Teva-Paclitaxel for Injection Product Monograph

ACTIONS AND CLINICAL PHARMACOLOGY

dimers and stabilizes microtubules by preventing depolymerization.

(see PHARMACOLOGY).

mg/m²,

g/m² given

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.

mg/m², m

mean total body clearance was 12.4 L/h/m².

Variability in systemic paclitaxel exposure, as measured by AUC_0-% for successive treatment courses

large increase in C_max a

plasma concentrations of paclitaxel are achieved. Saturable processes in distribution and elimination

/ metabolism may account for these findings.

ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

of paclitaxel has not been investigated.

² dose of radiolabeled paclitaxel as a 3-hour infusion, 14% of the

hydroxypaclitaxel, accounted for the balance.

INDICATIONS AND CLINICAL USE

ovary or breast or lung.

Ovarian Carcinoma

• First-line therapy in combination with other chemotherapeutic agents

C Second-line treatment of metastatic carcinoma of the ovary after failure of standard therapy.

Breast Carcinoma

•

negative tumors, but the benefit has been specifically demonstrated by available data (median follow-up 30 months) only in the patients with estrogen and progesterone receptor-negative tumors. (See PHARMACOLOGY - Clinical Trials)

C Second-line treatment of metastatic carcinoma of the breast after failure of standard therapy.

Lung Carcinoma

C First-line treatment of advanced non-small cell lung cancer.

CONTRAINDICATIONS

Paclitaxel should not be used in patients with severe baseline neutropenia (<1 500 cells/mm³).

WARNINGS

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

pretreated with corticosteroids, antihistamines, and H₂

diphenhydramine and cimetidine or ranitidine) to minimize hypersensitivity reactions (see DOSAGE

mediated. Rare fatal reactions have occurred in patients despite pre-treatment. In case of a severe

should not be rechallenged with the drug. (See DOSAGE AND ADMINISTRATION).

500 cells/mm³

ver to a level >100 000 cells/mm³

ADMINISTRATION).

therapy. If patients develop significant conduction abnormalities during administration, appropriate

performed during subsequent therapy with paclitaxel (see ADVERSE REACTIONS).

Use in Pregnancy

during therapy with paclitaxel.

Nursing Mothers

for the duration of paclitaxel therapy.

Use in Children

from 350 mg/m³ to 420 mg/m³. The

considered in assessing the safety of paclitaxel for use in this population.

PRECAUTIONS

administration sets.

Drug Interactions

Cisplatin

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

paclitaxel should be given before cisplatin when used in combination. Cimetidine

clearance of paclitaxel was not affected by cimetidine pretreatment.

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

(ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporine, teniposide, etoposide,

that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4.

Montelukast

Recent invitro studies have demonstrated that montelukast is a potent and selective reversible competitive inhibitor of cytochrome P450 2C8 enzyme and therefore has the potential for drug interactions with substrates of this pathway. Paclitaxel has been identified as a 2C8 substrate with potential risk of interactions with montelukast. Concomitant administration of montelukast has the potential to decrease the metabolic clearance of paclitaxel which may result in an increase in plasma concentration of paclitaxel.

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 and doxorubicin are used in combination. However, data from a trial using bolus doxorubicin and 3-hour paclitaxel infusion found no sequence effects on the pattern of toxicity.

Hematology

Paclitaxel should not be administered to patients with baseline neutrophil counts of less than 1

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

o

of paclitaxel therapy, a 20% reduction in dose for subsequent courses of therapy is recommended

(see DOSAGE AND ADMINISTRATION).

Hypersensitivity Reactions

EL should not be treated with paclitaxel (see WARNINGS, 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, 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 WARNINGS, ADVERSE REACTIONS).

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 severe neuropathy (see ADVERSE REACTIONS, DOSAGE AND

ADMINISTRATION).

Paclitaxel For Injection contains dehydrated alcohol, 49.7% v/v; consideration should be given to possible CNS and other effects of alcohol. Children may be more sensitive than the adults to the effects of alcohol (see WARNINGS: Use in Children).

Hepatic

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

REACTIONS).

Driving /Operating Machinery

Since paclitaxel contains alcohol, consideration should be given to the possibility of CNS and other effects.

