DOCETAXEL IMGSA

Docetaxel is an antineoplastic agent belonging to the taxoid family.

It is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants.

The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine,N.

• tert -butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate.

Docetaxel (anhydrous) has the following structural formula: Docetaxel is a white to almost-white powder with an empirical formula of C 43 H 53 NO 14, and a molecular weight of 807.88.

It is highly lipophilic and practically insoluble in water.

Injection, USP is a sterile, non-pyrogenic, clear, colorless to pale yellow solution at 10 mg/mL concentration.

Each mL contains 10 mg docetaxel (anhydrous), 260 mg polysorbate 80 NF, 4 mg anhydrous citric acid USP, 23% v/v dehydrated alcohol USP, and polyethylene glycol 300 NF.

Injection is available in single-dose vials containing 20 mg (2 mL) docetaxel (anhydrous) and multiple-dose vials containing 160 mg (16 mL) docetaxel (anhydrous).

Docetaxel Injection requires

NO prior dilution with a diluent and is ready to add to the infusion solution.

• Breast Cancer (BC): single agent for locally advanced or metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC.

• Non-small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC.

• Castration-Resistant Prostate Cancer (CRPC): with prednisone in metastatic castration-resistant prostate cancer.

• Gastric Adenocarcinoma (GC): with cisplatin and fluorouracil for untreated, advanced GC, including the gastroesophageal junction.

• Squamous Cell Carcinoma of the Head and Neck (SCCHN): with cisplatin and fluorouracil for induction treatment of locally advanced SCCHN 1.1 Breast Cancer Docetaxel Injection is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy.

Injection in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer. 1.2 Non-small Cell Lung Cancer Docetaxel Injection as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy.

Injection in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition. 1.3 Prostate Cancer Docetaxel Injection in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer. 1.4 Gastric Adenocarcinoma Docetaxel Injection in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease. 1.5 Head and Neck Cancer Docetaxel Injection in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

Lactation History of treatment with anthracycline

Combination with other cytotoxic agents Non-small cell bronchopulmonary cancer Stomach cancer Breast cancer Cancer ENT Female likely to be pregnant Pregnancy Hepatitis Male of childbearing age Hypersensitivity to paclitaxel Water inflation Mild to moderate hepatic impairment Severe renal impairment Neutropenia Presence of anti-HBc antibodies Radiotherapy Negative hepatitis B serology Elderly Subject at risk for tumour lysis syndrome Subject under 18.

Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions.

Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly.

This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells.

Docetaxel's binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use. 12.3 Pharmacokinetics Absorption The pharmacokinetics of docetaxel has been evaluated in cancer patients after administration of 20 mg/m to 115 mg/m in phase 1 studies.

The area under the curve (AUC) was dose proportional following doses of 70 mg/m to 115 mg/m with infusion times of to 2 hours.

Docetaxel’s pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with initial rapid distribution phase and the late (terminal) phase.

Mean steady state volume of distribution was 113 L. Docetaxel is approximately 94% protein bound in vitro, mainly to α1-acid glycoprotein, albumin, and lipoproteins.

In three cancer patients, the in vitro binding to plasma proteins was approximately 97%.

Dexamethasone does not affect the protein binding of docetaxel.

With extended plasma sampling up to to 22 days post infusion, the estimated mean total body clearance was 18 L/h/m 2 (range of means: 14 to 23) and mean terminal elimination half-life was 116 hours (range of means: 92 to 135).

Metabolism Docetaxel is metabolized by the

CYP3A4 isoenzyme in vitro.

In three cancer patients urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively, within 7 days.

About 80% of the radioactivity recovered in feces was excreted during the first 48 hours as 1 major and 3 minor metabolites with less than 8% as unchanged drug.

A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m 2.

Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies.

The pharmacokinetics of docetaxel was not influenced by age.

The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel.

The population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment (AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN), total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC).

This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients.

Patients with combined abnormalities of transaminase and alkaline phosphatase should not be treated with Docetaxel Injection.

Patients with severe hepatic impairment have not been studied.

Effect of Race Mean total body clearance for Japanese patients dosed at the range of 10 mg/m to 90 mg/m was similar to that of European/American populations dosed at 100 mg/m 2, suggesting no significant difference in the elimination of docetaxel in the two populations.

