Professional Drug Information > Taxotere

Docetaxel (Systemic )

VA CLASSIFICATION
Primary: AN900

Commonly used brand name(s): Taxotere.

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, breast (treatment)—Docetaxel is indicated for treatment of locally advanced or metastatic breast cancer after failure of first-line or subsequent chemotherapy. ^{{01} {02}{82}} [Docetaxel is also accepted as first-line chemotherapy for locally advanced or metastatic breast cancer, based on reports of objective tumor response rates (mostly partial but some complete) in phase II clinical trials. ^{{03} {04} {05} {07} {07} {36}}]¹

Carcinoma, lung, non–small cell (treatment)—Docetaxel is indicated for treatment of locally advanced or metastatic non–small cell lung carcinoma ^{{02} {08} {09} {10} {11} {12} {13} {14}} after platinum-based chemotherapy has failed ^{{02} {36}{82}}. [It is also accepted as first-line treatment for non–small cell lung carcinoma ^{36} , based on reports of objective tumor response rates in phase II clinical trials ^{{08} {09} {11} {12} {13} {14}} .]¹

[Carcinomas, esophageal (treatment) or]¹
[Carcinomas, gastric (treatment)]¹—Docetaxel is indicated, alone or in combination with other agents, for the treatment of advanced and/or metastatic esophageal, gastric, gastroesophageal (GE) junction carcinomas, including adenocarcinomas and squamous cell carcinomas.^{{91}{92}{93}{94}{95}{96}{97}{98}{99}{100}{101}{102}{103}{104}{105}{106}{107}}

[Carcinoma, lung, small cell (treatment) ]¹—Docetaxel is accepted for treatment of small-cell lung carcinoma after first-line chemotherapy has failed ^{36}, based on reports of objective tumor response rates in phase II clinical trials ^{48}.

[Carcinoma, ovarian (treatment)]¹—Docetaxel is accepted for treatment of ovarian carcinoma ^{36} after prior platinum-based therapy has failed, based on reports of objective tumor response rates in phase II clinical trials ^{{38} {39} {40} {41}}.

[Carcinoma, head and neck (treatment) ]¹—Docetaxel is indicated, alone or in combination with other chemotherapeutic agents, as reasonable medical therapy at some point in the management of patients with advanced, recurrent, or metastatic head and neck carcinoma (Evidence rating: IIID).^{{51}{52}{53}{54}{55}{56}{57}{58}{59}{60}{61}{62}{63}{64}{65}{66}{67}{68}{69}{81}}

[Carcinoma, prostate (treatment)]¹—Docetaxel is indicated, alone or in combination with other chemotherapeutic agents, as reasonable medical therapy at some point in the management of patients with hormone-refractory or hormone-sensitive prostate carcinoma (Evidence rating: IIID).^{{70}{71}{72}{73}{74}{75}{76}{77}{78}{79}{80}{81}}

[Carcinoma, bladder (treatment)]¹—Docetaxel is indicated, alone or in combination with other chemotherapeutic agents, as reasonable medical therapy at some point in the management of patients with bladder (urothelial) carcinoma.^{{83}{84}{85}{86}{87}{88}{89}{90}}

Acceptance not established
Use of docetaxel for the treatment of pancreatic carcinoma has not been established.^{{108}{109}{110}{111}{112}{113}{114}{115}{116}{117}{118}{119}{120}}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Semisynthetic ^{{01} {02} {15} {16}}, starting with a precursor extracted from the needles of the European ^{16} yew ^{{01} {02} {15} {16}}, Taxus baccata ^{16}.

Chemical group—
    Docetaxel is a member of the taxoid family ^{{02} {16}}; chemically related to paclitaxel ^{16}.
Molecular weight—
    861.94 ^{17}
    Practically insoluble in water; highly lipophilic. ^{{01} {02}}

Mechanism of action/Effect:

Docetaxel is an antimitotic agent. ^{{01} {02}} It binds to free tubulin, then promotes the polymerization of tubulin into stable microtubules and inhibits microtubule disassembly, resulting in blockade of cellular mitotic ^{{01} {02} {15} {16}} and interphase ^{{01} {02}} functions and, consequently, in inhibition of cell division ^{16}. Unlike paclitaxel ^{15} and other spindle poisons in clinical use ^{{01} {02}}, docetaxel does not alter the number of protofilaments in the bound microtubules ^{{01} {02} {16}}.

The mechanisms by which resistance to docetaxel occurs are not completely understood. ^{15} Studies have shown that docetaxel is active against several tumor cell lines overexpressing the multidrug resistance gene. ^{02} Also, cross-resistance between docetaxel and paclitaxel does not occur consistently. ^{15}


Other actions/effects:

Several in vitro and in vivo studies have shown that docetaxel has only moderate immunosuppressive activity. ^{02}

Distribution:

Volume of distribution at steady-state—Mean, 113 liters (L). ^{{01} {02}}

In animal studies, docetaxel was widely distributed to all tissues and organs other than the brain, in which very low concentrations were attained. ^{02}

Protein binding:

Very high (97%), primarily to alpha ₁-acid glycoprotein, albumin, and lipoproteins. ^{01}

Biotransformation:

Hepatic; extensively ^{15} metabolized by cytochrome P450 subfamily 3A (CYP 3A) isoenzymes ^{{01} {02} {15}} to one major and three minor metabolites ^{01}.

