Paclitaxel (Systemic)


VA CLASSIFICATION
Primary: AN900

Commonly used brand name(s): Taxol.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Carcinoma, ovarian, epithelial (treatment)—Paclitaxel is indicated as first-line and subsequent therapy for treatment of advanced ovarian carcinoma. When used as first-line therapy, paclitaxel is indicated in combination with cisplatin. {01} {03} {04} {05} {06} {07} {08} {09} {10} {11} {12} {19}{123}{124}
—Paclitaxel is indicated, in combination with carboplatin{154}{155}{156}{157}{158}{159}{160}{161}{162}{163}{164}{165}{166} or cisplatin{154}{157}{158}{160}{162}{164}{165}{167}{168}{169}{170}, for the [treatment of fallopian tube and peritoneal carcinomas, of ovarian origin]1.

Carcinoma, breast, node–positive (treatment adjunct)1—Paclitaxel is indicated for the adjuvant treatment of node–positive breast cancer when administered sequentially to standard doxorubicin–containing combination chemotherapy.{123}

Carcinoma, breast (treatment)—[ Paclitaxel is indicated as first line therapy, as a single agent or in combination with other chemotherapeutic agents, for treatment of metastatic breast carcinoma (Evidence rating: IA)]1 {105} {106} {107} {108} {109} {110} {111} {112} {113} {114} {115} {116} {117} {118} {119} {120} {121} {122}. Paclitaxel is also indicated for treatment of metastatic breast carcinoma after failure of combination chemotherapy or at relapse within 6 months of adjuvant chemotherapy.{01} {21} {22} {23} {24} {25} {26} {27} {28} {29} {30} {34} Prior therapy should have included an anthracycline unless clinically contraindicated.1{123}

Kaposi's sarcoma, acquired immunodeficiency syndrome (AIDS)–associated (treatment)1—Paclitaxel is indicated for second-line treatment of AIDS-associated Kaposi's sarcoma {01}{123}.

Carcinoma, lung, non–small cell (treatment)—Paclitaxel is indicated, in combination with cisplatin, for first-line treatment of non–small cell lung carcinoma in patients who are not candidates for radiation therapy or potentially curative surgery {01}{123}{124}.

[Carcinoma, bladder (treatment)]1 or
[Carcinoma, head and neck (treatment) ]1—Paclitaxel is indicated for treatment of transitional cell bladder carcinoma {45} {46} {47} (Evidence rating: IIID) and head and neck carcinoma {63} {64} {65} {66} {67} {68} {69} {70} {71} {72} {73} {75} {76} {77} {78} {79} {80} (Evidence rating: IIID).

[Carcinoma, cervical (treatment)]1
[Carcinoma, esophageal (treatment) ]1 or
[Carcinoma, endometrial (treatment) ]1—Paclitaxel is considered reasonable medical therapy at some point in the management of cervical carcinoma {49} {50} {51} {52} (Evidence rating: IIID), esophageal carcinoma {53} {54} {55} {56} {57} {58} {59} {60} {61} {62} {63} {64} (Evidence rating: IIID), and endometrial carcinoma {81} {82} {83} {84} {85} (Evidence rating: IIID).

[Carcinoma, lung, small cell (treatment) ]1—Paclitaxel is indicated for treatment of small cell lung carcinoma {41} {42}.

[Carcinoma, prostate (treatment)]1—Paclitaxel, in combination therapy, is considered reasonable medical therapy at some point in the management of hormone-refractory prostate carcinoma {86} {87} {88} {89} {90} {91} {92} {93} (Evidence rating: IIID).

[Carcinoma, gastric (treatment)]1—Paclitaxel, in combination therapy, is considered reasonable medical therapy at some point in the management of advanced gastric carcinoma {94} {95} {96} {97} {98} {99} {100} {101} {102} {103} {104} (Evidence rating: IIID).

