Paclitaxel

Note: Contact of the undiluted concentrate with plasticized 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 injection, USP solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

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

For patients with carcinoma of the ovary, the following regimens are recommended (see CLINICAL STUDIES: Ovarian Carcinoma):

For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see Table 11 in ADVERSE REACTIONS: Disease-Specific Adverse Event Experiences). Paclitaxel administered intravenously over 3 hours at a dose of 175 mg/m2 followed by cisplatin at a dose of 75 mg/m2; or Paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin at a dose of 75 mg/m2. In patients previously treated with chemotherapy for carcinoma of the ovary, Paclitaxel injection, USP has been used at several doses and schedules; however, the optimal regimen is not yet clear. The recommended regimen is paclitaxel 135 mg/m2 or 175 mg/m2 administered intravenously over 3 hours every 3 weeks.

For patients with carcinoma of the breast, the following regimens are recommended (see CLINICAL STUDIES: Breast Carcinoma):

For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for four courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used four courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES: Breast Carcinoma). After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks has been shown to be effective.

For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin, 75 mg/m2.

For patients with AIDS-related Kaposi’s sarcoma, paclitaxel administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 mg/m2/week). In the two clinical trials evaluating these schedules (see CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

Reduce the dose of dexamethasone as one of the three premedication drugs to 10 mg PO (instead of 20 mg PO); Initiate or repeat treatment with paclitaxel only if the neutrophil count is at least 1000 cells/mm3; Reduce the dose of subsequent courses of paclitaxel by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer); and Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of paclitaxel 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. Paclitaxel should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1,000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during paclitaxel therapy should have dosage reduced by 20% for subsequent courses of paclitaxel. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Hepatic Impairment: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III-IV myelosuppression (see CLINICAL PHARMACOLOGYand PRECAUTIONS: Hepatic). Recommendations for dosage adjustment for the first course of therapy are shown in Table 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

Table 17: Recommendations for Dosing in Patients With Hepatic Impairment Based on Clinical Trial Data*

Degree of Hepatic Impairment

Recommended

Paclitaxel Dose†

Transaminase
Levels

Bilirubin
Levels‡

* These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m 2 over 24 hours or 175 mg/m 2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma). † Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance. ‡ Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design.

24-hour infusion

<2 x ULN

and

≤1.5 mg/dL

135 mg/m2

2 to <10 x ULN

and

≤1.5 mg/dL

100 mg/m2

<10 x ULN

and

1.6 - 7.5 mg/dL

50 mg/m2

≥10 x ULN

or

> 7.5 mg/dL

Not recommended

3-hour infusion

<10 x ULN

and

≤1.25 x ULN

175 mg/m2

<10 x ULN

and

1.26 - 2. x ULN

135 mg/m2

<10 x ULN

and

2.01 - 5. x ULN

90 mg/m2

≥10 x ULN

or

> 5. x ULN

Not recommended

Preparation and Administration Precautions: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Paclitaxel Injection, USP. If Paclitaxel Injection, USP solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If Paclitaxel Injection, USP 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 PRECAUTIONS: Injection Site Reaction).

Preparation for Intravenous Administration: Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% Sodium Chloride Injection USP; 5% Dextrose Injection USP; 5% Dextrose and 0.9% Sodium Chloride Injection USP 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 (approximately 25 °C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line (0.22 micron) filter.

Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl)phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC containers and administration sets is not recommended. Paclitaxel solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.

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.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of paclitaxel since they can cause the stopper to collapse resulting in loss of sterile integrity of the paclitaxel solution.

Stability: Unopened vials of Paclitaxel injection, USP are stable until the date indicated on the package when stored between 20 °C to 25 °C (68 °F to 77 °F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the paclitaxel vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25 °C) and lighting conditions for up to 27 hours.

Parenteral drug Products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit.

Note: Contact of the undiluted concentrate with plasticized 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 Injection, USP solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

All patients should be premedicated prior to Paclitaxel Injection, USP administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before Paclitaxel Injection, USP, diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to Paclitaxel Injection, USP, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before Paclitaxel Injection, USP.

For patients with carcinoma of the ovary, the following regimens are recommended (see CLINICAL STUDIES: Ovarian Carcinoma):

For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see Table 11 in ADVERSE REACTIONS: Disease-Specific Adverse Event Experiences). Paclitaxel Injection, USP administered intravenously over 3 hours at a dose of 175 mg/m2 followed by cisplatin at a dose of 75 mg/m2; or Paclitaxel Injection, USP administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin at a dose of 75 mg/m2. In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel has been used at several doses and schedules; however, the optimal regimen is not yet clear. The recommended regimen is Paclitaxel Injection, USP 135 mg/m2 or 175 mg/m2 administered intravenously over 3 hours every 3 weeks.

For patients with carcinoma of the breast, the following regimens are recommended (see CLINICAL STUDIES: Breast Carcinoma):

For the adjuvant treatment of node-positive breast cancer, the recommended regimen is Paclitaxel Injection, USP, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for four courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used four courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES: Breast Carcinoma). After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks has been shown to be effective.