Half-life:

Dose-dependent. ^{{02} {19}} Doses of 70 mg per square meter of body surface area (mg/m ²) or higher ^{19} produce a triphasic elimination profile ^{{01} {02} {19}}. With lower doses, assay limitations precluded detection of the terminal elimination phase. ^{19}


Alpha (distribution):

4 minutes. ^{{01} {02}}



Beta:

36 minutes. ^{{01} {02}}



Gamma (terminal):

11.1 hours. ^{{01} {02}} The prolonged terminal elimination half-life is caused, in part, by relatively slow efflux from the peripheral compartment. ^{01}


Note: A preliminary study in pediatric patients receiving 55 mg/m ² of docetaxel reported bi-exponential elimination and a terminal half-life of 2.4 ± 1.8 hours. ^{20}


Peak serum concentration:

2.57 to 3.67 mcg per mL (mcg/mL), with doses of 70 to 100 mg/m ². ^{19}

Note: The area under the docetaxel concentration–time curve (AUC) is 3.13 to 4.83 mcg/mL per hour with doses of 70 to 100 mg/m ². ^{19} Values may be increased in patients with hepatic function impairment. ^{15}


Elimination:
    Primarily biliary ^{19}/fecal. ^{{01} {02} {19}} Following administration of radiolabeled docetaxel, fecal and urinary recovery over the next 7 days accounted for approximately 75% and 6%, respectively, of the administered radioactivity. ^{01} Approximately 80% of the radioactivity that appeared in the feces was excreted during the first 2 days as one major and three minor metabolites; < 8% was unchanged docetaxel. ^{01}
    Total body clearance is approximately 21 L per hour per square meter of body surface area ^{{01} {02}} (L/hr/m ²) and is not dose-dependent ^{19}. Values are decreased by an average of 27 ^{{01} {02}} to 30% ^{21}, but with substantial interpatient variability ^{01}, in patients with hepatic function test abnormalities ^{{01} {02} {21}} suggestive of mild to moderate hepatic function impairment ^{01}.

Note: In a preliminary study in pediatric patients, total body clearance was approximately 9.3 L/hr/m ². ^{20}



Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to paclitaxel may be hypersensitive to docetaxel also. ^{45}

Carcinogenicity

Carcinogenicity studies in animals have not been done. ^{{01} {02}}

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 the risk seems to increase with long-term use. ^{22} The risk of secondary malignancies developing after docetaxel therapy is not known. ^{49}

Mutagenicity

Docetaxel was clastogenic in the in vitro chromosome aberration test in Chinese hamster ovary K ₁ cells and in the in vivo mouse micronucleus test. ^{{01} {02}} No mutagenicity was observed in the Ames test or the Chinese hamster ovary/hypoxanthine-guanine phosphoribosyltransferase gene mutation assay. ^{{01} {02}}

Pregnancy/Reproduction
Fertility—
Decrease in testicular weight, but no overt impairment of fertility, occurred in rats given multiple doses of up to 0.3 mg per kg of body weight (mg/kg) intravenously (approximately one-fiftieth the recommended human dose on a mg per square meter of body surface area [mg/m ²] basis). ^{01} Testicular atrophy or degeneration also occurred in a 10-cycle study (in which the medication was given intravenously at 21-day intervals for 6 months) in rats given 5 mg/kg and dogs given 0.375 mg/kg (approximately one-third and one-fifteenth the recommended human dose on a mg/m ² basis, respectively). ^{01} Similar effects also occurred in rats given lower doses at an increased frequency of administration. ^{01}

Pregnancy—
Adequate and well-controlled ^{01} studies have not been done in humans ^{{01} {02}}.

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. ^{22}

Other hazards to the fetus include adverse reactions seen in adults. ^{22}

In general, use of contraception is recommended during cytotoxic drug therapy. ^{22}

Animal studies have shown that docetaxel is distributed to the fetus. ^{02} Maternal toxicity resulting in embryo- and fetotoxicity occurred in rats given 0.3 mg/kg or more per day and in rabbits given 0.03 mg/kg or more per day (equivalent to or higher than one-fiftieth and one-three hundredth, respectively, the maximum recommended human dose on a mg/m ² basis) during the period of organogenesis. ^{{01} {02}} Embryotoxic and fetotoxic effects were characterized by increased intrauterine deaths ^{{01} {02}}, increased resorptions ^{01}, decreased fetal weights ^{{01} {02}}, and delayed fetal ossification ^{{01} {02}}. However, no teratogenicity was apparent in rats and rabbits given doses of 1.8 and 1.2 mg/kg per day, respectively. ^{02}

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). ^{22} It is not known whether docetaxel is distributed into human breast milk ^{{01} {02}}, but it is distributed into the milk of lactating animals ^{02}.

Pediatrics

Docetaxel has been studied in a limited number of children with refractory cancer. ^{{20} {42}} Dose-ranging studies have shown the maximum tolerated dose to be lower in pediatric patients (especially if treated with several prior courses of chemotherapy) than in adults ^{20}, unless a colony-stimulating factor is used to reduce the occurrence of severe neutropenia ^{42}. However, safety and efficacy in children ^{{01} {02}} younger than 16 years of age ^{01} have not been established ^{{01} {02}}.


Geriatrics


Several clinical trials with docetaxel have included patients older than 65 years of age. ^{{01} {03} {04} {05} {07}} These studies did not show any differences between elderly patients and younger adults in the efficacy ^{{03} {04} {05} {07}}, toxicity ^{{03} {04} {05} {07}}, or pharmacokinetics ^{01} of docetaxel. Adjustment of dosage on the basis of age is not needed in geriatric patients. ^{01}


Pharmacogenetics

A pharmacokinetic study showed no significant differences in total body clearance of docetaxel between Japanese patients and American or European patients. ^{{01} {23}}


Dental

Docetaxel commonly causes neutropenia, and, less commonly, thrombocytopenia ^{{01} {02}}, which may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If severe neutropenia occurs, dental work should be deferred until blood counts have returned to normal. Also, patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks. ^{24}

Docetaxel commonly causes stomatitis (ulceration of the lips, tongue, and oral cavity), which is usually mild but in some patients may be severe. ^{01} There is some evidence that severe stomatitis tends to occur at the nadir of the neutrophil count and may contribute to the occurrence of neutropenic fever by providing an entry for pathogens into the body. ^{{15} {16}}

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 docetaxel may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of docetaxel, if necessary, should be based on blood counts ^{25})


» Bone marrow depressants, other (see Appendix II ) or
Radiation therapy    (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 ^{25})


» Enzyme inhibitors, hepatic, of the cytochrome P450 3A (CYP 3A) isoenzyme, such as:
Erythromycin ^{{01} {18}}
Ketoconazole ^{{01} {02} {18}}
Midazolam ^{18}
Orphenadrine ^{18}
Testosterone ^{18}
Troleandomycin ^{82}    (caution in concurrent use is recommended ^{{01} {02}} because in vitro studies have shown that inhibitors of the CYP 3A isoenzyme [but not inhibitors of other cytochrome P450 isoenzymes] significantly inhibit docetaxel metabolism ^{18})


