Paclitaxel Injection

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).

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). 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 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 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.

Paclitaxel is contraindicated in patients who have a history of hypersensitivity reactions to Paclitaxel or other drugs formulated in polyoxyl 35 castor oil.

Paclitaxel should not be used in patients with solid tumors who have baseline neutrophil counts of <1,500 cells/mm³ or in patients with AIDS-related Kaposi's sarcoma with baseline neutrophil counts of <1,000 cells/mm³.

Pooled Analysis of Adverse Event Experiences from Single-Agent Studies

Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with breast carcinoma) enrolled in 10 studies who received single-agent paclitaxel injection. Two hundred and seventy-five patients were treated in 8, Phase 2 studies with paclitaxel doses ranging from 135 to 300 mg/m² administered over 24 hours (in 4 of these studies, G-CSF was administered as hematopoietic support). Three hundred and one patients were treated in the randomized Phase 3 ovarian carcinoma study which compared 2 doses (135 or 175 mg/m²) and 2 schedules (3 or 24 hours) of paclitaxel. Two hundred and thirty-six patients with breast carcinoma received paclitaxel (135 or 175 mg/m²) administered over 3 hours in a controlled study.

TABLE 10. SUMMARY^a OF ADVERSE EVENTS IN PATIENTS WITH SOLID TUMORS RECEIVING SINGLE-AGENT PACLITAXEL

^a Based on worst course analysis.

^b All patients received premedication.

^c During the first 3 hours of infusion.

^†    Severe events are defined as at least Grade III toxicity.

None of the observed toxicities were clearly influenced by age.

Disease-Specific Adverse Event Experiences

First-Line Ovary in Combination

For the 1084 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy studies, TABLE 11 shows the incidence of important adverse events. For both studies, the analysis of safety was based on all courses of therapy (6 courses for the GOG-111 study and up to 9 courses for the Intergroup study).

TABLE 11. FREQUENCY^a OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA STUDIES 

^a Based on worst course analysis.

^b Paclitaxel (T) dose in mg/m²/infusion duration in hours.

^c Cyclophosphamide (C) or cisplatin (c) dose in mg/m².

^d P<0.05 by Fisher exact test.

^e <130,000/mm³ in the Intergroup study.

^f <12 g/dL in the Intergroup study.

^g All patients received premedication.

^h In the GOG-111 study, neurotoxicity was collected as peripheral neuropathy and in the Intergroup study, neurotoxicity was collected as either neuromotor or neurosensory symptoms.

^†      Severe events are defined as at least Grade III toxicity.

NC  Not Collected

Second-Line Ovary

For the 403 patients who received single-agent paclitaxel in the Phase 3 second-line ovarian carcinoma study, the following table shows the incidence of important adverse events.

 In a Phase 1 trial using escalating doses of paclitaxel (110 to 200 mg/m²) and cisplatin (50 or 75 mg/m²) given as sequential infusions, myelosuppression was more profound when paclitaxel was given after cisplatin than with the alternate sequence (i.e., paclitaxel before cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when paclitaxel was administered following cisplatin.

The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when administering paclitaxel concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CTP2C8 and CYP3A4. Caution should be exercised when paclitaxel is concomitantly administered with known substrates (e.g, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine) of CYP3A4. (see CLINICAL PHARMACOLOGY).

Caution should also be exercised when paclitaxel is concomitantly administered with known substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., rifampin) of CYP2C8. (see CLINICAL PHARMACOLOGY).

Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials.

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

Hematology

Paclitaxel therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm³. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel. Patients should not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm³ and platelets recover to a level >100,000 cells/mm³. In the case of severe neutropenia (<500 cells/mm³ for 7 days or more)during a course of paclitaxel therapy, a 20% reduction in dose for subsequent courses of therapy is recommended.



For patients with advanced HIV disease and poor-risk AIDS-related Kaposi's sarcoma, paclitaxel, at the recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 1,000 cells/mm³.



Hypersensitivity Reactions: Patients with a history of severe hypersensitivity reactions to products containing polyoxyl 35 castor oil (e.g., cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with paclitaxel. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with paclitaxel should be premedicated with corticosteroids (such as dexamethasone), diphenhydramine and H₂ antagonists (such as cimetidine or ranitidine). Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with paclitaxel.



Cardiovascular

Hypotension, bradycardia, and hypertension have been observed during administration of paclitaxel, but generally do not require treatment. Occasionally paclitaxel infusions must be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities. (see WARNINGS). When paclitaxel is used in combination with doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is recommended. (see ADVERSE REACTIONS).

Nervous System

Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of paclitaxel.

Paclitaxel contains dehydrated alcohol USP, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol. (see PRECAUTIONS, Pediatric Use).