For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is Paclitaxel Injection, USP administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin, 75 mg/m2.

For patients with AIDS related Kaposi's sarcoma, Paclitaxel Injection, USP administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 mg/m2/week). In the two clinical trials evaluating these schedules (see CLINICAL STUDIES: AIDS- related Kaposi's Sarcoma), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

Reduce the dose of dexamethasone as one of the three premedication drugs to 10 mg PO (instead of 20 mg PO); Initiate or repeat treatment with Paclitaxel Injection, USP only if the neutrophil count is at least 1000 cells/mm3; Reduce the dose of subsequent courses of Paclitaxel Injection, USP by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer); and Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of Paclitaxel Injection, USP should not be repeated until the neutrophil count is at least 1500 cells/mm3 and the platelet count is at least 100,000 cells/mm3. Paclitaxel Injection, USP should not be given to patients with AIDS-related Kaposi's sarcoma if the baseline or subsequent neutrophil count is less than 1000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during Paclitaxel Injection, USP therapy should have dosage reduced by 20% for subsequent courses of Paclitaxel Injection, USP. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Hepatic Impairment: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III to IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Hepatic). Recommendations for dosage adjustment for the first course of therapy are shown in Table 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

Table 17 Recommendations For Dosing In Patients With Hepatic Impairment Based On Clinical Trial Dataa a These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma)
b Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design
c Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance Degree of Hepatic Impairment Transaminase Levels Bilirubin Levelsb Recommended Paclitaxel Dosec 24-hour infusion <2 × ULN and ≤1.5 mg/dL 135 mg/m2 2 to <10 × ULN and ≤1.5 mg/dL 100 mg/m2 <10 × ULN and 1.6 to 7.5 mg/dL 50 mg/m2 ≥10 × ULN or >7.5 mg/dL Not recommended 3-hour infusion <10 × ULN and ≤1.25 × ULN 175 mg/m2 <10 × ULN and 1.26 to 2 × ULN 135 mg/m2 <10 × ULN and 2.01 to 5 × ULN 90 mg/m2 ≥10 × ULN or >5 × ULN Not recommended

Preparation and Administration Precautions: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Paclitaxel Injection, USP. If Paclitaxel Injection, USP solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If Paclitaxel Injection, USP 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 PRECAUTIONS: Injection Site Reaction).

Preparation for Intravenous Administration: Paclitaxel Injection, USP must be diluted prior to infusion. Paclitaxel Injection, USP should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; 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 48 hours at ambient temperature (approximately 25°C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have 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 Injection, USP 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.

Paclitaxel Injection, USP 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.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of Paclitaxel Injection, USP since they can cause the stopper to collapse resulting in loss of sterile integrity of the Paclitaxel Injection, USP solution.

Stability: Unopened vials of Paclitaxel Injection, USP, are stable until the date indicated on the package when stored between 20° to 25°C (68° to 77°F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration components in the Paclitaxel Injection, USP vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25°C) and lighting conditions for up to 48 hours.

HOW SUPPLIED

NDC 66758-043-01 30 mg/5 mL multidose vial individually packaged in a carton.

NDC 66758-043-02 100 mg/16.7 mL multidose vial individually packaged in a carton.

NDC 66758-043-03 300 mg/50 mL multidose vial individually packaged in a carton.

Storage

Store the vials in original cartons between 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Retain in the original package to protect from light.

Handling and Disposal

See DOSAGE AND ADMINISTRATION: Preparation and Administration Precautions.

Rx only

For Sandoz Inc. Customer Service call 1-800-525-8747.

Manufactured by:

EBEWE Pharma Ges.m.b.H. Nfg.KG
A-4866 Unterach, AUSTRIA

Manufactured for:

Princeton, NJ 08540

Rev. June 2011

REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling occupational exposure to hazardous drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html.

3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.

4. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society.

Chemo Dispensing Pin™ is a trademark of B. Braun Medical Incorporated.
____________________________________________________________________________

* Cremophor® EL is the registered trademark of BASF Aktiengesellschaft.

Cremophor® EL is further purified by a Bristol-Myers Squibb Company proprietary process before use.

DaunoXome® is a registered trademark of Gilead Sciences, Inc.

DOXIL® is a registered trademark of ALZA Corporation

Patient Information

PACLITAXEL INJECTION, USP

Read this patient information leaflet before you start taking Paclitaxel Injection, USP. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about Paclitaxel Injection, USP?

Paclitaxel Injection, USP can cause serious side effects including death.

Serious allergic reactions (anaphylaxis) can happen in people who receive Paclitaxel Injection, USP. Anaphylaxis is a serious medical emergency that can lead to death and must be treated right away.

Tell your healthcare provider right away if you have any of these signs of an allergic reaction:

trouble breathing sudden swelling of your face, lips, tongue, throat, or trouble swallowing hives (raised bumps) or rash

Your healthcare provider will give you medicines to lessen your chance of having an allergic reaction.