» Immunosuppressants, other, such as:
Azathioprine
Chlorambucil
Corticosteroids, glucocorticoid
Cyclophosphamide
Cyclosporine
Mercaptopurine
Muromonab CD-3
Tacrolimus    (concurrent use with docetaxel may increase the risk of infection ^{25})


Paclitaxel and
Other medications metabolized by the CYP 3A isoenzyme    (in vitro studies have shown that paclitaxel, which is partially metabolized by the CYP 3A isoenzyme, significantly inhibits docetaxel metabolism; also, docetaxel inhibits formation of the minor paclitaxel metabolite M4 via CYP 3A [but not formation of the major paclitaxel metabolite M5 via the cytochrome P450 2C isoenzyme]. ^{18} The possibility should be considered that other medications that are metabolized by the CYP 3A isoenzyme may also alter docetaxel metabolism ^{01})


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by docetaxel 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 ^{27})


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by docetaxel 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 docetaxel 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 ^{27})



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
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT]) and
Bilirubin concentrations, serum    (values may be increased ^{{01} {02}}; in clinical trials, bilirubin concentrations higher than the upper limit of normal, aminotransferase values > 1.5 times the upper limit of normal, alkaline phosphatase values > 2.5 times the upper limit of normal, and concomitant increases in aminotransferase and alkaline phosphatase values occurred in approximately 9%, 18%, 7.5%, and 4.5% of patients with normal pretreatment values, respectively ^{01}{82}. However, whether these changes were caused by docetaxel or the underlying disease has not been established ^{01}{82})


Hematocrit/hemoglobin values and
Leukocyte, especially neutrophil, count and
Platelet count    (may be decreased ^{01}{82}; the neutrophil count usually reaches a nadir at a median of 8 days after a treatment ^{{01} {02}{82}} and generally returns to pretreatment or near-pretreatment values within the next 1 or 2 weeks ^{{15} {28}})


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).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hepatic function impairment    (docetaxel clearance will be decreased ^{{15} {21} {29}}, resulting in an increased risk of toxic effects, including severe stomatitis ^{{01} {29}}, dermatological reactions ^{01}, and thrombocytopenia ^{01} as well as severe neutropenia ^{01}, febrile neutropenia ^{{01} {29}}, infections ^{{01} {29}}, and toxic death ^{{01} {29}}, even if dosage is decreased ^{{01} {29}}. Docetaxel is therefore not recommended for patients with hepatic function impairment, especially if bilirubin concentrations are elevated or when transaminase values are > 1.5 times the upper limit of normal and alkaline phosphastase values are > 2.5 times the upper limit of normal. ^{01}{82} If docetaxel is considered essential for a patient with mild hepatic function impairment, extreme caution and lower doses are recommended ^{43})


Risk-benefit should be considered when the following medical problems exist
Alcohol abuse or history of    (risk of severe neurotoxic reactions to docetaxel may be increased ^{06})


» Bone marrow depression    (will be exacerbated; treatment should be delayed until the neutrophil count recovers to > 1500 cells per cubic millimeter ^{{01} {02}} and the platelet count returns to > 100,000 cells per cubic millimeter ^{01}{82})


» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe, generalized disease ^{22})


Conditions that may predispose to pleural effusion, such as:
Chest radiotherapy, prior or
» Pleural effusion, pre-existing or
Pleural tumor or
Thoracotomy, prior    (increased risk of pleural effusion associated with docetaxel-induced fluid retention ^{{08} {09}})


» Hypersensitivity reaction, severe, history of, to docetaxel ^{{01} {02}{82}} , paclitaxel ^{45} , or other medications formulated with polysorbate 80 ^{{01} {02}}
» Infection, pre-existing    (recovery may be impaired ^{27})


» Caution should also be used in patients who have had previous cytotoxic drug therapy or radiation therapy ^{22}

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):

» Alanine aminotransferase (ALT [SGPT]) values and
» Alkaline phosphatase values and
» Aspartate aminotransferase (AST [SGOT]) values and
» Total bilirubin concentrations, serum    (recommended prior to each treatment cycle; it is recommended that docetaxel not be given if abnormalities indicative of hepatic function impairment are present ^{43} [e.g., bilirubin concentrations higher than the upper limit of normal or transaminase values > 1.5 times the upper limit of normal and alkaline phosphatase values > 2.5 times the upper limit of normal] ^{01}{82})


Hematocrit or hemoglobin and
» Leukocyte count, total and differential and
Platelet count    (determinations recommended prior to initiation of therapy and at frequent intervals during therapy; administration of docetaxel should be delayed if the neutrophil count is lower than 1500 cells per cubic millimeter ^{{01} {02}} and/or the platelet count is lower than 100,000 cells per cubic millimeter ^{01}. If severe neutropenia [fewer than 500 cells per cubic millimeter] persists for 7 days or more, a reduction in dose is recommended for subsequent courses of therapy ^{{01} {02}{82}})


» Skin appearance ^{45} and
» Vital signs    (should be monitored during, and for approximately 1 hour following, an infusion ^{44}, especially during the first two treatment cycles, to detect signs of a severe hypersensitivity reaction, e.g., dyspnea ^{01}, hypotension ^{01}, generalized urticaria ^{45}, or other signs of angioedema ^{45})




Side/Adverse Effects

Note: Many ``side effects'' of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration. ^{22}
Bone marrow depression ^{01} (primarily neutropenia ^{{15} {16} {26} {28}}) is the major dose-limiting toxicity ^{{01} {15} {16} {26}}.
Significant endocrine ^{26}, hepatic ^{26}, or renal ^{26} toxicity clearly attributable to docetaxel has not been reported.
In addition to the side/adverse effects reported below, the following have been reported, but a causal relationship has not been established: cardiovascular—atrial fibrillation, deep vein thrombosis, electrocardiographic abnormalities, pulmonary embolism, syncope, tachycardia, thrombophlebitis; gastrointestinal—constipation, duodenal ulcer, esophagitis, intestinal obstruction, ileus; nervous system—confusion, pain; respiratory—acute pulmonary edema, acute respiratory distress syndrome; urogenital—renal insufficiency. ^{01}