Hepatic

There is limited evidence that the myelotoxicity of paclitaxel may be exacerbated in patients with serum total bilirubin >2 times ULN (see CLINICAL PHARMACOLOGY). Extreme caution should be exercised when administering paclitaxel to such patients, with dose reduction as recommended in DOSAGE AND ADMINISTRATION, TABLE 17.

Injection Site Reaction

Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e., ''recall'' has been reported.



More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to 10 days.



A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Paclitaxel Injection, USP (6 mg/mL) is available as follows:

NDC 72205-061-01 30 mg/5 mL multidose vial individually packaged in a carton.

NDC 72205-062-01 100 mg/16.7 mL multidose vial individually packaged in a carton.

NDC 72205-063-01 300 mg/50 mL multidose vial individually packaged in a carton.

Storage

Store the vials in original cartons between 20^o to 25^oC (68^o to 77^oF)[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.

Paclitaxel (pak” li tax’ el) Injection, USP

Read this patient information leaflet before you start taking paclitaxel. 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?

Paclitaxel can cause serious side effects including death.

Serious allergic reactions (anaphylaxis) can happen in people who receive paclitaxel. 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?

Paclitaxel 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 is safe or effective in children.

Who should not receive paclitaxel?

Do not receive paclitaxel if:

• you are allergic to any of the ingredients in paclitaxel. See the end of this leaflet for a complete list of ingredients in paclitaxel.

• are allergic to medicines containing polyoxyl 35 castor oil*.

• you have low white blood cell counts.

What should I tell my healthcare provider before receiving paclitaxel?

Before receiving paclitaxel, 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 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 passes into your breast milk. You and your healthcare provider should decide if you will receive paclitaxel 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?

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

Your healthcare provider will do certain tests while you receive paclitaxel.

What are the possible side effects of paclitaxel?

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. 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.

Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use paclitaxel for a condition for which it was not prescribed. Do not give paclitaxel injection 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. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about paclitaxel injection that is written for health professionals. For more information call 1-855-668-2369 or go to www.novadozpharma.com

What are the ingredients in paclitaxel?

Active ingredient: paclitaxel, USP.

Inactive ingredients include: citric acid, dehydrated alcohol and purified polyoxyl 35 castor oil.

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:

MSN Laboratories Private Limited

Telangana – 509 228,

INDIA

Distributed by:

 

Novadoz Pharmaceuticals LLC

Piscataway, NJ 08854 -3714

Issued on: 08/2020

Paclitaxel Injection, USP is a clear, colorless to slightly yellow viscous solution. It is supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion. Paclitaxel Injection, USP is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multidose vials. Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, USP, 527 mg of purified polyoxyl 35 castor oil and 49.7% (v/v) dehydrated alcohol, USP and 2 mg citric acid, USP.



Paclitaxel is a natural product with antitumor activity. Paclitaxel is obtained via an extraction process from Taxus X media. The chemical name for paclitaxel is (2aR, 4S,4aS,6R, 9S ,11S ,12S ,12aR, 12bS )-1,2a,3,4, 4a,6,9,10, 11,12,12a,12b- Dodecahydro-4,6,9 ,11, 12, 12b-hexahydroxy-4a,8,13,13-tetramethyl-7,11-methano-5H-cyclodeca[3,4]-benz[1,2-b]oxet-5-one6,12b-diacetate,12-benzoate,9-esterwith(2R,3S)-N-benzoyl-3-phenylisoserine



Paclitaxel has the following structural formula:

Paclitaxel, USP is a white to off-white powder with the molecular formula C₄₇H₅₁NO₁₄ and a molecular weight of 853.91. It is highly lipophilic, insoluble in water, soluble in alcohol, and melts at around 213^o to 222^oC.

TABLE 2B. EFFICACY IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA INTERGROUP STUDY

^a Paclitaxel dose in mg/m²/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m².

^b Among patients with measurable disease only.

^c Unstratified.

Paclitaxel should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H₂ antagonists (see DOSAGE AND ADMINISTRATION). Patients who experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with the drug.

Paclitaxel therapy should not be given to patients with solid tumors who have baseline neutrophil counts of less than 1,500 cells/mm³ and should not be given to patients with AIDS-related Kaposi's sarcoma if the baseline neutrophil count is less than 1,000 cells/mm³. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel.

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H₂ antagonists. (see DOSAGE AND ADMINISTRATION). Patients who experience severe hypersensitivity reactions to Paclitaxel should not be rechallenged with the drug.

Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting toxicity. Neutrophil nadirs occurred at a median of 11 days. Paclitaxel should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm³ (<1,000 cells/mm³ for patients with KS). Frequent monitoring of blood counts should be instituted during paclitaxel treatment. Patients should not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm3 (>1,000 cells/mm³ for patients with KS) and platelets recover to a level >100,000 cells/mm³.

Severe conduction abnormalities have been documented in <1% of patients during paclitaxel therapy and in some cases requiring pacemaker placement. If patients develop significant conduction abnormalities during paclitaxel infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel.

Pregnancy

Paclitaxel can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3 mg/kg/day (about 0.2 the daily maximum recommended human dose on a mg/m² basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths. Maternal toxicity was also observed at this dose. No teratogenic effects were observed at 1 mg/kg/day (about 1/15 the daily maximum recommended human dose on a mg/m² basis); teratogenic potential could not be assessed at higher doses due to extensive fetal mortality.

There are no adequate and well-controlled studies in pregnant women. If paclitaxel is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant.

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

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.

Manufactured by:

MSN Laboratories Private Limited

Telangana – 509 228,

INDIA

Distributed by:

 

Novadoz Pharmaceuticals LLC

Piscataway, NJ 08854 -3714

Issued on: 08/2020

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

Paclitaxel should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2^® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

Of 2228 patients who received paclitaxel in 8 clinical studies evaluating its safety and effectiveness in the treatment of advanced ovarian cancer, breast carcinoma, or NSCLC, and 1,570 patients who were randomized to receive paclitaxel in the adjuvant breast cancer study, 649 patients (17%) were 65 years or older and 49 patients (1%) were 75 years or older. In most studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in elderly patients. In 2 clinical studies in NSCLC, the elderly patients treated with paclitaxel had a higher incidence of cardiovascular events. Estimates of efficacy appeared similar in elderly patients and in younger patients; however, comparative efficacy cannot be determined with confidence due to the small number of elderly patients studied. In a study of first-line treatment of ovarian cancer, elderly patients had a lower median survival than younger patients, but no other efficacy parameters favored the younger group. TABLE 9 presents the incidences of Grade IV neutropenia and severe neuropathy in clinical studies according to age.

TABLE 9. SELECTED ADVERSE EVENTS IN GERIATRIC PATIENTS RECEIVING PACLITAXEL IN CLINICAL STUDIES

*   p<0.05

^a Paclitaxel dose in mg/m²/infusion duration in hours; cisplatin doses in mg/m². 

^b Peripheral neuropathy was included within the neurotoxicity category in the Intergroup First-Line Ovarian Cancer study (see TABLE 11). 

^c Paclitaxel dose in mg/m²/infusion duration in hours. 

^d Paclitaxel (T) following 4 courses of doxorubicin and cyclophosphamide (AC) at a dose of 175 mg/m²/3 hours every 3 weeks for 4 courses. 

^e Peripheral neuropathy reported as neurosensory toxicity in the Intergroup Adjuvant Breast Cancer study (see TABLE 13). 

^f Peripheral neuropathy reported as neurosensory toxicity in the ECOG NSCLC study (see TABLE 15). 

Information for Patients (See Patient Information Leaflet).

The safety and effectiveness of paclitaxel in pediatric patients have not been established.

There have been reports of central nervous system (CNS) toxicity (rarely associated with death) in a clinical trial in pediatric patients in which paclitaxel was infused intravenously over 3 hours at doses ranging from 350 mg/m² to 420 mg/m². The toxicity is most likely attributable to the high dose of the ethanol component of the paclitaxel vehicle given over a short infusion time. The use of concomitant antihistamines may intensify this effect. Although a direct effect of the paclitaxel itself cannot be discounted, the high doses used in this study (over twice the recommended adult dosage) must be considered in assessing the safety of paclitaxel for use in this population.

It is not known whether the drug is excreted in human milk. Following intravenous administration of carbon 14-labeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving paclitaxel therapy.

Ovarian Carcinoma

First-Line Data

The safety and efficacy of paclitaxel followed by cisplatin in patients with advanced ovarian cancer and no prior chemotherapy were evaluated in 2, Phase 3 multicenter, randomized, controlled trials. In an Intergroup study led by the European Organization for Research and Treatment of Cancer involving the Scandinavian Group NOCOVA, the National Cancer Institute of Canada, and the Scottish Group, 680 patients with Stage II_B-C, III, or IV disease (optimally or non-optimally debulked) received either paclitaxel 175 mg/m² infused over 3 hours followed by cisplatin 75 mg/m² (Tc) or cyclophosphamide 750 mg/m2 followed by cisplatin 75 mg/m2 (Cc) for a median of 6 courses. Although the protocol allowed further therapy, only 15% received both drugs for 9 or more courses. In a study conducted by the Gynecological Oncology Group (GOG), 410 patients with Stage III or IV disease (>1 cm residual disease after staging laparotomy or distant metastases) received either paclitaxel 135 mg/m₂ infused over 24 hours followed by cisplatin 75 mg/m² or cyclophosphamide 750 mg/m² followed by cisplatin 75 mg/m² for 6 courses.