What Is Paclitaxel Injection, USP?

Paclitaxel Injection, USP is a prescription medicine used to treat some forms of:

ovarian cancer breast cancer lung cancer Kaposi’s sarcoma

It is not known if Paclitaxel Injection, USP is safe or effective in children.

Who should not receive Paclitaxel Injection, USP?

Do not receive Paclitaxel Injection, USP if:

you are allergic to any of the ingredients in Paclitaxel Injection, USP. See the end of this leaflet for a complete list of ingredients in Paclitaxel Injection, USP. are allergic to medicines containing Cremophor® EL* (polyoxyethylated castor oil). you have low white blood cell counts.

What should I tell my healthcare provider before receiving Paclitaxel Injection, USP?

Before receiving Paclitaxel Injection, USP, tell your healthcare provider about all your medical conditions, including if you:

have liver problems have heart problems are pregnant or plan to become pregnant. Paclitaxel Injection, USP can harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. are breast-feeding or plan to breast-feed. It is not known if Paclitaxel Injection, USP passes into your breast milk. You and your healthcare provider should decide if you will receive Paclitaxel Injection, USP or breast-feed.

Tell your healthcare provider about all the medicines you take, including prescription and non prescription medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How will I receive Paclitaxel Injection, USP?

Paclitaxel Injection, USP is injected into a vein (intravenous [IV] infusion) by your healthcare provider.

Your healthcare provider will do certain tests while you receive Paclitaxel Injection, USP.

What are the possible side effects of Paclitaxel Injection, USP?

Tell your healthcare provider right away if you have:

severe stomach pain severe diarrhea

The most common side effects of Paclitaxel Injection, USP include:

low red blood cell count (anemia) feeling weak or tired hair loss numbness, tingling, or burning in your hands or feet (neuropathy) joint and muscle pain nausea and vomiting hypersensitivity reaction - trouble breathing; sudden swelling of your face, lips, tongue, throat, or trouble swallowing; hives (raised bumps) or rash diarrhea mouth or lip sores (mucositis) infections - if you have a fever (temperature above 100.4°F) or other sign of infection, tell your healthcare provider right away swelling of your hands, face, or feet bleeding events irritation at the injection site low blood pressure (hypotension)

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Paclitaxel Injection, USP. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of Paclitaxel Injection, USP.

Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use Paclitaxel Injection, USP for a condition for which it was not prescribed. Do not give Paclitaxel Injection, USP to other people, even if they have the same symptoms that you have. It may harm them.

This patient information leaflet summarizes the most important information about Paclitaxel Injection, USP. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Paclitaxel Injection, USP that is written for health professionals. For more information call Sandoz Inc., at 1-800-525-8747.

What are the ingredients in Paclitaxel Injection, USP?

Active ingredient: paclitaxel.

Inactive ingredients include: purified Cremophor® EL (polyoxyethylated castor oil) and dehydrated alcohol, USP.

What is cancer?

Under normal conditions, the cells in your body divide and grow in an orderly, controlled way. Cell division and growth are necessary for the human body to perform its functions and to repair itself, when necessary. Cancer cells are different from normal cells because they are not able to control their own growth. The reasons for this abnormal growth are not yet fully understood.

A tumor is a mass of unhealthy cells that are dividing and growing fast and in an uncontrolled way. When a tumor invades surrounding healthy body tissue, it is known as a malignant tumor. A malignant tumor can spread (metastasize) from its original site to other parts of the body if not found and treated early.

Manufactured by:

Ges.m.b.H. Nfg.KG
A-4866 Unterach, AUSTRIA

Manufactured for:

Princeton, NJ 08540

Rev. June 2011

Note: Contact of the undiluted concentrate with plasticized 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 injection solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

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

For patients with carcinoma of the ovary, the following regimens are recommended (see CLINICAL STUDIES: Ovarian Carcinoma):

1) For previously untreated patients with carcinoma of the ovary, one of the following   recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see TABLE 11in ADVERSE REACTIONS: Disease-Specific Adverse Event Experiences).

                a. Paclitaxel Injection administered intravenously over 3 hours at a dose of 175 mg/m2 followed by cisplatin at a dose of 75 mg/m2; or

                b. Paclitaxel Injection administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin at a dose of 75 mg/m2.

2)  In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel injection has been used at several doses and schedules; however, the optimal regimen is not yet clear. The recommended regimen is paclitaxel injection 135 mg/m2 or 175 mg/m2 administered intravenously over 3 hours every 3 weeks.

For patients with carcinoma of the breast, the following regimens are recommended (see CLINICAL STUDIES: Breast Carcinoma):

For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel injection, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES: Breast Carcinoma).

2)  After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel injection at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks has been shown to be effective.

For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel injection administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin, 75 mg/m2.