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 (> 30%)
    
Anemia^{01} (unusual tiredness or weakness)
    
fever —not always associated with infection^{01}
    
fluid retention^{01} (more commonly, swelling of fingers, hands, feet, or lower legs; less commonly, swelling of abdomen or face; noisy, rattling breathing or troubled breathing while at rest; weight gain)
    
leukopenia or neutropenia^{01} —usually asymptomatic

Note: Although anemia occurs very frequently, severe anemia (hemoglobin < 8 grams per deciliter) is relatively infrequent in patients with normal hepatic function. However, the incidence of severe anemia is significantly increased in patients with mild to moderate hepatic function impairment. ^{01}
Fluid retention usually begins in the lower extremities, but may become generalized and, less frequently, lead to pleural effusions, pericardial effusions, or ascites. ^{{01} {02}} Prophylactic corticosteroid administration decreases the incidence and severity of this complication ^{{16} {28}} and increases the median cumulative dose at which moderate or severe edema occurs (from 400 ^{{02} {16} {26} {28}} to 705 [mg/m ²] ^{01}). However, even with recommended prophylaxis, docetaxel causes fluid retention in almost 50% of patients with normal hepatic function; moderate or severe fluid retention requiring medical treatment occurs in approximately 17% and 6%, respectively, of these patients. ^{01} The incidence and severity of fluid retention are significantly higher in patients with hepatic function impairment. ^{01} Fluid accumulation is due to increased capillary permeability ^{{28} {30}} rather than hypoalbuminemia or cardiac, hepatic, or renal damage ^{28}. Fluid retention is slowly reversible after treatment is discontinued ^{{01} {02} {28}} (median 29 [range, 0 to > 42] weeks to complete reversal) ^{01}.
Leukopenia and neutropenia occur in > 96% of patients receiving docetaxel; severe neutropenia (neutrophil count below 500 cells per cubic millimeter) is also very common. ^{01} In most patients, the neutropenia is reversible ^{{01} {02} {15} {26} {28}}, noncumulative ^{{01} {02} {16}}, and short-lasting ^{{15} {16}}. The nadir of the neutrophil count usually occurs 8 days after an infusion. ^{{01} {02} {28}} The median duration of severe neutropenia is 7 days ^{01}, and neutrophil counts usually return to pretreatment or near-pretreatment values in 1 to 2 weeks ^{{15} {28}}. Febrile neutropenia (severe neutropenia with fever > 38 °C [100.4 °F] and infection requiring intravenous antibiotic therapy and/or hospitalization) occurs less frequently, and deaths due to sepsis are uncommon, in patients with normal hepatic function. ^{01} Hepatic function impairment significantly increases the risk of severe neutropenia, febrile neutropenia, and septic deaths. ^{{01} {29}}


Incidence less frequent (5 to 29%)
    
Cutaneous reaction, severe^{01} (red, scaly, swollen, or peeling areas of skin)—especially likely to occur on the hands and/or feet
    
febrile neutropenia or other infection^{01} (fever with or without chills; cough or hoarseness; difficult or painful urination; lower back or side pain)
    
hypersensitivity reaction, mild^{01} (back pain; flushing; skin rash or itching, localized; troubled breathing, mild)
    
thrombocytopenia^{01} (rarely, unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic

Note: Infections have also been reported in the absence of febrile neutropenia ^{01}.
Fatalities have occurred with docetaxel therapy at doses of 100 mg/m ² (34 of 1435 patients with normal liver function and 6 of 55 patients with hepatic function impairment) and doses of 60 mg/m ² (3 of 481 patients with normal liver function and 3 of 7 patients with hepatic function impairment). ^{01} Most of the fatalities resulted from sepsis associated with neutropenia. ^{01}
Hypersensitivity reactions are most likely to occur during the first two cycles of docetaxel treatment ^{{16} {28}}, generally within the first few minutes after the infusion is started ^{{16} {26} {28}}. Signs and symptoms usually abate within 15 minutes after the infusion is stopped. ^{28} After a mild reaction, treatment can usually be reinstituted without further difficulty. ^{28} However, if a severe reaction (characterized by angioedema ^{45}, hypotension ^{02}, bronchospasm ^{02}, and/or generalized erythema ^{02}, urticaria ^{45}, or skin rash ^{02}) occurs, the infusion should be discontinued immediately and aggressive treatment instituted. ^{{02} {45}}


Incidence rare (< 5%)
    
Cardiovascular effects, including angina, unstable^{01} (chest pain), arrhythmia, such as sinus tachycardia^{01} , atrial flutter^{01}{02} , or paroxysmal atrial tachycardia^{01} (fast or irregular heartbeat), heart failure^{01} (shortness of breath; swelling of face, fingers, feet, or lower legs), hypertension^{01} (increase in blood pressure; dizziness; headaches), and hypotension^{01} (dizziness; fainting)—usually asymptomatic
    
hypersensitivity reaction, severe^{01} (decrease in blood pressure, sudden and severe^{01}; shortness of breath, troubled breathing, tightness in chest, or wheezing^{01}; hives^{45} , skin rash^{01} , or redness^{01} , generalized)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (> 30%)
    
Cutaneous reaction, mild^{01} (skin rash or redness)
    
diarrhea^{01}
    
nausea^{01}
    
neurologic effects, including asthenia^{01} (weakness), and paresthesias or dysesthesias^{01} (burning, numbness, tingling, or painful sensations)
    
stomatitis^{01} (sores or ulcers on lips or tongue or inside the mouth)

Note: Rarely, neurologic effects may result in moderate to severe neuropathy ^{{16} {31}}, leading to decreased dexterity and/or disturbances in gait, ^{31} usually after cumulative doses of 600 mg/m ² have been given ^{{16} {31}}.
Severe stomatitis may contribute to the occurrence of febrile neutropenia by providing a portal for entry of pathogens into the body. ^{{15} {16}}


Incidence less frequent (5 to 29%)
    