In both studies, patients treated with paclitaxel in combination with cisplatin had significantly higher response rate, longer time to progression, and longer survival time compared with standard therapy. These differences were also significant for the subset of patients in the Intergroup study with non-optimally debulked disease, although the study was not fully powered for subset analyses (TABLES 2A and 2B). Kaplan- Meier survival curves for each study are shown in FIGURES 1 and 2.

TABLE 2A. EFFICACY IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA STUDIES

^a Paclitaxel dose in mg/m²/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m².

^b Among patients with measurable disease only.

^cUnstratified for the Intergroup Study, Stratified for Study GOG-111.

Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

Following intravenous administration of paclitaxel, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.

Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of paclitaxel at dose levels of 135 and 175 mg/m² were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table.

TABLE 1. SUMMARY OF PHARMACOKINETIC PARAMETERS—MEAN VALUES

C_max = Maximum plasma concentration

AUC_(0-∞) = Area under the plasma concentration-time curve from time 0 to infinity

CL_T = Total body clearance



It appeared that with the 24-hour infusion of paclitaxel, a 30% increase in dose (135 mg/m² vs 175 mg/m²) increased the C_max by 87%, whereas the AUC_(0-∞) remained proportional. However, with a 3-hour infusion, for a 30% increase in dose, the C_max and AUC_(0-∞) were increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state, with the 24-hour infusion of paclitaxel, ranged from 227 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding of paclitaxel.

The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single doses of 15 to 135 mg/m² given by 1-hour infusions (n=15), 30 to 275 mg/m² given by 6-hour infusions (n=36), and 200 to 275 mg/m² given by 24-hour infusions (n=54) in Phase 1 and 2 studies. Values for CL_T and volume of distribution were consistent with the findings in the Phase 3 study. The pharmacokinetics of paclitaxel in patients with AIDS-related Kaposi's sarcoma have not been studied.

In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 mcg/mL, indicate that between 89 to 98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

After intravenous administration of 15 to 275 mg/m² doses of paclitaxel as 1-, 6-, or 24-hour infusions, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating extensive non-renal clearance. In 5 patients administered a 225 or 250 mg/m² dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Total recovery of radioactivity ranged from 56% to 101% of the dose. Paclitaxel represented a mean of 5% of the administered radioactivity recovered in the feces, while metabolites, primarily 6α-hydroxypaclitaxel, accounted for the balance. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to 2 minor metabolites, 3'-p-hydroxypaclitaxel and 6α, 3'-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4 (see PRECAUTIONS, Drug Interactions).



The disposition and toxicity of paclitaxel 3-hour infusion were evaluated in 35 patients with varying degrees of hepatic function. Relative to patients with normal bilirubin, plasma paclitaxel exposure in patients with abnormal serum bilirubin ≤2 times upper limit of normal (ULN) administered 175 mg/m² was increased, but with no apparent increase in the frequency or severity of toxicity. In 5 patients with serum total bilirubin >2 times ULN, there was a statistically nonsignificant higher incidence of severe myelosuppression, even at a reduced dose (110 mg/m²), but no observed increase in plasma exposure (see PRECAUTIONS, Hepatic and DOSAGE AND ADMINISTRATION). The effect of renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated.

Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.

Paclitaxel Injection, USP is indicated as subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line therapy, Paclitaxel Injection, USP is indicated in combination with cisplatin.



Paclitaxel Injection, USP is indicated for the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy. In the clinical trial, there was an overall favorable effect on disease-free and overall survival in the total population of patients with receptor-positive and receptor-negative tumors, but the benefit has been specifically demonstrated by available data (median follow-up 30 months) only in the patients with estrogen and progesterone receptor-negative tumors (see CLINICAL STUDIES: Breast Carcinoma).



Paclitaxel Injection, USP is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Paclitaxel Injection, USP, in combination with cisplatin, is indicated for the first-line treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy.



Paclitaxel Injection, USP is indicated for the second-line treatment of AIDS-related Kaposi's sarcoma.

Paclitaxel injection-30 mg/5ml-vial-label

The carcinogenic potential of paclitaxel has not been studied.

Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.

Administration of paclitaxel prior to and during mating produced impairment of fertility in male and female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum recommended human dose on a mg/m² basis). At this dose, paclitaxel caused reduced fertility and reproductive indices, and increased embryo- and fetotoxicity. (See WARNINGS.)