ADVERSE REACTIONS

The frequency and severity of adverse events are generally similar between patients receiving paclitaxel for the treatment of ovarian, breast or non-small cell lung carcinoma.

The incidences of adverse reactions in the table that follows are derived from ten clinical trials in carcinoma of the ovary and of the breast involving 812 patients treated with single-agent

schedule is also included in the table.

l

over 24 hours) / cisplatin

l), has been evaluated. The combination of paclitaxel with platinum agents has not resulted in any clinically relevant changes to the safety profile of the drug when used at the recommended dosage.

Safety data were collected for 3121 patients in the Phase III adjuvant breast carcinoma study.

The adverse event profile for the patients who received paclitaxel subsequent to

cyclophosphamide and doxorubicin was consistent with that seen in the pooled analysis of data from 812 patients treated with single-agent paclitaxel in 10 clinical studies.

Unless otherwise stated, the following safety data relate to 62 patients with ovarian cancer and

n 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. Bone marrow suppression and peripheral neuropathy were the principle dose-related adverse effects associated with paclitaxel. Compared to 24-hour infusion schedules, neutropenia was less common when paclitaxel was given as a 3-hour infusion. Neutropenia was generally rapidly reversible and did not worsen with cumulative exposure. The frequency of neurologic symptoms increases with repeated exposure.

None of the observed toxicities were influenced by age.

Adverse Experiences by Body System

Unless otherwise noted, the following discussion refers to the overall safety database of 812 patients with solid tumors treated with single-agent paclitaxel in 10 clinical studies. Toxicities that occurred with greater severity or frequency in previously untreated patients with ovarian carcinoma or NSCLC who received paclitaxel in combination with cisplatin or in patients with breast cancer who received paclitaxel after doxorubicin/cyclophosphamide in the adjuvant setting and that occurred with a difference that was clinically significant in these poplulations are also described. In addition, rare events have been reported from postmarketing experience or from other clinical studies.

HEMATOLOGIC

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

Neutropenia was dose and schedule dependent and was generally rapidly reversible. Severe

t was not associated with febrile episodes. Only 1% of patients experienced severe neutropenia for 7 days or more. Neutropenia was not more frequent or severe in patients who received prior radiation therapy, nor did it appear to be affected by treatment duration or cumulative exposure.

When paclitaxel was administered to patients with ovarian carcinoma at a dose of 175 mg/m²/3 hours in combination with cisplatin versus the control arm of cyclophosphamide plus cisplatin, the incidences of severe neutropenia and of febrile neutropenia were similar in the paclitaxel plus cisplatin arm and in the control arm.

When paclitaxel was administered in combination with cisplatin to patients with advanced NSCLC in the Eastern Cooperative Oncology Group (ECOG) study, the incidence of

received cisplatin/etoposide. Considerable less Grade IV neutropenia was observed in the

European Organization for Research and Treatment of Cancer (EORTC) (28%) and CA139-208

Fever was frequent (12% of all treatment courses). Infectious episodes occurred in 30% of all patients and 9% of all courses; these episodes were fatal in 1% of all patients, and included sepsis, pneumonia and peritonitis. In the Phase 3 second-line ovarian study, infectious episodes

by a 3-hour infusion. Urinary tract infections and upper respiratory tract infections were the most frequently reported infectious complications.

Twenty percent of the patients experienced a drop in their platelet count below 100,000

time of their worst nadir. Bleeding episodes were reported in 4% of all courses and by 14% of all patients, but most of the hemorrhagic episodes were localized and the frequency of these events was unrelated to the paclitaxel dose and schedule. In the Phase III second-line ovarian cancer study, bleeding episodes were reported in 10% of the patients who received study medication;

however, none of the patients treated with the 3-hour infusion received platelet transfusions. In the adjuvant breast carcinoma trial, the incidence of severe thrombocytopenia and platelet transfusions increased with higher doses of doxorubicin.

Anemia (Hb<11 g/dL) was observed in 78% of all patients and was severe (Hb<8 g/dL) in 16% of the cases. No consistent relationship between dose or schedule and the frequency of anemia was observed. Among all patients with normal baseline hemoglobin, 69% became anemic on study but only 7% had severe anemia. Red cell transfusions were required in 25% of all patients and in 12% of those with normal baseline hemoglobin levels.