Arthralgias or myalgias^{01} (pain in joints or muscles)
    
headache^{01}
    
infusion site reactions^{01} (dry, red, hot, or irritated skin; pain; or swelling or lump under the skin at place of injection)
    
nail disorder^{01} (discoloration of fingernails or toenails; rarely, loosening or loss of nails and pain)
    
vomiting^{01}



Those not indicating need for medical attention
Incidence more frequent
    
Alopecia (loss of hair)—occurs in 80% of patients^{01} , but is fully reversible after therapy has ended^{26}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic
    
Bone marrow suppression ^{01} , including anemia (unusual tiredness or weakness), leukopenia or neutropenia, with or without infection ( fever with or without chills; cough or hoarseness; lower back or side pain; painful or difficult urination), and/or thrombocytopenia (black, tarry stools; blood in urine or stools; pinpoint red spots on skin; unusual bleeding or bruising)
    
stomatitis ^{01} (sores or ulcers on lips or tongue or inside the mouth)
    
peripheral neuropathy ^{01} (burning, numbness, tingling, or painful sensations; weakness in arms, hands, legs, or feet)


Treatment of overdose
It is recommended that the patient be hospitalized for close monitoring of vital functions and treatment of observed effects. ^{01} Therapeutic G-CSF should be given as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.^{82} Severe bone marrow depression may require transfusion of required blood components. ^{01} Febrile neutropenia should be treated empirically with broad-spectrum antibiotics, pending bacterial cultures and appropriate diagnostic tests. ^{22}


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

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

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to docetaxel, paclitaxel, or polysorbate 80

Pregnancy—Use is not recommended because of embryotoxic, fetotoxic, and carcinogenic potential; advisability of using contraception; informing physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of potential serious adverse effects
Other medications, especially other bone marrow depressants, other immunosuppressants, inhibitors of the cytochrome P450 3A isoenzyme, such as erythromycin, ketoconazole, midazolam, orphenadrine, testosterone, and troleandomycin, and radiation therapy
Other medical problems, especially hepatic function impairment, chickenpox, herpes zoster, infection, or pleural effusion

Proper use of this medication
Frequency of nausea and vomiting and/or neuropathy; importance of continuing treatment despite feeling ill

» Importance of compliance with peritreatment corticosteroid regimen

» 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 cell counts; checking with physician immediately if fever with or without 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 washed immediately before

Using caution to avoid accidental cuts when using 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 anemia, fever, fluid retention, severe cutaneous reactions, febrile neutropenia, thrombocytopenia, and cardiovascular effects

» Possibility of hypersensitivity; notifying physician or nurse immediately if back pain, breathing problems, or itching occurs during infusion; physician or nurse will monitor for other signs of allergic reaction and be prepared to institute treatment

Some side effects may be asymptomatic, including anemia, leukopenia or neutropenia, thrombocytopenia, and cardiovascular effects

Physician or nurse can help in dealing with side effects

Probability of hair loss; regrowth should return after treatment has ended


General Dosing Information
Docetaxel should be administered only under the supervision of a physician experienced in cancer chemotherapy. ^{{01} {02}} Adequate facilities and medications for diagnosis and treatment of complications should be readily available. ^{{01} {02}}

Peritreatment administration of an oral corticosteroid is recommended to decrease the frequency ^{{01} {02} {33}} and severity ^{{01} {02} {32} {33}} and delay the onset ^{{28} {32} {33}} of docetaxel-induced fluid retention. Aggressive, early diuretic treatment may also be required. ^{{26} {28}}

Peritreatment administration of an oral corticosteroid ^{{01} {16} {26} {28}}, with or without antihistamines (both H ₁- and H ₂-receptor antagonists) ^{{26} {28}}, also reduces the severity of docetaxel-induced hypersensitivity reactions ^{{01} {28}} and cutaneous toxicity ^{28}. A commonly used regimen consists of 8 mg of dexamethasone orally two times a day for 5 days, beginning 1 day before the docetaxel infusion ^{{01} {02} {28}}; the antihistamines, if used, are given intravenously 30 minutes prior to the start of the docetaxel infusion ^{28}. A recent study has shown that administering 8 mg of dexamethasone orally two times a day for only 3 days, beginning 1 day before the docetaxel infusion, is as effective as the 5-day regimen in reducing the severity of hypersensitivity reactions ^{46} and fluid retention ^{50} and also decreases the occurrence of severe stomatitis and infection. ^{46} Palmar-plantar erythrodysesthesias that occur despite prophylaxis may respond to administration of 50 mg three times a day ^{37} of pyridoxine ^{{28} {37}}.

Docetaxel is not highly emetogenic; routine prophylaxis with antiemetics is generally not required. ^{{15} {16}}

Docetaxel is administered by intravenous infusion. ^{{01} {02}} Docetaxel for injection concentrate must be diluted before use. ^{{01} {02}} The needle or catheter should be properly positioned to prevent leakage into surrounding tissue, which may result in irritation, local tissue necrosis, and thrombophlebitis. ^{02} If extravasation occurs, the infusion should be stopped immediately and the remainder of the dose administered into another vein. ^{02}

Mild hypersensitivity reactions (flushing, localized skin reactions, back pain, fever, chills, mild dyspnea) do not require interruption of docetaxel therapy. ^{02} However, severe reactions (angioedema ^{45}, hypotension requiring treatment ^{02}, severe dyspnea ^{02}, bronchospasm ^{02}, or generalized rash ^{02}, urticaria ^{45}, or erythema ^{02}) require immediate discontinuation of the infusion and aggressive treatment. It is generally recommended that docetaxel not be readministered to patients who experience a severe hypersensitivity reaction despite adequate premedication. ^{02} However, in patients with objective tumor responses and without other options to docetaxel therapy, re-treatment may be attempted with extreme caution and aggressive premedication by experienced practitioners ^{36}. It is recommended that a slower rate of infusion be used. ^{45} One patient who experienced major hypersensitivity symptoms during the first two cycles of docetaxel therapy despite prophylaxis with a corticosteroid and a histamine H ₁-blocking antagonist was able to continue treatment without further difficulty after cromolyn (400 mg four times a day, orally, starting immediately after the second cycle) was added to the prophylactic regimen. ^{35}

A reduction in subsequent doses is recommended for patients who develop severe neutropenia (neutrophil count < 500 cells per cubic millimeter) that persists for 7 days or more ^{{01} {02}}, febrile neutropenia ^{45}, severe (grade 4) infection ^{45}, severe peripheral neuropathy ^{{01} {02}}, or severe or cumulative cutaneous reactions ^{{01} {02}}.