[Carcinoma, unknown primary site (treatment )]1—Paclitaxel is indicated for the first-line treatment of carcinoma of unknown primary site (CUPS), as part of a combination regimen with carboplatin and etoposide. There was not a clear consensus by the USP medical experts. Some of the experts are hesitant about the use of this regimen and suggest that individual case factors (e.g. metastatic sites, disease factors, patient characteristics, etc.) be considered when choosing an appropriate treatment.{132}{133}{134}{135}{136}{137}

[Tumors, germ cell, testicular (treatment) ]1—Paclitaxel is indicated for the treatment of testicular germ cell tumors, alone or in combination with other agents (e.g., cisplatin, ifosfamide, etoposide), in patients with disease refractory to cisplatin-based chemotherapy.{138}{139}{140}{141}{142}{143}{144}{145}{146}{147}{148}{149}{150}{151}{152}{153}

Acceptance not established
Use of paclitaxel for the treatment of malignant melanoma has not been established. There is currently not enough medical literature or clinical experience to consider the use of paclitaxel in the treatment of malignant melanoma.{125}{126}{127}{128}{129}{130}{131}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Note: Pharmacokinetic studies were conducted in adult cancer patients who received paclitaxel in single doses of 15 to 135 mg per square meter of body surface area (mg/m 2) given by 1-hour infusions (15 patients), 30 to 275 mg/m 2 given by 6-hour infusions (36 patients), and 200 to 275 mg/m 2 given by 24-hour infusions (54 patients) {01}. Pharmacokinetic studies were also conducted in ovarian cancer patients who received single doses of 135 mg/m 2 given by 3-hour infusions (seven patients), 135 mg/m 2 given by 24-hour infusions (two patients), 175 mg/m 2 given by 3-hour infusions (five patients), and 175 mg/m 2 given by 24-hour infusions (four patients) {01}.


Physicochemical characteristics:
Source—
    Semi-synthetic. Obtained from Taxus baccata. {01}

Chemical group—
    Paclitaxel is a diterpenoid {20} taxane {03} {05} {20}.
Molecular weight—
    853.93 {48}

Mechanism of action/Effect:

Paclitaxel belongs to the class of medications known as antimicrotubule agents {01} {06}. It 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. {01} {03} {04} {05} {06} {07}


Other actions/effects:

Paclitaxel enhances the cytotoxic effects of ionizing radiation in vitro. {03}

Distribution:

The mean steady-state volume of distribution (Vol D) ranged from 227 to 688 liters per square meter of body surface area following single doses of 135 and 175 mg/m 2 given over 24 hours. Similar Vol D were obtained following single doses of 15 to 135 mg/m 2 given over 1 hour and single doses of 30 to 275 mg/m 2 given over 6 hours. This indicates extensive extravascular distribution and/or tissue binding {01}.

The mean area under the plasma concentration–time curve (AUC) (24-hour infusion) was 6300 and 7993 nanograms per hour per mL for doses of 135 and 175 mg/m 2, respectively. The mean maximum plasma concentration following a 24-hour infusion of paclitaxel was 195 and 365 nanograms per mL for doses of 135 and 175 mg/m 2, respectively {01}.

The mean AUC (3-hour infusion) was 7952 and 15,007 nanograms per hour per mL for doses of 135 and 175 mg/m 2, respectively. The mean maximum plasma concentration following a 3-hour infusion of paclitaxel was 2170 and 3650 nanograms per mL for doses of 135 and 175 mg/m 2, respectively {01}.

Protein binding:

Very high (89 to 98%) {01} {03} {05} {06}.

Biotransformation:

Hepatic. Metabolized via the cytochrome P450 isoenzyme CYP2C8 to one major metabolite (6-alpha-hydroxypaclitaxel), and via the cytochrome P450 isoenzyme CYP3A4 to two minor metabolites (3-para-hydroxypaclitaxel and 6-alpha,3"-para-dihydroxypaclitaxel) {01} {05}.

Half-life:

Terminal—Mean (standard deviation): Range 5.3 (4.6) to 17.4 (4.7) hours {01}, following 1-hour and 6-hour infusions at doses of 15 to 275 mg per square meter of body surface area {01}.