HYPERSENSITVITY REACTIONS (HSR)

All patients received premedication prior to paclitaxel (see WARNINGS section). The frequency and severity of HSR were not affected by the dose or schedule of paclitaxel administration. In the Phase III second-line ovarian study, the 3-hour infusion was not associated with a greater increase in HSR when compared to the 24-hour infusion. Hypersensitivity reactions were observed in 20% of all courses and in 41% of all patients. These reactions were severe in less than 2% of the patients and 1% of the courses. No severe reactions were observed after course 3 and severe symptoms occurred generally within the first hour of paclitaxel infusion. The most frequent symptoms observed during these severe reactions were dyspnea, flushing, chest pain and tachycardia.

The minor hypersensitivity reactions consisted mostly of flushing (28%), rash (12%), hypotension (4%), dyspnea (2%), tachycardia (2%) and hypertension (1%). The frequency of hypersensitivity reactions remained relatively stable during the entire treatment period.

Rare reports of chills and reports of back pain in association with hypersensitivity reactions have been received as part of the continuing surveillance of paclitaxel safety.

CARDIOVASCULAR

Hypotension, during the first 3 hours of infusion, occurred in 12% of all patients and 3% of all courses administered. Bradycardia, during the first 3 hours of infusion, occurred in 3% of all patients and 1% of all courses. In the Phase III second-line ovarian study, neither dose nor schedule had an effect on the frequency of hypotension and bradycardia. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. The frequency of hypotension and bradycardia were not influenced by prior anthracycline therapy.

Significant cardiovascular events possibly related to single-agent paclitaxel occurred in approximately 1% of all patients. These events included syncope, rhythm abnormalities, hypertension and venous thrombosis. One of the patients with syncope treated with paclitaxel at

asymptomatic ventricular tachycardia, bigeminy and complete AV block requiring pacemaker placement. The incidence of Grade III or greater cardiovascular events was 13% (paclitaxel 135

administered to patients with advanced NSCLC; there was a similar incidence in the non-paclitaxel-containing control arms. The apparent increase in these cardiovascular events in patients with NSCLC compared to patients with breast or ovarian cancer is possibly related to the difference in cardiovascular risk factors among patients with lung cancer.

Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 23% of all patients. Among patients with a normal ECG prior to study entry, 14% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, sinus tachycardia and premature beats. Among patients with normal ECG at basline, prior therapy with anthracyclines did not influence the frequency of ECG abnormalities.

Cases of myocardial infarction have been reported rarely. Congestive heart failure has been reported typically in patients who have received other chemotherapy, notably anthracyclines.

(See PRECAUTIONS: Drug Interactions).

Rare reports of atrial fibrillation and supraventricular tachycardia have been received as part of the continuing surveillance of paclitaxel safety.

RESPIRATORY

Rare reports of interstitial pneumonia, lung fibrosis and pulmonary embolism, have been received as part of the continuing surveillance of paclitaxel safety. Rare reports of radiation pneumonitis have been received in patients receiving concurrent radiotherapy.

NEUROLOGIC

The frequency and severity of neurologic manifestations were dose-dependent, but were not influenced by infusion duration. Peripheral neuropathy was observed in 60% of all patients (3% severe) and in 52% (2% severe) of the patients without pre-existing neuropathy. The frequency of peripheral neuropathy increased with cumulative dose. Neurologic symptoms were observed in 27% of the patients after the first course of treatment and in 34-51% from course 2 to 10. Peripheral neuropathy was the cause of paclitaxel discontinuation in 1% of all patients. Sensory symptoms have usually improved or resolved within several months of paclitaxel discontinuation. The incidence of neurologic symptoms did not increase in the subset of patients previously treated with cisplatin. Pre-existing neuropathies resulting from prior therapies are not a contraindication for paclitaxel therapy. In patients with NSCLC, administration of paclitaxel followed by cisplatin resulted in greater incidence of severe neurotoxicity compared to the incidence in patients with ovarian or breast cancer treated with single-agent paclitaxel. Severe neurosensory symptoms were noted in 13% of NSCLC patients

NSCLC patients receiving cisplatin/etoposide.

Other than peripheral neuropathy, serious neurologic events following paclitaxel administration have been rare (<1%) and have included grand mal seizures, ataxia and encephalopathy.