Patients who develop leukopenia should be observed carefully for signs and symptoms 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. ^{22}

Special precautions are recommended for patients who develop thrombocytopenia as a result of docetaxel therapy. 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; 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. ^{22}

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: ^{22}

• 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 and organizations ^{47} have developed detailed guidelines for handling of antineoplastic agents.

If docetaxel comes into contact with the skin, the skin should be washed immediately and thoroughly with soap and water. If the medication comes into contact with a mucous membrane, the area should be immediately and thoroughly flushed with water. ^{{01} {02}}


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.

DOCETAXEL FOR INJECTION CONCENTRATE

Usual adult dose
Carcinoma, breast
Intravenous infusion, 60 to 100 mg per square meter of body surface area, administered as a one-hour infusion every three weeks. ^{01}{82}

Note: If patients initially receiving a dose of 100 mg per square meter of body surface area experience febrile neutropenia, neutrophil count < 500 cells per cubic millimeter for more than 1 week, or severe or cumulative cutaneous reactions, the dose of docetaxel should be reduced to 75 mg per square meter of body surface area. Further reduction to 55 mg per square meter of body surface area or discontinuation of therapy should be considered if these reactions continue. Conversely, patients initially receiving 60 mg per square meter of body surface area who do not manifest the reactions listed above or severe peripheral neuropathy may tolerate higher doses. Docetaxel therapy should be discontinued entirely if patients experience ³ grade 3 peripheral neuropathy.^{82}


[Carcinoma, head and neck]¹
Intravenous, 60^{53}{54} to 100 mg per square meter of body surface area administered as a one-hour infusion every three to four^{53}{54} weeks, for an average of two to six cycles (maximum four to eight).^{{51}{52}{53}{54}{55}{56}{57}{58}{59}{60}{61}{62}{63}{64}}

Note: Dose-limiting toxicities and the use of other chemotherapeutic agents (e.g., cisplatin and 5–fluorouracil) may warrant a dose reduction^{58}{59}{60}
Doses of 20 to 80 mg per square meter of body surface area administered as a one-hour intravenous infusion once every seven to seventeen days, for a maximum of six cycles^{68}{69} or 25 to 90 mg per square meter of body surface area (with cisplatin, 5-fluorouracil, and with or without leucovorin) , administered as one-hour intravenous infusion, once every four weeks, for a maximum of three cycles^{65}{66}{67} have been reported.


Carcinoma, lung, non-small cell
Intravenous, 75 mg per square meter of body surface area, administered as a one-hour infusion every three weeks.^{82}

Note: A dose of 100 mg per square meter of body surface area in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized, controlled trials.^{82}
If patients initially receiving a dose of 75 mg per square meter of body surface area experience febrile neutropenia, neutrophil count < 500 cells per cubic millimeter for more than 1 week, severe or cumulative cutaneous reactions, or other grade 3 or 4 non-hematologic toxicities, docetaxel therapy should be withheld until the toxic reaction is resolved. Docetaxel therapy should then be resumed at a dose of 55 mg per square meter of body surface area. Docetaxel therapy should be discontinued entirely if patients experience ³ grade 3 peripheral neuropathy.^{82}


[Carcinoma, esophageal]¹ or
[ Carcinoma, gastric]¹
Patients have benefited from intravenous doses of 60 to 85 mg/m ², by 1–hour infusion, every 21 to 28 days, in combination with other agents (e.g., gemcitabine, cisplatin, 5–fluorouracil, leucovorin) and radiation therapy.^{107} As single-agent therapy, patients have benefited from an intravenous dose of 100 mg/m ², by 1–hour infusion, every 21 days.^{107}

[Carcinoma, lung, small cell or ^{48}]¹
[Carcinoma, ovarian]¹
Intravenous, 100 mg per square meter of body surface area, administered as a one-hour infusion every three weeks. ^{{02} {48}}

[Carcinoma, prostate]¹
Intravenous, 40 to 80 mg per square meter of body surface area administered as a one-hour infusion once every three weeks, for an average of five to nine cycles.^{{71}{72}{73}{74}{75}{76}{78}{79}{80}}Dose-limiting toxicities and the use of other chemotherapeutic agents (e.g., estramustine) may warrant a dose reduction.^{72} Other studies reported using doses of 20 to 40 mg per square meter of body surface area given by one-hour intravenous infusion once a week, for two weeks with a one-week rest^{77} or for six weeks with a two-week rest^{70}{77}.


Note: For all indications, docetaxel administration should be delayed if the neutrophil count is lower than 1500 cells per cubic millimeter ^{{01} {02}{82}} and/or the platelet count is lower than 100,000 cells per cubic millimeter ^{01}{82}.
A reduction in subsequent doses is recommended for patients who develop severe neutropenia (neutrophil count < 500 cells per cubic millimeter) that persists for 7 days or more ^{{01} {02}{82}}, febrile neutropenia ^{45}, severe (grade 4) infection ^{45}, severe peripheral neuropathy ^{{01} {02}{82}}, or severe or cumulative cutaneous reactions ^{{01} {02}{82}}. Dosage in patients originally receiving 100 mg per square meter of body surface area should be decreased by 25%, to 75 mg per square meter of body surface area. ^{{01} {02}{82}} If these complications persist or recur, dosage should be further decreased to 55 mg per square meter of body surface area ^{{01} {02}{82}} or treatment discontinued ^{01}{82}.
Docetaxel is not recommended for patients with hepatic function impairment, especially moderate to severe impairment, because of the considerably higher risk of severe toxicity. If docetaxel is considered essential for a patient with mild hepatic function impairment, initial doses of 60 to 75 mg per square meter of body surface area should be used. However, the risk of severe toxicity and septic death will still be significantly higher than for patients with normal hepatic function. ^{43}
Patients who originally receive 60 mg per square meter of body surface area and who do not develop severe neutropenia, cutaneous reactions, or peripheral neuropathy may tolerate higher doses. ^{01}

[Carcinoma, bladder (treatment)]¹
Patients have benefited from 1–hour intravenous infusions of 75 to 100 mg per square meter of body surface area, every 21 days, for up to 6 treatment cycles.^{90}