Elimination:
    Not completely understood {01}. Mean (standard deviation) values for urinary recovery of unchanged drug following 1-, 6-, and 24-hour infusions at doses of 15 to 275 mg per square meter of body surface area ranged from 1.3% (0.5%) to 12.6% (16.2%) of the dose, indicating extensive nonrenal clearance {01}. High concentrations of paclitaxel {01} {03} {06} and its metabolites {03} {06} have been reported in the bile {01}.
    The decline in plasma concentrations is biphasic {01} {03} {04} {05}; the initial rapid decline represents distribution to the peripheral compartment and significant elimination {01}. The later phase is due, in part, to a relatively slow efflux from the peripheral compartment {01}.
    Mean values for total body clearance were 21.7 and 23.8 liters per hour per square meter of body surface area, following single doses of 135 and 175 mg/m 2 given by 24-hour infusions, respectively. Clearance values following single doses of 135 and 175 mg/m 2 given by 3-hour infusions were 17.7 and 12.2 liters per hour per square meter of body surface area, respectively {01}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to polyoxyethylated castor oil may be sensitive to paclitaxel also, since the injection contains a polyoxyethylated castor oil vehicle {01}.

Carcinogenicity

Studies with paclitaxel have not been done {01}.

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use.

Mutagenicity

Paclitaxel is mutagenic in in vitro (chromosome aberrations in human lymphocytes) and in in vivo (micronucleus test in mice) mammalian test systems {01}. However, it was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay {01}.

Pregnancy/Reproduction
Fertility—
Studies in rats at doses of 1 mg per kg of body weight (mg/kg) (6 mg per square meter of body surface area) found that paclitaxel reduced fertility {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.

First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered.

Other hazards to the fetus include adverse reactions seen in adults.

In general, use of contraception is recommended during cytotoxic drug therapy.

Paclitaxel was found to cause maternal and embryo-fetal toxicity in rabbits at intravenous doses of 3 mg/kg (33 mg per square meter of body surface area) given during organogenesis {01}. In rats and rabbits, paclitaxel was found to cause abortions, decreased corpora lutea, a decrease in implantations and live fetuses, and increased resorptions and embryo-fetal deaths {01}. No gross external, soft tissue, or skeletal alterations occurred {01}.

FDA Pregnancy Category D {01}.

Breast-feeding

Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended during chemotherapy because of the potential risks to the infant (adverse effects, mutagenicity, carcinogenicity). It is not known whether paclitaxel is distributed into breast milk {01}.

Pediatrics

No information is available on the relationship of age to the effects of paclitaxel in pediatric patients, although phase I studies in children have been reported {10} {35}. Safety and efficacy have not been established {01}.


Geriatrics


One retrospective study on the relationship of age to the effects of paclitaxel found no difference in dose intensity achieved in elderly patients {16}.


Dental

The bone marrow depressant effects of paclitaxel may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Paclitaxel also may cause mucositis, which is usually mild but which at high doses may be associated with considerable discomfort {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of paclitaxel may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of paclitaxel, if necessary, should be based on blood counts {43})


» Bone marrow depressants, other (see Appendix II ) or
Radiation therapy{01}    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)

    (severity of paclitaxel-induced neutropenia may be related to the extent of prior myelotoxic therapy {03} {05} {06})

    (in one Phase I study, administration of cisplatin before paclitaxel, rather than after, was found to reduce paclitaxel clearance by approximately 25% {01} {15})


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by paclitaxel therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by paclitaxel therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the paclitaxel therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alkaline phosphatase values, serum{01} and
Aspartate aminotransferase (AST [SGOT]) values, serum{01} and
Bilirubin concentrations, serum{01}    (may be increased transiently {01}; elevations of alkaline phosphatase and bilirubin may be dose-related {01})