For patients with AIDS-related Kaposi’s sarcoma, paclitaxel injection administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45–50 mg/m2/week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO);

Initiate or repeat treatment with paclitaxel injection only if the neutrophil count is    

at least 1000 cells/mm3;

      3)  Reduce the dose of subsequent courses of paclitaxel injection by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer); and

Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of paclitaxel injection should not be repeated until the neutrophil count is at least 1500 cells/mm3 and the platelet count is at least    100,000 cells/mm3. Paclitaxel Injection should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during paclitaxel injection therapy should have dosage reduced by 20% for subsequent courses of paclitaxel injection. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Hepatic Impairment

Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGYand PRECAUTIONS: Hepatic). Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 17   for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

TABLE 17 RECOMMENDATIONS FOR DOSING IN PATIENTS WITH HEPATICIMPAIRMENT BASED ON CLINICAL TRIAL DATAa

a These recommendations are based on dosages for patients without hepatic impairment of

135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose

adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma).

b Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to

differences in clinical trial design.

c Dosage recommendations are for the first course of therapy; further dose reduction in

subsequent courses should be based on individual tolerance.

Degree of Hepatic Impairment

Transaminase Levels        
Bilirubin Levelsb
                                                   24-hour infusion
<2 נULN
and
≤1.5 mg/dL
135 mg/m2
2 to <10 נULN
and
≤1.5 mg/dL
100 mg/m2
<10 נULN
and
1.6–7.5 mg/dL
50 mg/m2
≥10 נULN
or
>7.5 mg/dL
Not recommended
                                                   3-hour infusion
<10 נULN
and
≤1.25 נULN
175 mg/m2
<10 נULN
and
1.26–2.0 נULN
135 mg/m2
<10 נULN
and
2.01–5.0 נULN
90 mg/m2
≥10 נULN
or
>5.0 נULN
Not recommended
Preparation and Administration Precautions

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel Injection. If paclitaxel injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If paclitaxel 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 PRECAUTIONS: Injection Site Reaction).

Preparation for Intravenous Administration

Paclitaxel Injection must be diluted prior to infusion. Paclitaxel Injection should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; 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 (approximately 25° C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have 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 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.

Paclitaxel 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® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of paclitaxel injection since they can cause the stopper to collapse resulting in loss of sterile integrity of the paclitaxel injection solution.

Chemo Dispensing Pin™ is a trademark of B. Braun Medical Incorporated.

Stability

Unopened vials of paclitaxel injection are stable until the date indicated on the package when stored between 20°–25° C (68°–77° F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the paclitaxel injection vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25° C) and lighting conditions for up to 27 hours.

Note: Contact of the undiluted concentrate with plasticized 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 injection solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

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

For patients with carcinoma of the ovary, the following regimens are recommended (see CLINICAL STUDIES: Ovarian Carcinoma ):

For previously untreated patients with carcinoma of the ovary, one of the following   recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see TABLE 11 in ADVERSE REACTIONS: Disease-Specific Adverse Event Experiences ). Paclitaxel Injection administered intravenously over 3 hours at a dose of 175 mg/m2 followed by cisplatin at a dose of 75 mg/m2; or Paclitaxel Injection administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin at a dose of 75 mg/m2. In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel injection has been used at several doses and schedules; however, the optimal regimen is not yet clear. The recommended regimen is paclitaxel injection 135 mg/m2 or 175 mg/m2 administered intravenously over 3 hours every 3 weeks.

For patients with carcinoma of the breast, the following regimens are recommended (see CLINICAL STUDIES: Breast Carcinoma ):

For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel injection, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES: Breast Carcinoma ). After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel injection at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks has been shown to be effective.

For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel injection administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin, 75 mg/m2.

For patients with AIDS-related Kaposi’s sarcoma, paclitaxel injection administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45–50 mg/m2/week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma ), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO); Initiate or repeat treatment with paclitaxel injection only if the neutrophil count is atleast 1000 cells/mm3; Reduce the dose of subsequent courses of paclitaxel injection by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer); and Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of paclitaxel injection should not be repeated until the neutrophil count is at least 1500 cells/mm3 and the platelet count is at least    100,000 cells/mm3. Paclitaxel Injection should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during paclitaxel injection therapy should have dosage reduced by 20% for subsequent courses of paclitaxel injection. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Hepatic Impairment

Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Hepatic ). Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

TABLE 17RECOMMENDATIONS FOR DOSING IN PATIENTS WITH HEPATICIMPAIRMENT BASED ON CLINICAL TRIAL DATAa

a These recommendations are based on dosages for patients without hepatic impairment of

135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose

adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma).

b Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to

differences in clinical trial design.

c Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.