Usual pediatric dose
Safety and efficacy in patients up to 16 years of age have not been established. ^{01}{82}

Usual geriatric dose
See Usual adult dose . ^{{01} {02}{82}}

Strength(s) usually available
U.S.—


20 mg per 0.5 mL (single-dose vial) (Rx) [Taxotere (polysorbate 80 1040 mg per mL)]


80 mg per 2 mL (single-dose vial) (Rx) [Taxotere (polysorbate 80 1040 mg per mL)]

Note: Product is packaged together with accompanying diluent (0.5 mL for the 20 mg per 0.5 mL vial; 2 mL for the 80 mg per 2 mL vial). The diluent contains 13% (w/w) ethanol. ^{01}{82} The vials contain overfills of docetaxel and diluent ^{01} to allow for loss due to foaming, adhesion to vial walls, and dead space during initial dilution of the concentrate ^{45}.


Canada—


20 mg per 0.5 mL (single-dose vial) (Rx) [Taxotere (polysorbate 80 1040 mg per mL)]


80 mg per 2 mL (single-dose vial) (Rx) [Taxotere (polysorbate 80 1040 mg per mL)]

Note: Product is packaged together with accompanying diluent (0.5 mL for the 20 mg per 0.5 mL vial; 2 mL for the 80 mg per 2 mL vial). The diluent contains 13% (w/w) ethanol. ^{02} The vials contain overfills of docetaxel and diluent ^{02} to allow for loss due to foaming, adhesion to vial walls, and dead space during initial dilution of the concentrate ^{45}.


Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). ^{{01} {02}} Protect from bright light. ^{{01} {02}}

Note: Docetaxel for injection concentrate is not adversely affected by freezing. ^{01}


Preparation of dosage form:
Docetaxel for injection concentrate must be diluted, using the following procedure—


To prepare premix solution:
Remove docetaxel and diluent from the refrigerator and allow to stand for approximately 5 minutes at room temperature. Using aseptic technique and a syringe, transfer the entire contents of the diluent vial to the vial containing docetaxel. Rotate the vial gently for approximately 15 seconds to assure complete mixture of the medication and diluent. The final concentration of docetaxel will be 10 mg per mL. Allow the solution to stand for a few minutes to allow any foam to dissipate. However, the foam need not dissipate completely before the preparation process is continued. Discard the premix solution if it is not clear or contains a precipitate. ^{{01} {02}{82}}



To prepare the infusion:
Using aseptic technique and a calibrated syringe, transfer the required quantity of premix solution into a 250-mL infusion bag or bottle containing 5% dextrose injection or 0.9% sodium chloride injection to achieve a final concentration of 0.3 to 0.9 mg per mL. If a dose greater than 240 mg of docetaxel is required, a larger volume of vehicle should be used so that the concentration does not exceed 0.9 mg per mL. Thoroughly mix by manual rotation of the container. Discard the infusion if it is not clear or contains a precipitate. ^{{01} {02}{82}}


Stability:
The premix solution is stable for up to 8 hours at room temperature (15 to 25 °C [59 to 77 °F]) or in a refrigerator (2 to 8 °C [36 to 46 °F]). However, it is recommended that the solution be used as soon as possible after preparation. ^{{01} {02}{82}}

Incompatibilities:
Contact of undiluted docetaxel with plasticized polyvinyl equipment is not recommended because such contact may cause leaching of the plasticizer, di-2-ethylhexyl phthalate (DEHP). It is recommended that glass bottles or polypropylene or polyolefin plastic products be used for preparation and storage of the infusion, and that the infusion be administered through polyethylene-lined administration sets. ^{01}{82}

Auxiliary labeling:
   • Must be diluted prior to administration.

Developed: 09/17/1997
Revised: 07/23/2001

References

1. Taxotere package insert (Rhône-Poulenc Rorer—US), Rec 6/96; Rev 1/99, Rec 4/99.
   

2. Taxotere product monograph (Rhône-Poulenc Rorer—Canada), Rev 8/21/95, Rec 2/4/96.
   

3. Hudis CA, Seidman AD, Crown JPA, et al. Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer. J Clin Oncol 1996; 14: 58-65.
   

4. Trudeau ME, Eisenhauer EA, Higgins BP, et al. Docetaxel in patients with metastatic breast cancer: a phase II study of the National Cancer Institute of Canada–Clinical Trials Group. J Clin Oncol 1996; 14: 422-8.
   

5. Fumoleau P, Chevallier B, Kerbrat P, et al. A multicentre phase II study of the efficacy and safety of docetaxel as first-line chemotherapy for patients with advanced breast cancer: report of the Clinical Screening Group of the EORTC. Ann Oncol 1996; 7: 165-71.
   

6. Dieras V, Chevallier B, Kerbrat P, et al. A multicentre phase II trial of docetaxel 75 mg m-2 as first-line chemotherapy for patients with advanced breast cancer: report of the Clinical Screening Group of the EORTC. Br J Cancer 1996; 74: 650-6.
   

7. Chevallier B, Fumoleau P, Kerbrat P, et al. Docetaxel is a major cytotoxic drug for the treatment of advanced breast cancer: a phase II trial of the Clinical Screening Cooperative Group of the European Organization for Research and Treatment of Cancer. J Clin Oncol 1995; 13: 314-22.
   

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17. Fleeger CA, editor. USP dictionary of USAN and international drug names. Rockville, MD: United States Pharmacopeial Convention; 1997. p. 245.
    

18. Royer I, Monsarrat B, Sonnier M, et al. Metabolism of docetaxel by human cytochromes P450: Interactions with paclitaxel and other antineoplastic drugs. Cancer Res 1996; 56: 58-65.
    

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22. Standard statement/precaution approved by Panel consensus for all antineoplastics monographs.
    

23. Tanigawara Y, Sasaki Y, Otsu T, et al. Population pharmacokinetics of docetaxel in Japanese patients [abstract 1518]. Proc Am Soc Clin Oncol 1996; 15: 479.
    