Triglycerides    (elevations in serum concentrations have been reported {06})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression{01}{44}    (will be increased; it is recommended that paclitaxel not be administered to patients with solid tumors when baseline neutrophil counts are lower than 1500 cells per cubic millimeter {01}, and that subsequent doses not be administered until neutrophil counts have returned to greater than 1500 cells per cubic millimeter and platelet counts to greater than 100,000 cells per cubic millimeter {01} or to baseline values {36}; it is also recommended that paclitaxel not be administered to patients with AIDS-associated Kaposi's sarcoma when baseline neutrophil counts are lower than 1000 cells per cubic millimeter {01})


Cardiac function impairment, including:
Angina
» Cardiac conduction abnormalities
Congestive heart failure, history of
Myocardial infarction within the past 6 months    (the patient's ability to tolerate the cardiovascular side effects of paclitaxel may be reduced {37})


» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


» Infection
» Sensitivity to paclitaxel{01}
» Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
» Platelet count    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


» Vital signs    (recommended frequently, especially during the first hour of paclitaxel infusion {01})




Side/Adverse Effects

Note: Neutropenia is the major dose-limiting effect {01} {03} {04} {06} {08}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Anemia{01}{05}{12} (unusual tiredness or weakness)—usually asymptomatic
    
hypersensitivity reaction{01}{17} (flushing of face; skin rash or itching; shortness of breath; rarely [with proper premedication], severe shortness of breath; severe skin reaction)
    
leukopenia or neutropenia, with or without infection{01}{08}{12} (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)
    
thrombocytopenia{01}{05}{09}{12} (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic

Note: Incidence and severity of anemia seem to increase with increasing exposure to paclitaxel {01}.
With proper premedication, hypersensitivity reactions are usually mild (flushing of face, skin rash, shortness of breath) {01}. However, severe reactions (hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema or generalized urticaria, chest pain) can occur {01} {17} {18}, even with premedication, and necessitate immediate discontinuation of paclitaxel and aggressive symptomatic therapy {01} {17}. Severe symptoms usually occur within the first 10 minutes of paclitaxel infusion {01} {06} {17} {20}, after the first or second dose of paclitaxel {01} {03} {06}. A fatal reaction occurred in a patient who was not premedicated {01} {03} {05}. In general, it is recommended that paclitaxel not be readministered to patients who have experienced a severe hypersensitivity reaction {01}. However, in patients with objective tumor responses and without other options to paclitaxel therapy, re-treatment may be attempted with extreme caution and aggressive premedication by experienced practitioners {18} {39}.
Severe neutropenia (neutrophil count below 500 cells per cubic millimeter) is common {01} {03} {05} {12} but only infrequently persists for more than 7 days {01}. The nadir of the neutrophil counts usually occurs at approximately day 11 of paclitaxel therapy {01} {06}; in general, neutropenia is rapidly reversible {01}, with recovery by day 15 to 21 {06} {12}. Cumulative neutropenia does not occur {03} {05} {06} {08}. The most common infections associated with neutropenia are urinary tract infections, upper respiratory infections, and sepsis {01}. Fatalities have occurred from neutropenia-related sepsis {01} {05} {08} {12}.
In thrombocytopenia, the nadir of the platelet counts usually occurs at approximately day 8 or 9 of paclitaxel therapy {01}. Platelet counts generally do not fall below 100,000 cells per cubic millimeter {01}. Hemorrhagic episodes may also be disease-related {01}.


Incidence less frequent
    
Cardiovascular effects, including bradycardia{01}{03}{06}{13}
hypotension{01}
or abnormal electrocardiogram (ECG){01} —usually asymptomatic
    
elevated serum hepatic enzymes{01} —asymptomatic

Note: Cardiovascular effects have also included more severe atrioventricular (AV) blocks, occasionally resulting in third-degree block requiring cardiac pacing {03} {06} {13}. Atypical chest pains and a fatal myocardial infarction have also occurred {03} {06} {13}, as well as asymptomatic bundle branch block and transient ventricular tachycardia {03} {06} {13}, although the exact relationship to paclitaxel is unknown.