Drug Interaction Studies Effect of Ketoconazole

The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients.

Patients were randomized to receive either docetaxel (100 mg/m 2 intravenous) alone or docetaxel (10 mg/m 2 intravenous) in combination with ketoconazole (200 mg orally once daily for 3 days) in a crossover design with a 3-week washout period.

The results of this study indicated that the mean dose-normalized AUC of docetaxel was increased 2.2-fold and its clearance was reduced by 49% when docetaxel was coadministered with ketoconazole.

• Dexamethasone: Docetaxel total body clearance was not modified by pretreatment with dexamethasone.

• Cisplatin: Clearance of docetaxel in combination therapy with cisplatin was similar to that previously observed following monotherapy with docetaxel.

The pharmacokinetic profile of cisplatin in combination therapy with docetaxel was similar to that observed with cisplatin alone.

• Cisplatin and Fluorouracil: The combined administration of docetaxel, cisplatin and fluorouracil in 12 patients with solid tumors had no influence on the pharmacokinetics of each individual drug.

• Prednisone: A population pharmacokinetic analysis of plasma data from 40 patients with metastatic castration-resistant prostate cancer indicated that docetaxel systemic clearance in combination with prednisone is similar to that observed following administration of docetaxel alone.

• Cyclophosphamide and Doxorubicin: A study was conducted in 30 patients with advanced breast cancer to determine the potential for drug-drug interactions between docetaxel (75 mg/m 2 ), doxorubicin (50 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ) when administered in combination.

The coadministration of docetaxel had no effect on the pharmacokinetics of doxorubicin and cyclophosphamide when the three drugs were given in combination compared to coadministration of doxorubicin and cyclophosphamide only.

In addition, doxorubicin and cyclophosphamide had no effect on docetaxel plasma clearance when the three drugs were given in combination compared to historical data for docetaxel monotherapy.

Mechanism of action

Docetaxel is an antineoplastic agent that acts by promoting the assembly of tubulin into stable microtubules and inhibiting their depolymerization leading to a marked decrease in free tubulin.

Docetaxel's binding to microtubules does not alter the number of protofilaments.

In vitro, docetaxel disorganizes the intracellular network of microtubules, which is essential to the vital functions of mitosis and interphase.

Docetaxel was cytotoxic in vitro on several murine and human tumour cell lines as well as on newly excreted human tumour cells during clonogenic tests that were performed.

Docetaxel penetrates cells at high concentrations and persists for a prolonged period of time.

Docetaxel was also active on many but not on all cell lines, overstating glycoprotein-p coded by the multiresistance gene.

In vivo, the proximal and the proximal processes of the proximal process were shown to be independent.