24. Standard dental precaution statement approved by Panel consensus for leukopenia/neutropenia-inducing medications.
    

25. Standard drug interaction precaution statement approved by Panel consensus for bone marrow depressants.
    

26. van Oosterom AT, Schriivers D. Docetaxel (Taxotere), a review of preclinical and clinical experience. Part II: clinical experience. Anti-Cancer Drugs 1995; 6: 356-68.
    

27. Standard drug interaction precaution statement approved by Panel consensus for immunosuppressants.
    

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30. Pujade-Lauraine E, Brun B, Maurel A, et al. Pathophysiology and management of docetaxel-induced fluid retention [abstract 234]. Proc Am Soc Clin Oncol 1996; 15: 166.
    

31. Hilkens PHE, Verweij J, Stoter G, Vecht ChJ, van Putten WLJ, van den Bent MJ. Peripheral neurotoxicity induced by docetaxel. Neurology 1996; 46: 104-8.
    

32. Piccart MJ, Klijm J, Paridaens R, et al. Steroids do reduce the severity and delay the onset of docetaxel (DXT) induced fluid retention: final results of a randomized trial of the EORTC investigational drug branch for breast cancer (IDBBC) [abstract 347]. Eur J Cancer 1995; 31A(Suppl 5): S75.
    

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34. Responses to Panel Question #3, Paclitaxel (Systemic) monograph, 7/93.
    

35. Westermann AM, ten Bokkel Huinink WW, Rodenhuis S. Successful docetaxel rechallenge with cromoglycate after major sensitivity reactions. Ann Oncol 1996; 7: 104.
    

36. Panel consensus on monograph draft of 5/22/97.
    

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38. Piccart MJ, Gore M, ten Bokkel Huinink W, et al. Docetaxel: an active new drug for treatment of advanced epithelial ovarian cancer. J Natl Cancer Inst 1995; 87: 676-81.
    

39. Aapro MS, Pujade-Laurane E, Lhomme C, et al. EORTC clinical screening group: Phase II study of Taxotere (docetaxel) in ovarian cancer [abstract 508]. Ann Oncol 1994; 5(Suppl 5): 202.
    

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41. Kavanagh J, Kudelka A, Freedman R, et al. Taxotere (docetaxel): Activity in platin refractory ovarian cancer and amelioration of toxicity [abstract 732]. Proc Am Soc Clin Oncol 1994; 13: 237.
    

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43. Panel responses to Questions 6 and 12, monograph draft 5/22/97.
    

44. Panelist comment on monograph draft 5/22/97.
    

45. Manufacturer comment on monograph draft 5/22/97.
    

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47. Panelist comment on monograph draft 5/22/97.
    

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50. Personal communication, Wendy Palmby, Medical Information Associate, Rhône-Poulenc Rorer—US, 08/29/97.
    

51. Catimel G, Verweij J, Mattijssen V, et al. Docetaxel (Taxotere®): An active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. Ann Oncol 1994; 5: 533-7.
    

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58. Schoffski P, Catimel G, Planting AST, et al. Docetaxel and cisplatin: an active regimen in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 1999; 10(1): 119-22.
    

59. Manzione L, Caponigro F, Massa E, et al. A phase II study of docetaxel (DTX) + cisplatin (CDDP) in locally advanced and metastatic squamous cell carcinoma of the head and neck [Abstract 1537]. Am Soc Clin Oncol 1999; 18: 398a.
    

60. Mel JR, Rodriguez R, Constenla M, et al. Phase II study of docetaxel and cisplatin as induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck (SCCHD): preliminary results [Abstract 1549]. Am Soc Clin Oncol 1999; 18: 401a.
    

61. Kienzer HR, Schweiger J, Bauer, et al. Docetaxel (D)/cisplatin (P) as first-line therapy in head and neck cancer (HNC) [Abstract 1566]. Proc Am Soc Clin Oncol 1998; 17: 406a.
    

62. Forastiere A, Glisson B, Murphy B, et al. A phase II study of docetaxel and cisplatin in patients with locally advanced, recurrent, and/or metastatic squamous cell carcinoma of the head and neck (SCCHN), not curable by standard therapy [Abstract 1540]. Proc Am Soc Clin Oncol 1998; 17: 399a.
    

63. Posner MR, Glisson B, Al-Sarraf M, et al. A multi-center phase II study of induction chemotherapy with taxotere (T), cisplatinium (P), and 5-fluorouracil (F) (TFP) for curative treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN) [Abstract 1523]. Proc Am Soc Clin Oncol 1999; 18: 137a.
    

64. Schrijvers D, Ban Herpen C, Kerger J, et al. Phase I-II study with docetaxel (D), cisplatin © and 5-fluorouracil (5-FU) in patients (PTS) with locally advanced inoperable squamous cell carcinoma of the head and neck (SCCHN) [Abstract 1524]. Am Soc Clin Oncol 1999; 18: 137a.
    

65. Janinis J, Papadakou M, Panagos G, et al. A phase II study of combined chemotherapy with docetaxel, cisplatin and 5-fluorouracil (5-FU) in patients with advanced squamous cell carcinoma of the head and neck (SCCHN) [Abstract 1436]. Proc Am Soc Clin Oncol 1997; 16: 402a.
    

66. Colevas DA, Busse PM, Norris CM, et al. Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: a phase I/II trial. J Clin Oncol 1998; 16(4): 1331-9.
    

67. Norris CM, Posner MR, Tishler RB, et al. A phase I study of outpatient docetaxel (Taxotere), cisplatin, 5-FU, and leucovorin (OP-TPFL) as induction chemotherapy for patients with squamous cell carcinoma of the head and neck (SCCHN) [Abstract 1536]. Proc Am Soc Clin Oncol 1999; 18: 397a.
    

68. Airoldi M, Marchionatti S, Pedani C, et al. Docetaxel (TXT) + vinorelbine (VNB) in recurrent heavily pre-treated head and neck cancer (HNC) patients (pts) [Abstract 1554]. Proc Am Soc Clin Oncol 1999; 18: 402a.
    

69. Tishler RB, Posner MR, Colevas HI, et al. Phase I study of concurrent Taxotere/Radiation (TRT) after induction chemotherapy in patients with squamous cell cancer of the head and neck [Abstract 1457]. Proc Am Soc Clin Oncol 1999; 18: 400a.
    

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