Incidence rare
    
Extravasation, with phlebitis or cellulitis{07} (pain or redness at site of injection)
    
mucositis{01}{03}{05}{06}{08}{20} (sores in mouth and on lips)

Note: Oropharyngeal mucositis is dose-related {03} {05} {06}; it is infrequent or mild at usual recommended doses {20} and usually resolves 5 to 7 days following treatment {05} {06} {19}. However, esophageal and intestinal epithelial necrosis and ulceration have been reported {19}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Arthralgias or myalgias{01}{05}{06}{08}{12} (pain in joints or muscles, especially in arms or legs)
    
diarrhea{01}{08}
    
nausea and vomiting{01}{08}
    
peripheral neuropathy, including mild paresthesia{01}{05}{06}{08}{10} (numbness, burning, or tingling in hands or feet)

Note: Arthralgias or myalgias usually begin 2 to 3 days after treatment and resolve within 5 days {03} {05} {06} {12} {14}. Pain is usually relieved by analgesics {12}, but occasionally may be severe enough to require narcotics {14}.
Nausea and vomiting are usually mild or moderate {20}.
Incidence and severity of peripheral neuropathy are dose-related {01} {06}; at usual doses, a sensory neuropathy in a glove-and-stocking distribution occurs {03} {04} {05} {06}. Only rarely is withdrawal of paclitaxel necessary {01}. Symptoms usually appear after multiple doses {03} {06} and improve or resolve within several months after paclitaxel is discontinued {01} {04} {06}. High doses (over 250 mg per square meter of body surface area) may cause dose-limiting motor and autonomic dysfunction {03} {06}, especially in patients with pre-existing neuropathies {03}, beginning as early as 24 to 72 hours after treatment {03} {06}.




Those not indicating need for medical attention
Incidence more frequent
    
Alopecia{01}{05}{06}{08}{10}{12} (loss of hair)

Note: Complete loss of hair (including scalp hair, eyebrows, eyelashes, and pubic hair) occurs in almost all patients {06} {10} between days 14 and 21 {06}, but is reversible after therapy has ended {05}.






Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Paclitaxel (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to paclitaxel

Pregnancy—Use not recommended because of mutagenic, teratogenic, and carcinogenic potential; advisability of using contraception; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of risk of serious side effects
Other medications, especially other bone marrow depressants, or other cytotoxic drugs or radiation therapy
Other medical problems, especially cardiac conduction abnormalities, chickenpox, herpes zoster, or infection

Proper use of this medication
Frequency of nausea and vomiting; importance of continuing medication despite stomach upset

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by the physician

» Avoiding immunizations unless approved by physician; other persons in patient"s household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands are washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur


Side/adverse effects
May cause adverse effects such as blood problems; importance of discussing possible effects with physician

Signs of potential side effects, especially hypersensitivity reaction, leukopenia or neutropenia, thrombocytopenia, extravasation, and mucositis

Asymptomatic side effects, including anemia, thrombocytopenia, cardiovascular effects, and elevated hepatic enzymes

Physician or nurse can help in dealing with side effects

Possibility of hair loss; normal hair growth should return after treatment has ended


General Dosing Information
Patients receiving paclitaxel should be under supervision of a physician experienced in cancer chemotherapy {01}.

A variety of dosage schedules and regimens of paclitaxel, alone or in combination with other antitumor agents, are used. The prescriber may consult the medical literature as well as the manufacturer"s literature in choosing a specific dosage.

It is recommended that patients receiving paclitaxel be under continuous observation for at least the first 30 minutes of the infusion {38} and at frequent intervals after that. Equipment and medications (including epinephrine and oxygen) necessary for treatment of a possible anaphylactic reaction should be immediately available during each administration of paclitaxel {05}.

Paclitaxel concentrate for injection must be diluted before administration by intravenous infusion {01}.

The needle should be carefully positioned in the vein to avoid extravasation and resulting phlebitis and cellulitis.

In order to prevent severe hypersensitivity reactions, it is recommended that all patients be premedicated with corticosteroids (such as dexamethasone), diphenhydramine, and histamine H2-receptor antagonists (such as cimetidine or ranitidine) {01} (see Parenteral Dosage Forms for specific dosing).