Degree of Hepatic  Impairment Recommended  Paclitaxel Transaminase Levels         Bilirubin Levelsb Injection Dosec    24-hour                                         infusion <2 נULN
and
≤1.5 mg/dL
135 mg/m2

2 to <10 נULN
and
≤1.5 mg/dL
100 mg/m2

<10 נULN
and
1.6–7.5 mg/dL
50 mg/m2

≥10 נULN
or
>7.5 mg/dL
Not 
recommended

3-hour 
infusion


<10 נULN
and
≤1.25 נULN
175 mg/m2

<10 נULN
and
1.26–2.0 נULN
135 mg/m2

<10 נULN
and
2.01–5.0 נULN
90 mg/m2

≥10 נULN
or
>5.0 נULN
Not 
recommended
Preparation and Administration Precautions

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel Injection. If paclitaxel injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If paclitaxel 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  PRECAUTIONS: Injection Site Reaction ).

Preparation for Intravenous Administration

Paclitaxel Injection must be diluted prior to infusion. Paclitaxel Injection should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; 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 (approximately 25° C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have 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 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.

Paclitaxel 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® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of paclitaxel injection since they can cause the stopper to collapse resulting in loss of sterile integrity of the paclitaxel injection solution.

Chemo Dispensing Pin™ is a trademark of B. Braun Medical Incorporated.

Stability

Unopened vials of paclitaxel injection are stable until the date indicated on the package when stored between 20°–25° C (68°–77° F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the paclitaxel injection vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25° C) and lighting conditions for up to 27 hours.

Note: Contact of the undiluted concentrate with plasticized 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 Injection, USP solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

All patients should be premedicated prior to Paclitaxel Injection, USP administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before Paclitaxel Injection, USP, diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to Paclitaxel Injection, USP, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before Paclitaxel Injection, USP.

For patients with carcinoma of the ovary, the following regimens are recommended (see CLINICAL STUDIES: Ovarian Carcinoma):

For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see TABLE 11 in ADVERSE REACTIONS: Disease-Specific Adverse Event Experiences). Paclitaxel administered intravenously over 3 hours at a dose of 175 mg/m2 followed by cisplatin at a dose of 75 mg/m2; or Paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin at a dose of 75 mg/m2. In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel has been used at several doses and schedules; however, the optimal regimen is not yet clear. The recommended regimen is paclitaxel 135 mg/m2 or 175 mg/m2 administered intravenously over 3 hours every 3 weeks.

For patients with carcinoma of the breast, the following regimens are recommended (see CLINICAL STUDIES: Breast Carcinoma):

For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES: Breast Carcinoma). After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks has been shown to be effective.

For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin, 75 mg/m2.

For patients with AIDS-related Kaposi's sarcoma, paclitaxel administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 mg/m2/week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES: AIDS-Related Kaposi's Sarcoma), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO); Initiate or repeat treatment with Paclitaxel Injection, USP only if the neutrophil count is at least 1000 cells/mm3; Reduce the dose of subsequent courses of Paclitaxel Injection, USP by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer); and Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of Paclitaxel Injection, USP should not be repeated until the neutrophil count is at least 1500 cells/mm3 and the platelet count is at least 100,000 cells/mm3. Paclitaxel Injection, USP should not be given to patients with AIDS-related Kaposi's sarcoma if the baseline or subsequent neutrophil count is less than 1000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during Paclitaxel Injection, USP therapy should have dosage reduced by 20% for subsequent courses of Paclitaxel Injection, USP. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Hepatic Impairment: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Hepatic). Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

TABLE 17

a These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi's sarcoma).

b Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design.

c Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.

RECOMMENDATIONS FOR DOSING IN PATIENTS WITH HEPATIC IMPAIRMENT BASED ON CLINICAL TRIAL DATAa Degree of Hepatic Impairment Transaminase
Levels Bilirubin
Levelsb Recommended
PACLITAXEL Dosec 24-hour infusion <2 x ULN and ≤1.5 mg/dL 135 mg/m2 2 to <10 x ULN and ≤1.5 mg/dL 100 mg/m2 <10 x ULN and 1.6 to 7.5 mg/dL 50 mg/m2 ≥10 x ULN or >7.5 mg/dL Not recommended 3-hour infusion <10 x ULN and ≤1.25 x ULN 175 mg/m2 <10 x ULN and 1.26 to 2.0 x ULN 135 mg/m2 <10 x ULN and 2.01 to 5.0 x ULN 90 mg/m2 ≥10 x ULN or >5.0 x ULN Not recommended Preparation and Administration Precautions

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Paclitaxel Injection, USP. If Paclitaxel Injection, USP solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If Paclitaxel Injection, USP 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 PRECAUTIONS: Injection Site Reaction).

Preparation for Intravenous Administration

Paclitaxel Injection, USP must be diluted prior to infusion. Paclitaxel Injection, USP should be diluted in 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, 5% Dextrose and 0.9% Sodium Chloride Injection, USP, 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 (approximately 25° C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have 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 Injection, USP 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.

Paclitaxel Injection, USP 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.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of Paclitaxel Injection, USP since they can cause the stopper to collapse resulting in loss of sterile integrity of the Paclitaxel Injection, USP solution.

Parenteral products should be visually inspected for particulate matter.