TABLE 2B. EFFICACY IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA INTERGROUP STUDY

^a Paclitaxel dose in mg/m²/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m².

^b Among patients with measurable disease only.

^c Unstratified.

Paclitaxel should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H₂ antagonists (see DOSAGE AND ADMINISTRATION). Patients who experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with the drug.

Paclitaxel therapy should not be given to patients with solid tumors who have baseline neutrophil counts of less than 1,500 cells/mm³ and should not be given to patients with AIDS-related Kaposi's sarcoma if the baseline neutrophil count is less than 1,000 cells/mm³. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel.

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H₂ antagonists. (see DOSAGE AND ADMINISTRATION). Patients who experience severe hypersensitivity reactions to Paclitaxel should not be rechallenged with the drug.

Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting toxicity. Neutrophil nadirs occurred at a median of 11 days. Paclitaxel should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm³ (<1,000 cells/mm³ for patients with KS). Frequent monitoring of blood counts should be instituted during paclitaxel treatment. Patients should not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm3 (>1,000 cells/mm³ for patients with KS) and platelets recover to a level >100,000 cells/mm³.

Severe conduction abnormalities have been documented in <1% of patients during paclitaxel therapy and in some cases requiring pacemaker placement. If patients develop significant conduction abnormalities during paclitaxel infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel.

Pregnancy

Paclitaxel can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3 mg/kg/day (about 0.2 the daily maximum recommended human dose on a mg/m² basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths. Maternal toxicity was also observed at this dose. No teratogenic effects were observed at 1 mg/kg/day (about 1/15 the daily maximum recommended human dose on a mg/m² basis); teratogenic potential could not be assessed at higher doses due to extensive fetal mortality.

There are no adequate and well-controlled studies in pregnant women. If paclitaxel is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant.

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

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.

Manufactured by:

MSN Laboratories Private Limited

Telangana – 509 228,

INDIA

Distributed by:

 

Novadoz Pharmaceuticals LLC

Piscataway, NJ 08854 -3714

Issued on: 08/2020

Paclitaxel Injection, USP is a clear, colorless to slightly yellow viscous solution. It is supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion. Paclitaxel Injection, USP is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multidose vials. Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, USP, 527 mg of purified polyoxyl 35 castor oil and 49.7% (v/v) dehydrated alcohol, USP and 2 mg citric acid, USP.



Paclitaxel is a natural product with antitumor activity. Paclitaxel is obtained via an extraction process from Taxus X media. The chemical name for paclitaxel is (2aR, 4S,4aS,6R, 9S ,11S ,12S ,12aR, 12bS )-1,2a,3,4, 4a,6,9,10, 11,12,12a,12b- Dodecahydro-4,6,9 ,11, 12, 12b-hexahydroxy-4a,8,13,13-tetramethyl-7,11-methano-5H-cyclodeca[3,4]-benz[1,2-b]oxet-5-one6,12b-diacetate,12-benzoate,9-esterwith(2R,3S)-N-benzoyl-3-phenylisoserine



Paclitaxel has the following structural formula:

Paclitaxel, USP is a white to off-white powder with the molecular formula C₄₇H₅₁NO₁₄ and a molecular weight of 853.91. It is highly lipophilic, insoluble in water, soluble in alcohol, and melts at around 213^o to 222^oC.

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

Paclitaxel should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2^® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

Paclitaxel Injection, USP (6 mg/mL) is available as follows:

NDC 72205-061-01 30 mg/5 mL multidose vial individually packaged in a carton.

NDC 72205-062-01 100 mg/16.7 mL multidose vial individually packaged in a carton.

NDC 72205-063-01 300 mg/50 mL multidose vial individually packaged in a carton.

Storage

Store the vials in original cartons between 20^o to 25^oC (68^o to 77^oF)[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.

Of 2228 patients who received paclitaxel in 8 clinical studies evaluating its safety and effectiveness in the treatment of advanced ovarian cancer, breast carcinoma, or NSCLC, and 1,570 patients who were randomized to receive paclitaxel in the adjuvant breast cancer study, 649 patients (17%) were 65 years or older and 49 patients (1%) were 75 years or older. In most studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in elderly patients. In 2 clinical studies in NSCLC, the elderly patients treated with paclitaxel had a higher incidence of cardiovascular events. Estimates of efficacy appeared similar in elderly patients and in younger patients; however, comparative efficacy cannot be determined with confidence due to the small number of elderly patients studied. In a study of first-line treatment of ovarian cancer, elderly patients had a lower median survival than younger patients, but no other efficacy parameters favored the younger group. TABLE 9 presents the incidences of Grade IV neutropenia and severe neuropathy in clinical studies according to age.