Mild hypersensitivity symptoms (flushing, skin reactions, dyspnea, hypotension, tachycardia) do not require interruption of paclitaxel therapy {01}. However, severe reactions (hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria) require immediate withdrawal of paclitaxel and aggressive symptomatic therapy {01}. It is generally recommended that paclitaxel administration not be repeated in patients who have experienced severe hypersensitivity reactions to the medication {01}. However, in patients with objective tumor responses and without other options to paclitaxel therapy, re-treatment may be attempted with extreme caution and aggressive premedication by experienced practitioners {18} {39}.

If severe peripheral neuropathy occurs, it is recommended that subsequent dosage of paclitaxel be reduced by 20% {01}.

If significant cardiac conduction abnormalities occur during administration of paclitaxel, appropriate therapy is recommended, along with continuous cardiac monitoring during subsequent paclitaxel administration {01}.

If severe neutropenia (neutrophil counts of less than 500 cells per cubic millimeter for 7 days or more) occurs during a course of paclitaxel, it is recommended that the paclitaxel dose for subsequent courses be reduced by 20% {01}.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests. Patients with advanced acquired immunodeficiency syndrome (AIDS) may require concomitant administration of a hematopoietic growth factor such as granulocyte colony stimulating factor (G-CSF) {01}.

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of paclitaxel. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required. {03}

Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include {01}:    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.


Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.


PACLITAXEL CONCENTRATE FOR INJECTION

Usual adult dose
Ovarian carcinoma
For previously untreated patients: Intravenous (as a twenty–four hour infusion), 135 mg per square meter of body surface area, followed by cisplatin 75 mg per square meter of body surface area, repeated every twenty-one days. {123}(Canadian product labeling recommends a dose of 175 mg per square meter of body surface area, followed by cisplatin 75 mg per square meter of body surface area, as a three-hour intravenous infusion, repeated every twenty-one days).{124}

For previously treated patients: Intravenous (as a three or twenty-four-hour infusion), 135 or 175 mg per square meter of body surface area, repeated every twenty-one days {01} {02}{123}. (Canadian product labeling recommends a dose of 175 mg per square meter of body surface area as a three - or twenty-four-hour intravenous infusion, repeated every twenty-one days.) {02}
For the treatment of [fallopian tube and peritoneal carcinomas of ovarian origin]1, patients have benefited from intravenous doses of paclitaxel 135 to 175 mg/m2 (by 3–hour infusion), in combination with carboplatin AUC 5 to 6{166} , every 21 days, for 5 to 9 treatment cycles. Duration of paclitaxel infusion may be adjusted from 1 hour to 24 hours, depending on toxcicity.{166}

Patients have also benefited from intravenous doses of paclitaxel 135 to 175 mg/m 2 (by 3–hour infusion), in combination with cisplatin 50 to 75 mg/m2{170}, , every 21 to 28 days. Duration of paclitaxel infusion may be increased to 24 hours, depending on toxcicity.{170}

Breast carcinoma
Intravenous (as a three-or twenty-four-hour infusion), 175 mg per square meter of body surface area, repeated every twenty-one days {01} {02}{123}{124}.

Breast carcinoma, node-positive 1
Intravenous (as a three-hour infusion), 175 mg per square meter of body surface area, repeated every twenty–one days for four courses administered sequentially to doxorubicin–containing combination chemotherapy.{123}

AIDS-associated Kaposi's sarcoma1
Intravenous (as a three- or twenty-four-hour infusion), 135 mg per square meter of body surface area, repeated every twenty-one days {01} or

Intravenous (as a three- or twenty-four-hour infusion), 100 mg per square meter of body surface area, repeated every fourteen days {01}.

Carcinoma, lung, non–small cell
Intravenous (as a twenty-four-hour infusion), 135 mg per square meter of body surface area followed by cisplatin 75 mg per square meter of body surface area, repeated every twenty-one days {01}(Canadian product labeling recommends a dose of 175 mg per square meter of body surface area as a three-hour intravenous infusion, followed by cisplatin, repeated every twenty-one days.){124}.