Stability

Unopened vials of Paclitaxel Injection, USP are stable until the date indicated on the package when stored between 20°–25° C (68°–77° F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the Paclitaxel Injection, USP vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25° C) and lighting conditions for up to 27 hours.

• before using this product read the enclosed consumer information leaflet for complete directions and information • adults and children 12 years of age and over: • vaginal insert: with the applicator place the vaginal insert into the vagina. Throw applicator away after use. • external cream: squeeze a small amount of cream onto your fingertip. Apply the cream onto the itchy, irritated skin outside the vagina. Use 2 times daily for up to 7 days, as needed. • children under 12 years of age: ask a doctor

Note: Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

All patients should be premedicated prior to paclitaxel administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its equivalent) 50 mg 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.

For patients with carcinoma of the ovary, the following regimens are recommended (see CLINICAL STUDIES, Ovarian Carcinoma):

1. For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see TABLE 11 in ADVERSE REACTIONS, Disease-Specific Adverse Event Experiences). 1. Paclitaxel administered intravenously over 3 hours at a dose of 175 mg/m 2 followed by cisplatin at a dose of 75 mg/m 2; or 2. Paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m 2 followed by cisplatin at a dose of 75 mg/m 2. 2. In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel has been used at several doses and schedules; however, the optimal regimen is not yet clear (see CLINICAL STUDIES, Ovarian Carcinoma). The recommended regimen is paclitaxel 135 mg/m2 or 175 mg/m 2 administered intravenously over 3 hours every 3 weeks.

For patients with carcinoma of the breast, the following is recommended (see CLINICAL STUDIES, Breast Carcinoma):

1. For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel, at a dose of 175 mg/m 2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES, Breast Carcinoma). 2. After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m 2 administered intravenously over 3 hours every 3 weeks has been shown to be effective.

For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin, 75 mg/m2.

For patients with AIDS-related Kaposi’s sarcoma, paclitaxel administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 mg/m2/week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES, AIDS-Related Kaposi’s Sarcoma), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

1. Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO); 2. Initiate or repeat treatment with paclitaxel only if the neutrophil count is at least 1,000 cells/mm 3; 3. Reduce the dose of subsequent courses of paclitaxel by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm 3 for a week or longer); and 4. Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of paclitaxel 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. Paclitaxel should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1,000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during paclitaxel therapy should have dosage reduced by 20% for subsequent courses of paclitaxel. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

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. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning and redness. 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.

Hepatic Impairment

Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS, Hepatic). Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

Table 17. Recommendations for Dosing in Patients with Hepatic Impairment Based on Clinical Trial Dataa

Degree of Hepatic Impairment

Recommended Paclitaxel Dosec

Transaminase

Levels

Bilirubin Levelsb

24-Hour Infusion

<2 x ULN

and

≤1.5 mg/dL

135 mg/m2

2 to <10 x ULN

and

≤1.5 mg/dL

100 mg/m2

<10 x ULN

and

1.6 to 7.5 mg/dL

50 mg/m2

≥10 x ULN

or

>7.5 mg/dL

Not recommended

3-Hour Infusion

<10 x ULN

and

≤1.25 x ULN

175 mg/m2

<10 x ULN

and

1.26 to 2.0 x ULN

135 mg/m2

<10 x ULN

and

2.01 to 5.0 x ULN

90 mg/m2

≥10 x ULN

or

>5.0 x ULN

Not recommended

a   These recommendations are based on dosages for patients without hepatic imairement of 135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma).

b   Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design.

c   Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.

Preparation and Administration Precautions

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel injection. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. 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.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration (see PRECAUTIONS, Injection Site Reaction).

Preparation for Intravenous Administration

Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; 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 (approximately 25° C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line (0.22 micron) filter.

Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl)phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC containers and administration sets is not recommended. Paclitaxel solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.

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.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of paclitaxel since they can cause the stopper to collapse resulting in loss of sterile integrity of the paclitaxel solution.

Stability

Unopened vials of paclitaxel are stable until the date indicated on the package when stored between 20° to 25°C (68° to 77°F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the paclitaxel vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25°C) and lighting conditions for up to 27 hours.

NOTE: Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

All patients should be premedicated prior to paclitaxel administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its equivalent) 50 mg 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.

For patients with carcinoma of the ovary the following regimen is recommended: (see CLINICAL STUDIES: Ovarian Carcinoma):

1)   For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see Table 11 in ADVERSE REACTIONS: Disease-Specific Adverse Event Experiences).

a.   Paclitaxel administered intravenously over 3 hours at a dose of 175 mg/m2 followed by cisplatin at a dose of 75 mg/m2; or

b.   Paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin at a dose of 75 mg/m2.

2)   In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel has been used at several doses and schedules; however, the optimal regimen is not yet clear. (See CLINICAL STUDIES: Ovarian Carcinoma section). The recommended regimen is paclitaxel 135 mg/m2 or 175 mg/m2 administered intravenously over 3 hours every 3 weeks.