TABLE 9. SELECTED ADVERSE EVENTS IN GERIATRIC PATIENTS RECEIVING PACLITAXEL IN CLINICAL STUDIES

*   p<0.05

^a Paclitaxel dose in mg/m²/infusion duration in hours; cisplatin doses in mg/m². 

^b Peripheral neuropathy was included within the neurotoxicity category in the Intergroup First-Line Ovarian Cancer study (see TABLE 11). 

^c Paclitaxel dose in mg/m²/infusion duration in hours. 

^d Paclitaxel (T) following 4 courses of doxorubicin and cyclophosphamide (AC) at a dose of 175 mg/m²/3 hours every 3 weeks for 4 courses. 

^e Peripheral neuropathy reported as neurosensory toxicity in the Intergroup Adjuvant Breast Cancer study (see TABLE 13). 

^f Peripheral neuropathy reported as neurosensory toxicity in the ECOG NSCLC study (see TABLE 15). 

Information for Patients (See Patient Information Leaflet).

The safety and effectiveness of paclitaxel in pediatric patients have not been established.

There have been reports of central nervous system (CNS) toxicity (rarely associated with death) in a clinical trial in pediatric patients in which paclitaxel was infused intravenously over 3 hours at doses ranging from 350 mg/m² to 420 mg/m². The toxicity is most likely attributable to the high dose of the ethanol component of the paclitaxel vehicle given over a short infusion time. The use of concomitant antihistamines may intensify this effect. Although a direct effect of the paclitaxel itself cannot be discounted, the high doses used in this study (over twice the recommended adult dosage) must be considered in assessing the safety of paclitaxel for use in this population.

It is not known whether the drug is excreted in human milk. Following intravenous administration of carbon 14-labeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving paclitaxel therapy.

Ovarian Carcinoma

First-Line Data

The safety and efficacy of paclitaxel followed by cisplatin in patients with advanced ovarian cancer and no prior chemotherapy were evaluated in 2, Phase 3 multicenter, randomized, controlled trials. In an Intergroup study led by the European Organization for Research and Treatment of Cancer involving the Scandinavian Group NOCOVA, the National Cancer Institute of Canada, and the Scottish Group, 680 patients with Stage II_B-C, III, or IV disease (optimally or non-optimally debulked) received either paclitaxel 175 mg/m² infused over 3 hours followed by cisplatin 75 mg/m² (Tc) or cyclophosphamide 750 mg/m2 followed by cisplatin 75 mg/m2 (Cc) for a median of 6 courses. Although the protocol allowed further therapy, only 15% received both drugs for 9 or more courses. In a study conducted by the Gynecological Oncology Group (GOG), 410 patients with Stage III or IV disease (>1 cm residual disease after staging laparotomy or distant metastases) received either paclitaxel 135 mg/m₂ infused over 24 hours followed by cisplatin 75 mg/m² or cyclophosphamide 750 mg/m² followed by cisplatin 75 mg/m² for 6 courses.

In both studies, patients treated with paclitaxel in combination with cisplatin had significantly higher response rate, longer time to progression, and longer survival time compared with standard therapy. These differences were also significant for the subset of patients in the Intergroup study with non-optimally debulked disease, although the study was not fully powered for subset analyses (TABLES 2A and 2B). Kaplan- Meier survival curves for each study are shown in FIGURES 1 and 2.

TABLE 2A. EFFICACY IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA STUDIES

^a Paclitaxel dose in mg/m²/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m².

^b Among patients with measurable disease only.

^cUnstratified for the Intergroup Study, Stratified for Study GOG-111.

Pooled Analysis of Adverse Event Experiences from Single-Agent Studies

Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with breast carcinoma) enrolled in 10 studies who received single-agent paclitaxel injection. Two hundred and seventy-five patients were treated in 8, Phase 2 studies with paclitaxel doses ranging from 135 to 300 mg/m² administered over 24 hours (in 4 of these studies, G-CSF was administered as hematopoietic support). Three hundred and one patients were treated in the randomized Phase 3 ovarian carcinoma study which compared 2 doses (135 or 175 mg/m²) and 2 schedules (3 or 24 hours) of paclitaxel. Two hundred and thirty-six patients with breast carcinoma received paclitaxel (135 or 175 mg/m²) administered over 3 hours in a controlled study.

TABLE 10. SUMMARY^a OF ADVERSE EVENTS IN PATIENTS WITH SOLID TUMORS RECEIVING SINGLE-AGENT PACLITAXEL

^a Based on worst course analysis.

^b All patients received premedication.

^c During the first 3 hours of infusion.

^†    Severe events are defined as at least Grade III toxicity.