Rare reports of autonomic neuropathy resulting in paralytic ileus and motor neuropathy with resultant minor distal weakness have been received as part of the continuing surveillance of paclitaxel safety. Optic nerve and/or visual disturbances (scintillating scotoma) have also been reported, particularly in patients who have received higher doses than those recommended.

These effects generally have been reversible. However, rare reports in the literature of abnormal visual evoked potentials in patients have suggested persistent optic nerve damage.

ARTHRALGIA / MYALGIA

There was no consistent relationship between dose or schedule of paclitaxel and the frequency or severity of arthralgia/myalgia. Sixty percent of all patients treated in single-agent trials experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after paclitaxel administration, and resolved within a few days. The frequency and severity of musculoskeletal symptoms remained unchanged throughout the treatment period.

ALOPECIA

Alopecia was observed in almost all patients.

GASTROINTESTINAL

Nausea/vomiting, diarrhea and mucositis were reported by 52%, 38% and 31% of all patients, respectively. These manifestations were usually mild to moderate. Mucositis was schedule dependent and occurred more frequently with the 24-hour than with the 3-hour infusion.

In the first-line Phase III ovarian carcinoma study, the incidence of nausea and vomiting when paclitaxel was administered in combination with cisplatin appeared to be greater compared with the database for single-agent paclitaxel in ovarian and breast carcinoma. In the same study, diarrhea of any grade was reported more frequently (16%) compared to the control arm (8%)

(p=0.008), but there was no difference for severe diarrhea.

Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis, and dehydration have been received as part of the continuing surveillance of paclitaxel safety. Rare reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with paclitaxel alone and in combination with other

chemotherapeutic agents.

HEPATIC

No relationship was observed between liver function abnormalities and either dose or schedule of paclitaxel administration. Among patients with normal baseline liver function 7%, 22% and

19% had elevations in bilirubin, alkaline phosphatase and AST (SGOT), respectively. There is no evidence that paclitaxel when given as a 3-hour infusion to patients with mildly abnormal liver function causes exacerbation of abnormal liver function. Prolonged exposure to paclitaxel was not associated with cumulative hepatic toxicity.

Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel safety.

INJECTION SITE REACTIONS

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 3-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.

OTHER

Transient skin changes due to paclitaxel-related hypersensitivity reactions have been observed, but no other skin toxicities were significantly associated with paclitaxel administration. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon (2%). Edema was reported in 21% of all patients (17% of those without baseline edema); only 1% had severe edema and none of these patients required treatment discontinuation. Edema was most commonly focal and disease-related. Edema was observed in 5% of all courses for patients with normal baseline and did not increase with time on study.

Rare reports of skin abnormalities related to radiation recall as well as reports of maculopapular rash and pruritus have been received as part of the continuing surveillance of paclitaxel safety.

Reports of asthenia and malaise have been received as part of the continuing surveillance of

cisplatin as first-line therapy of ovarian cancer, asthenia was reported in 17% of the patients, significantly greater than the 10% incidence observed in the control arm of

cyclophophamide/cisplatin.

SYMPTOMS AND TREATMENT OF 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 alcohol toxicity (see

PRECAUTIONS, Pediatric Use section).

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

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 I.V. (or its equivalent), 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before paclitaxel.

Metastatic Carcinoma of the Ovary

advanced carcinoma of the ovary. Paclitaxel should be given before cisplatin when used in combination

administered intravenously over 3 hours every 3 weeks.

Carcinoma of the Breast

For the adjuvant treatment of node-positive breast cancer, the recommended regimen is

administered sequentially to standard combination therapy.

After failure of initial chemotherapy for metastatic disease or relapse within 6 months of

hours every 3 weeks has been shown to be effective.

Non-small Cell Lung Carcinoma

The recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 3

Single courses of paclitaxel should not be repeated until the neutrophil count is at least 1 500

therapy should have the dosage reduced by 20% for subsequent courses of paclitaxel.

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.

Preparation for Intravenous Administration

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

timeframe. There have been rare reports of precipitation with longer than the recommended 3-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 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.