For patients with carcinoma of the breast, the following is recommended (see CLINICAL STUDIES: Breast Carcinoma section):

1)   For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES: Breast Carcinoma).

2)   After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks has been shown to be effective.

For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin, 75 mg/m2.

For patients with AIDS-related Kaposi’s sarcoma, paclitaxel administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45–50 mg/m2/week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

1)   Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO);

2)   Initiate or repeat treatment with paclitaxel only if the neutrophil count is at least 1,000 cells/mm3;

3)   Reduce the dose of subsequent courses of paclitaxel by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer); and

4)   Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

For the therapy of patients with solid tumors (ovary, breast and NSCLC), courses of paclitaxel 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. Paclitaxel should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1,000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during Paclitaxel Injection, USP therapy should have dosage reduced by 20% for subsequent courses of paclitaxel. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Hepatic Impairment: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Hepatic). Recommendations for dosage adjustment for the first course of therapy are shown in Table 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

Table 17. Recommendations for Dosing in Patients with Hepatic Impairment Based on Clinical Trial Dataa

Degree of Hepatic Impairment

Recommended Paclitaxel Dosec

Transaminase

Levels

Bilirubin Levelsb

24-Hour Infusion

<2 x ULN

and

≤1.5 mg/dL

135 mg/m2

2 to <10 x ULN

and

≤1.5 mg/dL

100 mg/m2

<10 x ULN

and

1.6-7.5 mg/dL

50 mg/m2

≥10 x ULN

or

>7.5 mg/dL

Not recommended

3-Hour Infusion

<10 x ULN

and

≤1.25 x ULN

175 mg/m2

<10 x ULN

and

1.26-2.0 x ULN

135 mg/m2

<10 x ULN

and

2.01-5.0 x ULN

90 mg/m2

≥10 x ULN

or

>5.0 x ULN

Not recommended

a   These recommendations are based on dosages for patients without hepatic imairement of 135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma).

b   Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design.

c   Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.

Preparation and Administration Precautions: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel Injection. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. 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.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. (See PRECAUTIONS: Injection Site Reaction section.)

Preparation for Intravenous Administration: Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP 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 (approximately 25°C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have 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.

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.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of paclitaxel since they can cause the stopper to collapse resulting in loss of sterile integrity of the paclitaxel solution.

Stability: Unopened vials of Paclitaxel Injection, USP are stable until the date indicated on the package when stored between 20° to 25°C (68° to 77°F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration components in the paclitaxel vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25°C) and lighting conditions for up to 27 hours.

Note: Contact of the undiluted concentrate with plasticized 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 injection solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

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

For patients with carcinoma of the ovary, the following regimens are recommended (see CLINICAL STUDIES: Ovarian Carcinoma ):

For previously untreated patients with carcinoma of the ovary, one of the following   recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see TABLE 11 in ADVERSE REACTIONS: Disease-Specific Adverse Event Experiences ). Paclitaxel Injection administered intravenously over 3 hours at a dose of 175 mg/m2 followed by cisplatin at a dose of 75 mg/m2; or Paclitaxel Injection administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin at a dose of 75 mg/m2. In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel injection has been used at several doses and schedules; however, the optimal regimen is not yet clear. The recommended regimen is paclitaxel injection 135 mg/m2 or 175 mg/m2 administered intravenously over 3 hours every 3 weeks.

For patients with carcinoma of the breast, the following regimens are recommended (see CLINICAL STUDIES: Breast Carcinoma ):

For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel injection, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES: Breast Carcinoma ). After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel injection at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks has been shown to be effective.

For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel injection administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin, 75 mg/m2.

For patients with AIDS-related Kaposi’s sarcoma, paclitaxel injection administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45–50 mg/m2/week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma ), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO); Initiate or repeat treatment with paclitaxel injection only if the neutrophil count is atleast 1000 cells/mm3; Reduce the dose of subsequent courses of paclitaxel injection by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer); and Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of paclitaxel injection should not be repeated until the neutrophil count is at least 1500 cells/mm3 and the platelet count is at least    100,000 cells/mm3. Paclitaxel Injection should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during paclitaxel injection therapy should have dosage reduced by 20% for subsequent courses of paclitaxel injection. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Hepatic Impairment

Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Hepatic ). Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

TABLE 17RECOMMENDATIONS FOR DOSING IN PATIENTS WITH HEPATICIMPAIRMENT BASED ON CLINICAL TRIAL DATAa

a These recommendations are based on dosages for patients without hepatic impairment of

135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose

adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma).

b Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to

differences in clinical trial design.

c Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.

