190. Grem T.L., Tutsch K.D., Simon K.J., Alberti D.B., Willson J.K.V., Tormey D.C., Swaminathan S., Trump D.L. Phase I study of taxol administered as a short iv infusion daily for 5 days. Cancer Treat Reports 1987; 71(12): 1179-1184. Harris J.W., Rahman A., Kim B.-R., et al. Metabolism of TAXOL by human hepatic microsomes and liver slices: Participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Res 1994; 54: 4026-4035. Kecker R.W., Jamis-Dow C.A., Egorin M.J., et al. Effect of cimetidine, probenecid, and ketoconazole on the distribution, biliary secretion, and metabolism of [3H] TAXOL in the Sprague-Dawley rat. Drug Metab Disposit 1994; 22; 254-258. Legha S.S., Tenney D.M., Krakoff I.R. Phase I study of taxol using a 5-day intermittent schedule. J Clin Oncol 1986; 4(5): 762-766. Manfredi J.J. and Horwitz S.B. An antimitotic agent with a new mechanism of action. Pharmacol Ther 1984; 25: 83-125. Manfredi J.J., Parness J., and Horwitz S.B. Taxol binds to cellular microtubules. J Cell Biol 1982; 94: 688-696. McGuire W.P., Rowinsky E.K., Rosenshein N.B., Grumbine F.C., Ettinger D.S., Armstrong D.K., and Donehower R.C. Taxol: A unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Int Med 1989; 111: 273-279. McGuire W.P., Hoskins W.J., Brady M.F., Kugera P.R., Partridge E.E., Look K.Y., Clarke- Pearson D.L. and Davidson M. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. New Eng J Med 1996; 334: 1-6. Mole-Bajer J. and Bajer A.S. Action of taxol on mitosis: modification of microtubule arrangements and function of the mitotic spindle in Haemanthus endosperm. J Cell Biol 1983; 96: 527-540. O'Shaghnessy J.A., Fisherman J.S., Cowan K.H. Combination paclitaxel (TAXOL) and doxorubicin therapy for metastatic breast cancer. Sem Oncol 1994; 21(suppl 8): 19-23 Roberts L.P., Nath J., Friedman M.M. and Gallin J.I. Effects of taxol on human neutrophils. J Immunol 1982; 129: 2134-2141. Rowinsky E.K., Burke P.J., Karp J.E., Tucker R.W. Ettinger D.S., and Donehower R.C. Phase I and pharmacodynamic study of taxol in refractory acute leukemias. Cancer Res 1989 49: 4640-4647. Rowinsky E.K., Cazenave L.A., and Donehower R.C. Taxol: a novel investigational antimicrotubule agent. J Natl Canc Inst 1990; 82: 1247-1259. Rowinsky E.K., Gilbert M.R., McGuire W.P., Noe D.A., Grochow L.B., Forastiere A.A., Erringer D.S., Lubejko B.G. Clark B., Sartorius S.E., Cornblath D.R., Hendricks C.B. and Donehower R.C. Sequences of taxol and cisplatin: A Phase I and pharmacologic study. J Clin Oncol 1991; 9(9): 1692-1703. Sarosy G., Kohn E., Stone D.A., Rothenberg M., Jacob J., Adamo D.O., Ognibene F.P., Cunnoin R.E. and Reed E. Phase I study of taxol and granulocyte colony-stimulating factor in patients with refractory ovarian cancer. J Clin Oncol 1992; 10(7): 1165-1170. Schiff P.B. and Horwitz S.B. Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci, USA 1980; 77: 1561-1565. Seidman A.D., Barrett S., Canezo S. Photopsia during 3-hour paclitaxel administration at doses $250 mg/m2. J Clin Oncol 1994; 12:1741-1742. Slichenmyer W.J., and Von Hoff D.D. Taxol: A new and effective anti-cancer drug. Anti- Cancer Drugs 1991; 2: 519-530. Turner P.F. and Margolis R.L. Taxol-induced bundling of brain-derived microtubules. J Cell Biol 1984; 99: 940-946. Venook A.P., Egorin M., Brown T.D., et al Paclitaxel (Taxol) in patients with liver dysfunction (CALGB 9264) pROC asco 1994; 13: 139 (Abstract #350). Waugh W.N., Trissel L.A., and Stella V.J. Stability, compatibility and plasticizer extraction of taxol injection diluted in infusion solutions and stored in various containers. Am J Hosp Pharm 1991; 48: 1520-1524. Weiss R.B., Donehower R.C., Wiernik P.H. et al. Hypersensitivity reactions from taxol. J Clin Oncol 1990; 8: 1263-1268. Wiernik P.H., Schwartz E.L., Strauman J.J., Dutcher J.P., Lipton R.B., and Einzig A. Phase I trial of taxol given as a 24-hour infusion every 21 days: Responses observed in metastatic melanoma. J Clin Oncol 1987; 5(8): 1232-1239. Wiernik P.H., Schwartz E.L., Strauman J.J., Dutcher J.P., Lipton R.B., and Paietta E. Phase I clinical and pharmacokinetic study of taxol. Cancer Res 1987; 47: 2486-2493. Wright M., Monsarrat B., Alvinerie P., et al. Hepatic metabolism and biliary excretion of taxol. Second National Cancer Institute Workshop on Taxol and Toxus. Alexandria, Virginia (1992). Kelly K., Crowley J., Bunn P.A., et al. A Randomized Phase III Trial of Paclitaxel Plus Carboplatin (PC) Versus Vinorelbine Plus Cisplatin (VC) in Untreated Advanced Non-Small Cell Lung Cancer (NSCLC): A Southwest Oncology Group (SWOG) Trial. Norton L., Slamon D., Leyland-Jones B., et al. Overall Survival (OS) Advantage to Simultaneous Chemotherapy (Crx) Plus the Humanized Anti-HER2 Monoclonal Antibody Herceptin (H) in HER2-Overexpressing (HER2+) Metastatic Breast Cancer (MBC). Walsky RL, Obach RS, Gaman EA, et al. Selective Inhibition of Human Cytochrome P4502C8 by Montelukast. Drug Metabolism and Disposition 2005; 33 (3): 413-418. Walsky RL, Gaman EA and Obach RS. Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol 2005; 45: 68-78. Taxol (paclitaxel) Product Monograph. Bristol-Myers Squibb Pharmaceutical Group (Canada). January 10, 2006, Control No. 102455. Summary of Product Characteristics for Paclitaxel for Injection. Mayne Pharma (Europe). August 15, 2003. IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