O

O

OH

O

N

H CH₃

H₃C

O

O

H₃C

O

O OH

O

H

O

O

O

CH₃

O

H₃C

H

CH₃

PHARMACEUTICAL INFORMATION

PROPER NAME: Paclitaxel

CHEMICAL NAME: (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-1,2a,3,4,4a,6,9,10,11,12,12a,12 b-Dodecahydro-4,6,9,11,12,12b-hexahydroxy-4a,8,13,13-tetramethyl-7,

11- methano-5H-cyclodeca(3,4)benz(1,2-b)oxet-5-one 6,12b-diacetate,

12-benzoate, 9-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.

STRUCTURAL FORMULA:

MOLECULAR FORMULA: C₄₇H

MOLECULAR WEIGHT: 853.9

DESCRIPTION: Paclitaxel is a white to off-white crystalline powder with a melting point of 216-223°C. It is highly lipophilic and insoluble in water.

COMPOSITION: Each mL of Paclitaxel For Injection contains paclitaxel 6 mg, cremophor^® EL-P (polyethoxylated castor oil) 527 mg and dehydrated alcohol 49.7% v/v.

III. STABILITY AND STORAGE RECOMMENDATIONS

Paclitaxel For Injection should be stored at (15-25°C). Retain in the original package and protected from light. Paclitaxel For Injection is for single use only. Discard any unused portion.

Solutions for infusion prepared as recommended may be stored at ambient room temperature

reconstitution.

IV. PREPARATION FOR INTRAVENOUS ADMINISTRATION

Contact of undiluted paclitaxel with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended (see DOSAGE AND ADMINISTRATION).

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.

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

V. SPECIAL INSTRUCTIONS

1. 1.

   Preparation of paclitaxel should be done in a vertical laminar flow hood (Biological

   Safety Cabinet -Class II).

2. 2. Personnel preparing paclitaxel should wear PVC gloves, safety glasses, disposable gowns and masks.
3. 3. All needles, syringes, vials and other materials which have come in contact with

may explode. Intact vials should be returned to the Manufacturer for destruction.

Proper precautions should be taken in packaging these materials for transport.

1. 4.

   Personnel regularly involved in the preparation and handling of paclitaxel should have bi-annual blood examinations.

   AVAILABILITY OF DOSAGE FORMS

Paclitaxel For Injection is available in 5 mL and 16.7 mL single dose vials containing 30 mg and

100 mg paclitaxel at a concentration of 6 mg/mL.

PHARMACOLOGY

In vitro

Paclitaxel exhibits cytotoxic activity against a wide variety of both human and rodent tumor cell

colon carcinoma, CNS carcinoma, melanoma, renal carcinoma, ovarian carcinoma and breast

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

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.

Clinical Trials

in previous clinical studies (see ADVERSE REACTIONS). Second-Line data: In addition to the Phase 3 trial described above, data from five Phase 1 and 2 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 6 months from completion of, a platinum containing regimen) with response rates of 14% in the Phase 3 study and 31% in the

Phase 1 & 2 clinical studies. The adverse event profile in this Phase 3 study was consistent with that seen in previous clinical studies (see ADVERSE REACTIONS).

administered by a 3-hour intravenous infusion. The same doses administered by 24-hour infusion were more toxic.

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 3 trial described above, data from three Phase 2 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).

TOXICOLOGY

ACUTE TOXICITY

^aRange-Finding phase

^bLethality 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

a

^b Untreated

CHRONIC TOXICITY

MUTAGENECITY AND GENOTOXICITY

Paclitaxel was not mutagenic in the Ames/Salmonella and Escherichia Coli WP2 reverse

human lymphocytes.

erythrocyte micronucleus assay.

REFERENCES

1.

2.

1. 3. 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.

4.

5.

d

6.

7.

8.

1. 9. Gianni L., Kearns C.M., Giani A., et al. Nonlinear pharmacokinetics and metabolism of

10.

13.

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16.

17.

18.

19.

20.

21.

22.

23.

,

factor in patients with refractory ovarian cancer. J Clin Oncol 1992; 10(7): 1165-1170. 25.

26.

27.

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29.

30.

1. 31. Walsky R.L., Obach R.S., Gaman E.A., Gleeson J-P. R., and Proctor W.R. Selective

32.

33.

34.

35.

36.

,

37.

38.

Herceptin (H) in HER2-Overexpressing (HER2+) Metastatic Breast Cancer (MBC). 39.