Degree of Hepatic  Impairment Recommended  Transaminase Levels         Bilirubin Levelsb Paclitaxel Injection Dosec    24-hour                                         infusion <2 נULN
and
≤1.5 mg/dL
135 mg/m2
2 to <10 נULN
and
≤1.5 mg/dL
100 mg/m2
<10 נULN
and
1.6–7.5 mg/dL
50 mg/m2
≥10 נULN
or
>7.5 mg/dL
Not recommended

3-hour 
infusion

<10 נULN
and
≤1.25 נULN
175 mg/m2
<10 נULN
and
1.26–2.0 נULN
135 mg/m2
<10 נULN
and
2.01–5.0 נULN
90 mg/m2
≥10 נULN
or
>5.0 נULN
Not recommended
Preparation and Administration Precautions

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel Injection. If paclitaxel injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If paclitaxel 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  PRECAUTIONS: Injection Site Reaction ).

Preparation for Intravenous Administration

Paclitaxel Injection must be diluted prior to infusion. Paclitaxel Injection should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; 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 (approximately 25° C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have 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 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.

Paclitaxel 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® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of paclitaxel injection since they can cause the stopper to collapse resulting in loss of sterile integrity of the paclitaxel injection solution.

Chemo Dispensing Pin™ is a trademark of B. Braun Medical Incorporated.

Stability

Unopened vials of paclitaxel injection are stable until the date indicated on the package when stored between 20°–25° C (68°–77° F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the paclitaxel injection vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25° C) and lighting conditions for up to 27 hours.

Note: Contact of the undiluted concentrate with plasticized 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 Injection USP solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

All patients should be premedicated prior to Paclitaxel Injection USP administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before Paclitaxel Injection USP, diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to Paclitaxel Injection USP, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before Paclitaxel Injection USP.

For patients with carcinoma of the ovary, the following regimens are recommended (see CLINICAL STUDIES: Ovarian Carcinoma):

1) For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see TABLE 11 in ADVERSE REACTIONS: Disease-Specific Adverse Event Experiences).

Paclitaxel administered intravenously over 3 hours at a dose of 175 mg/m2 followed by cisplatin at a dose of 75 mg/m2; or Paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin at a dose of 75 mg/m2.

2) In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel has been used at several doses and schedules; however, the optimal regimen is not yet clear. The recommended regimen is paclitaxel 135 mg/m2 or 175 mg/m2 administered intravenously over 3 hours every 3 weeks.

For patients with carcinoma of the breast, the following regimens are recommended (see CLINICAL STUDIES: Breast Carcinoma):

1) For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES: Breast Carcinoma).

2) After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks has been shown to be effective.

For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin, 75 mg/m2.

For patients with AIDS-related Kaposi’s sarcoma, paclitaxel administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 mg/m2/week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

1) Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO);

2) Initiate or repeat treatment with Paclitaxel Injection USP only if the neutrophil count is at least 1000 cells/mm3;

3) Reduce the dose of subsequent courses of Paclitaxel Injection USP by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer); and

4) Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of Paclitaxel Injection USP should not be repeated until the neutrophil count is at least 1500 cells/mm3 and the platelet count is at least 100,000 cells/mm3. Paclitaxel Injection USP should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during Paclitaxel Injection USP therapy should have dosage reduced by 20% for subsequent courses of Paclitaxel Injection USP. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Hepatic Impairment: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Hepatic). Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

TABLE 17 RECOMMENDATIONS FOR DOSING IN PATIENTS WITH HEPATIC IMPAIRMENT BASED ON CLINICAL TRIAL DATAa   Degree of Hepatic Impairment      Transaminase Levels   Bilirubin Levelsb   Recommended PACLITAXEL Dosec   a These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma).   b Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design.   c Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.   24-hour infusion   <2 x ULN   and   ≤1.5 mg/dL   135 mg/m2   2 to <10 x ULN   and   ≤1.5 mg/dL   100 mg/m2   <10 x ULN   and   1.6 to 7.5 mg/dL   50 mg/m2   ≥10 x ULN   or   >7.5 mg/dL   Not recommended   3-hour infusion   <10 x ULN   and   ≤1.25 x ULN   175 mg/m2   <10 x ULN   and   1.26 to 2.0 x ULN   135 mg/m2   <10 x ULN   and   2.01 to 5.0 x ULN   90 mg/m2   ≥10 x ULN   or   >5.0 x ULN   Not recommended Preparation and Administration Precautions

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Paclitaxel Injection USP. If Paclitaxel Injection USP solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If Paclitaxel Injection USP 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 PRECAUTION: Injection Site Reaction).

Preparation for Intravenous Administration 

Paclitaxel Injection USP must be diluted prior to infusion. Paclitaxel Injection USP should be diluted in 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, 5% Dextrose and 0.9% Sodium Chloride Injection, USP, 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 (approximately 25° C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have 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 Injection USP 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.

Paclitaxel Injection USP 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.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of Paclitaxel Injection USP since they can cause the stopper to collapse resulting in loss of sterile integrity of the Paclitaxel Injection USP solution.

Parenteral products should be visually inspected for particulate matter.

Stability

Unopened vials of Paclitaxel Injection USP are stable until the date indicated on the package when stored between 20°–25° C (68°–77° F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the Paclitaxel Injection USP vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25° C) and lighting conditions for up to 27 hours.