Pr

Paclitaxel for Injection Mayne Standard

Solution for Injection, 6 mg/mL Sterile

This leaflet is part III of a three-part "Product Monograph" published when Paclitaxel for Injection was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about Paclitaxel for Injection. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for?

This medicine is used to treat:

• ovarian cancer

• breast cancer

• lung cancer

What it does?

This medicine belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines.

It works by killing cancer cells and stopping cancer cells from growing and multiplying.

When it should not be used?

If you have an allergy to:

any medicine containing paclitaxel

any of the ingredients listed at the end of this leaflet

any medicines containing PEG 35 castor oil (Cremophor(r) EL), such as cyclosporin injection or teniposide injection.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

You must not be given this medicine if you have a very low white blood cell (WBC) count.

Tell your doctor if you have an infection or high temperature. Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

If you are pregnant or plan to become pregnant.

What the medicinal ingredient is?

Paclitaxel

What the important nonmedicinal ingredients are?

Anhydrous citric acid, absolute alcohol (ethanol), PEG 35 castor oil (Cremophor(r) EL)

What dosage forms it comes in?

Solution for Injection, 6 mg/mL

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• Should only be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.

• Patients should be pre-treated with corticosteroids, antihistamines, and H2 antagonists.

C

Should not be administered to patients with

baseline neutrophil counts of less than 1,500 cells/mm3.

BEFORE you use Paclitaxel for Injection always talk to your doctor or pharmacist especially if:

• you have or have had any of the following medical conditions:

• liver disease

• heart problems

• any blood disorder with a reduced number of red blood cells, white blood cells, or platelets

• any disease of the nerves

• lowered immunity due to diseases such as HIV/AIDS

• Lowered immunity due to treatment with medicines such as cyclosporin, or other medicines used to treat cancer (including radiation therapy).

you plan to become pregnant

you have any allergies to this drug or its ingredients

you are receiving radiation therapy

INTERACTIONS WITH THIS MEDICATION

Paclitaxel for Injection interacts with other drugs. Before therapy, talk to your doctor if you are using any other medications (prescription, non-prescription or herbal remedies).

Drugs that may interact with Paclitaxel for Injection include: cisplatin, doxorubicin cimetidine, ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporine, teniposide,

etoposide, vincristin, testosterone, 17"-ethinyl estradiol, retinoic acid, and quercetin.

PROPER USE OF THIS MEDICATION

Usual dose:

Your doctor will decide what dose of Paclitaxel for Injection you will receive. This depends on your condition and other factors, such as your weight and other chemotherapy medicines you are being given.

Before you are given Paclitaxel for Injection, you must take some other medicines to prevent allergic reactions occurring during your treatment. You will need to take dexamethasone tablets 12 hours and six hours before your treatment, which your doctor will prescribe for you. You will also be given two different injections 30 to 60 minutes prior to receiving Paclitaxel for Injection. This will minimize the risk of allergic reactions occurring.

Several courses of Paclitaxel for Injection therapy may be needed depending on your response to treatment.

Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any uncontrolled effects have been controlled. Your doctor will decide.

Overdose:

As Paclitaxel for Injection is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience severe side effects after being given this medicine, tell your doctor or nurse immediately. You may need urgent medical attention.

Symptoms of overdose include the side effects listed below in the 'Side Effects' section, but are usually of a more severe nature.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Tell your doctor if you notice any of the following and they worry you:

C

muscle or joint pain on the arms and legs

C

nausea and vomiting

C

hair loss

C

diarrhoea

C

changes in skin or nail appearance

C

soreness or ulceration of the mouth.

The above list includes the more common side effects of your medicine.

This is not a complete list of side effects. For any unexpected effects while taking Paclitaxel for Injection, contact your doctor or pharmacist.

HOW TO STORE IT

Paclitaxel for Injection will be stored in the pharmacy or on the ward. The injection is kept in a cool, dry place, protected from light, where the temperature stays between 15- 25degC.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs . If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax: 866-678-6789

By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be obtained by contacting the sponsor

Hospira Healthcare Corporation at: 1-866-488-6088

This leaflet was prepared by Hospira Healthcare Corporation . Last revised: June 25, 2007