[Carcinoma, bladder]1 or
[Carcinoma, head and neck]1or
[Carcinoma, cervical]1 or
[Carcinoma, esophageal]1or
[Carcinoma, endometrial]1 or
[Carcinoma, lung, small cell]1or
[Carcinoma, prostate]1 or
[Carcinoma, gastric]1
Consult medical literature and manufacturer's literature for specific dosage.

[Carcinoma, unknown primary site ]1
Patients have benefited from a 1–hour intravenous infusion of 200 mg/m2, on day 1 of a 21–day treatment cycle, combined with intravenous carboplatin and oral etoposide, for 4 to 8 cycles.{132}

[Tumors, germ cell, testicular]1
Patients have benefited from intravenous doses of 175–250 mg/m2, by 3– to 24–hour infusion, every 21 days. The shorter infusion time is equally effective and less troublesome for the patient.{138}


Note: To prevent severe hypersensitivity reactions, all patients should be premedicated with corticosteroids (e.g., dexamethasone 20 mg orally {01} {03} or intravenously {20} {40} [patients with solid tumors] or dexamethasone 10 mg orally [patients with AIDS-associated Kaposi's sarcoma] approximately twelve and six hours prior to paclitaxel administration); diphenhydramine (e.g., 50 mg intravenously, thirty to sixty minutes prior to paclitaxel) or its equivalent; and cimetidine (e.g., 300 mg intravenously, thirty to sixty minutes prior to paclitaxel), ranitidine (e.g., 50 mg intravenously, thirty to sixty minutes prior to paclitaxel) {01} {03}, or famotidine (e.g., 20 mg intravenously, thirty to sixty minutes prior to paclitaxel) {36}{123}{124}.
Contact of paclitaxel with plasticized polyvinyl chloride (PVC) equipment or devices must be avoided because of the risk of patient exposure to the plasticizer DEHP (di-[2-ethylhexyl]phthalate), which may be leached from PVC infusion bags or sets {01}. Paclitaxel solutions should be diluted and stored in glass or polypropylene bottles or in plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets {01}{123}{124}.
Paclitaxel intravenous infusion should be administered through an in-line filter {01} {05} with a microporous membrane not greater than 0.22 microns {01}. Use of filter devices that incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP {01}{123}{124}. Frequent changing of filters (e.g., every twelve hours) may be necessary because of clogging during the infusion {40}.


Usual pediatric dose
Safety and efficacy in pediatric patients have not been established {01}.

Strength(s) usually available
U.S.—


6 mg per mL (5-, 16.7-, and 50-mL multidose vials) (Rx) [Taxol ( polyoxyethylated castor oil 527 mg per mL) (dehydrated alcohol USP 49.7% v/v)]{123}

Canada—


6 mg per mL (single-dose vials) (Rx) [Taxol (polyoxyethylated castor oil 527 mg per mL) (dehydrated alcohol USP 49.7% v/v)]{02}

Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F) {01}{123}, unless otherwise specified by the manufacturer. Not adversely affected by freezing {01}.

Preparation of dosage form:
Paclitaxel concentrate for injection must be diluted before administration. Paclitaxel concentrate for injection is prepared for administration by intravenous infusion by diluting it to a concentration of 0.3 to 1.2 mg per mL in 5% dextrose injection, 0.9% sodium chloride injection, or 5% dextrose in Ringer's injection {01}{123}{124}.

Note: Diluted solutions of paclitaxel may show haziness {01} {05}, which is attributed to the formulation vehicle {01}{123}{124}.


Stability:
Diluted solutions of paclitaxel are physically and chemically stable for up to 27 hours at ambient room temperature (approximately 25 °C [77 °F]) and room lighting conditions {01}.

Auxiliary labeling:
   • Must be diluted prior to administration.

Note: If paclitaxel solution contacts the skin, the skin should be washed immediately and thoroughly with soap and water {01}. If paclitaxel contacts mucous membranes, thorough flushing with water is recommended {01}.




Revised: 12/12/2002



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