None of the observed toxicities were clearly influenced by age.

Disease-Specific Adverse Event Experiences

First-Line Ovary in Combination

For the 1084 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy studies, TABLE 11 shows the incidence of important adverse events. For both studies, the analysis of safety was based on all courses of therapy (6 courses for the GOG-111 study and up to 9 courses for the Intergroup study).

TABLE 11. FREQUENCY^a OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA STUDIES 

^a Based on worst course analysis.

^b Paclitaxel (T) dose in mg/m²/infusion duration in hours.

^c Cyclophosphamide (C) or cisplatin (c) dose in mg/m².

^d P<0.05 by Fisher exact test.

^e <130,000/mm³ in the Intergroup study.

^f <12 g/dL in the Intergroup study.

^g All patients received premedication.

^h In the GOG-111 study, neurotoxicity was collected as peripheral neuropathy and in the Intergroup study, neurotoxicity was collected as either neuromotor or neurosensory symptoms.

^†      Severe events are defined as at least Grade III toxicity.

NC  Not Collected

Second-Line Ovary

For the 403 patients who received single-agent paclitaxel in the Phase 3 second-line ovarian carcinoma study, the following table shows the incidence of important adverse events.

Paclitaxel is contraindicated in patients who have a history of hypersensitivity reactions to Paclitaxel or other drugs formulated in polyoxyl 35 castor oil.

Paclitaxel should not be used in patients with solid tumors who have baseline neutrophil counts of <1,500 cells/mm³ or in patients with AIDS-related Kaposi's sarcoma with baseline neutrophil counts of <1,000 cells/mm³.

 In a Phase 1 trial using escalating doses of paclitaxel (110 to 200 mg/m²) and cisplatin (50 or 75 mg/m²) given as sequential infusions, myelosuppression was more profound when paclitaxel was given after cisplatin than with the alternate sequence (i.e., paclitaxel before cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when paclitaxel was administered following cisplatin.

The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when administering paclitaxel concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CTP2C8 and CYP3A4. Caution should be exercised when paclitaxel is concomitantly administered with known substrates (e.g, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine) of CYP3A4. (see CLINICAL PHARMACOLOGY).

Caution should also be exercised when paclitaxel is concomitantly administered with known substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., rifampin) of CYP2C8. (see CLINICAL PHARMACOLOGY).

Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials.

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

Hematology

Paclitaxel therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm³. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel. Patients should not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm³ and platelets recover to a level >100,000 cells/mm³. In the case of severe neutropenia (<500 cells/mm³ for 7 days or more)during a course of paclitaxel therapy, a 20% reduction in dose for subsequent courses of therapy is recommended.



For patients with advanced HIV disease and poor-risk AIDS-related Kaposi's sarcoma, paclitaxel, at the recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 1,000 cells/mm³.



Hypersensitivity Reactions: Patients with a history of severe hypersensitivity reactions to products containing polyoxyl 35 castor oil (e.g., cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with paclitaxel. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with paclitaxel should be premedicated with corticosteroids (such as dexamethasone), diphenhydramine and H₂ antagonists (such as cimetidine or ranitidine). Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with paclitaxel.



Cardiovascular

Hypotension, bradycardia, and hypertension have been observed during administration of paclitaxel, but generally do not require treatment. Occasionally paclitaxel infusions must be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities. (see WARNINGS). When paclitaxel is used in combination with doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is recommended. (see ADVERSE REACTIONS).

Nervous System

Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of paclitaxel.

Paclitaxel contains dehydrated alcohol USP, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol. (see PRECAUTIONS, Pediatric Use).

Hepatic

There is limited evidence that the myelotoxicity of paclitaxel may be exacerbated in patients with serum total bilirubin >2 times ULN (see CLINICAL PHARMACOLOGY). Extreme caution should be exercised when administering paclitaxel to such patients, with dose reduction as recommended in DOSAGE AND ADMINISTRATION, TABLE 17.

Injection Site Reaction

Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e., ''recall'' has been reported.



More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to 10 days.



A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Paclitaxel (pak” li tax’ el) Injection, USP

Read this patient information leaflet before you start taking paclitaxel. 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?

Paclitaxel can cause serious side effects including death.

Serious allergic reactions (anaphylaxis) can happen in people who receive paclitaxel. 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?

Paclitaxel 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 is safe or effective in children.

Who should not receive paclitaxel?

Do not receive paclitaxel if:

• you are allergic to any of the ingredients in paclitaxel. See the end of this leaflet for a complete list of ingredients in paclitaxel.

• are allergic to medicines containing polyoxyl 35 castor oil*.

• you have low white blood cell counts.

What should I tell my healthcare provider before receiving paclitaxel?

Before receiving paclitaxel, 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 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 passes into your breast milk. You and your healthcare provider should decide if you will receive paclitaxel 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?

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

Your healthcare provider will do certain tests while you receive paclitaxel.

What are the possible side effects of paclitaxel?

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. 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.

Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use paclitaxel for a condition for which it was not prescribed. Do not give paclitaxel injection 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. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about paclitaxel injection that is written for health professionals. For more information call 1-855-668-2369 or go to www.novadozpharma.com

What are the ingredients in paclitaxel?

Active ingredient: paclitaxel, USP.

Inactive ingredients include: citric acid, dehydrated alcohol and purified polyoxyl 35 castor oil.

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:

MSN Laboratories Private Limited

Telangana – 509 228,

INDIA

Distributed by:

 

Novadoz Pharmaceuticals LLC

Piscataway, NJ 08854 -3714

Issued on: 08/2020

Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

Following intravenous administration of paclitaxel, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.

Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of paclitaxel at dose levels of 135 and 175 mg/m² were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table.

TABLE 1. SUMMARY OF PHARMACOKINETIC PARAMETERS—MEAN VALUES

C_max = Maximum plasma concentration

AUC_(0-∞) = Area under the plasma concentration-time curve from time 0 to infinity

CL_T = Total body clearance



It appeared that with the 24-hour infusion of paclitaxel, a 30% increase in dose (135 mg/m² vs 175 mg/m²) increased the C_max by 87%, whereas the AUC_(0-∞) remained proportional. However, with a 3-hour infusion, for a 30% increase in dose, the C_max and AUC_(0-∞) were increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state, with the 24-hour infusion of paclitaxel, ranged from 227 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding of paclitaxel.

The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single doses of 15 to 135 mg/m² given by 1-hour infusions (n=15), 30 to 275 mg/m² given by 6-hour infusions (n=36), and 200 to 275 mg/m² given by 24-hour infusions (n=54) in Phase 1 and 2 studies. Values for CL_T and volume of distribution were consistent with the findings in the Phase 3 study. The pharmacokinetics of paclitaxel in patients with AIDS-related Kaposi's sarcoma have not been studied.

In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 mcg/mL, indicate that between 89 to 98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

After intravenous administration of 15 to 275 mg/m² doses of paclitaxel as 1-, 6-, or 24-hour infusions, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating extensive non-renal clearance. In 5 patients administered a 225 or 250 mg/m² dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Total recovery of radioactivity ranged from 56% to 101% of the dose. Paclitaxel represented a mean of 5% of the administered radioactivity recovered in the feces, while metabolites, primarily 6α-hydroxypaclitaxel, accounted for the balance. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to 2 minor metabolites, 3'-p-hydroxypaclitaxel and 6α, 3'-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4 (see PRECAUTIONS, Drug Interactions).



The disposition and toxicity of paclitaxel 3-hour infusion were evaluated in 35 patients with varying degrees of hepatic function. Relative to patients with normal bilirubin, plasma paclitaxel exposure in patients with abnormal serum bilirubin ≤2 times upper limit of normal (ULN) administered 175 mg/m² was increased, but with no apparent increase in the frequency or severity of toxicity. In 5 patients with serum total bilirubin >2 times ULN, there was a statistically nonsignificant higher incidence of severe myelosuppression, even at a reduced dose (110 mg/m²), but no observed increase in plasma exposure (see PRECAUTIONS, Hepatic and DOSAGE AND ADMINISTRATION). The effect of renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated.

Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.

Paclitaxel Injection, USP is indicated as subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line therapy, Paclitaxel Injection, USP is indicated in combination with cisplatin.



Paclitaxel Injection, USP is indicated for the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy. In the clinical trial, there was an overall favorable effect on disease-free and overall survival in the total population of patients with receptor-positive and receptor-negative tumors, but the benefit has been specifically demonstrated by available data (median follow-up 30 months) only in the patients with estrogen and progesterone receptor-negative tumors (see CLINICAL STUDIES: Breast Carcinoma).



Paclitaxel Injection, USP is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Paclitaxel Injection, USP, in combination with cisplatin, is indicated for the first-line treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy.



Paclitaxel Injection, USP is indicated for the second-line treatment of AIDS-related Kaposi's sarcoma.

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).

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). 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 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 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.

Paclitaxel injection-30 mg/5ml-vial-label

The carcinogenic potential of paclitaxel has not been studied.

Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.

Administration of paclitaxel prior to and during mating produced impairment of fertility in male and female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum recommended human dose on a mg/m² basis). At this dose, paclitaxel caused reduced fertility and reproductive indices, and increased embryo- and fetotoxicity. (See WARNINGS.)