• Hypocalcaemia (Common)
• Neutropenia (Very common)
• Alkaline phosphates (increase) (Common)
• ALT (increase) (Common)
• Hypophosphataemia (Common)
• Hypokalaemia (Common)
• ASAT (increase) (Common)
• Bilirubinaemia (increase) (Common)
• Hypomagnesaemia Hyponatremia Cancer pain (Common)
• Tumor lysis syndrome Radiation pneumonia Non-Hodgkin's malignant lymphoma Radic reactivation
• Secondary cancer Skin reaction (Very common)
• Dry skin (Common)
• Skin toxicity (Very common)
• Mucite (Very common)
• Pruritus (Common)
• Dermatitis (Common)
• Erythematous rash (Common)
• Skin desquamation (Common)
• Nail discolouration (Common)
• Palmoplantary Erythrodysaesthesia (Very common)
• Onychopathy (Very common)
• Onycholysis (Common)
• Skin Erythema (Very common)
• Alopecia (Very common)
• Pruriginous rash (Very common)
• Melanonymychie Toxic epidermal necrolysis Stevens-Johnson Syndrome
• Rash Lyell's syndrome Scleroderma Generalised acute exanthemous pusulosis Onychalgia
• Bully dermatosis Generalised Erythema Ungated colour alteration Polymorphic Erythema
• Pain (Very common)
• Irflu pseudo-influenza syndrome (Very common)
• Edema (Very common)
• Pain in the extremities (Very common)
• Weakness (Very common)
• Chest pain (Very common)
• Frisher (Very common)
• Non-heart pain (Common)
• Asthenia (Very common)
• Fever (Very common)
• Fatigue (Very common)
• Peripheral edema (Very common)
• Multi-viscer defect Deaths Amenorrhea (Very common)
• Haemorrhage (Common)
• Thrombocytopenia (Very common)
• Haematotoxicity (Very common)
• Myelodysplastic syndrome (Uncommon)
• Haematological injury (Very common)
• Febrile neutropenia (Very common)
• Anemia (Very common)
• Acute myeloblast leukaemia (Uncommon)
• Dispersed intravascular coagulation
• Cardiac aplasia Acute leukaemia Hepatitis (Very rare)
• Hypersensitivity (Very common)
• Anaphylactic shock Skin erythematous lupus Oral candidiasis (Common)
• Neutropenic sepsis (Very common)
• Infection (Very common)
• Neutropenic infection (Very common)
• Sepsis Septicaemia Injection site reaction (Common)
• Phlebitis at the injection site Skin colour at injection site (change)
• Erythema at the injection site
• Dryness at the injection site Extravasation at the injection site Inflammation at the injection site
• Resurgent reaction at the injection site Anorexia (Very common)
• Water inflation (Very common)
• Diabetes (Common)
• Appetite decreased (Very common)
• Weight (increase) (Very common)
• Weight (decrease) (Very common)
• Dysphagia (Very common)
• Hydroelectrolytic disorder
• Dehydration Conjunctivitis (Very common)
• Blurty vision (Common)
• Lacrimal hypersecretion (Very common)
• Vision disorder (Very rare)
• Flashlight Dacryostenosis Scintillating Scotoma Scotome
• Cystoid macular edema Dysgueusia (Very common)
• Hearing disorder (Very common)
• Pharyngitis (Very common)
• Pharyngo-laryngyngeal pain (Very common)
• Odynophagia (Very common)
• Epistaxis (Very common)
• Stomatitis (Very common)
• Rhinophyryngitis (Very common)
• Vertigo (Common)
• Oral dryness (Common)
• Parosmia (Very common)
• Rhinorrhea (Very common)
• Ototoxicity (Rare)
• Deafness (Rare)
• Insomnia (Very common)
• Lethargy (Very common)
• Lymphedema (Very common)
• Hypertension (Common)
• Syncope (Uncommon)
• Heart failure (Common)
• Vein disorder (Common)
• Hypotension (Common)
• Left ventricular ejection fraction decreased (Common)
• Arrhythmia (Common)
• Vasodilatation (Very common)
• Phlebitis (Common)
• Myocardial Ischemia (Common)
• Myocardial infarction (Rare)
• Ventricular arrhythmia
• Venous thromboembolic accident Ventricular tachycardia Pericardial efanchement Cardiovascular disease
• Congestive heart failure Esophagitis (Very common)
• Gastrointestinal haemorrhage (Common)
• Nausea (Very common)
• Diarrhoea (Very common)
• Abdominal pain (Very common)
• Vomiting (Very common)
• Constipation (Common)
• Epigastric pain (Common)
• Flatulence (Very common)
• Dyspepsia (Very common)
• Intestinal occlusion (Rare)
• Enterocolitis (Rare)
• Ileus (Rare)
• Collision Ischemic colitis
• Neutropenic colitis Ascite Intestinal perforation Digestive disorder Bone pain (Very common)
• Joint pain (Very common)
• Sleeping (Very common)
• Muscle pain (Very common)
• Myositis
• Hypoesthesia (Very common)
• Somnolence (Uncommon)
• Neurotoxicity (Uncommon)
• Dysesthesia (Very common)
• Peripheral sensory neuropathy (Very common)
• Headache (Very common)
• Peripheral motor neuropathy (Very common)
• Paraesthesia (Very common)
• Peripheral neuropathy (Common)
• Convulsions Loss of consciousness
• Upper respiratory tract infection (Very common)
• Cough (Very common)
• Pulmonary dysfunction (Rare)
• Acute respiratory distress syndrome (Rare)
• Pneumonia (Rare)
• Interstitial pneumopathy (Rare)
• Respiratory impairment (Rare)
• Pleural effusion Bronchospasm Bronchoconstriction Pulmonary edema
• Dyspnoea Renal impairment.

There is no known antidote for Docetaxel Injection overdosage.

In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored.

Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis.

Patients should receive therapeutic

G-CSF as soon as possible after discovery of overdose.

Other appropriate symptomatic measures should be taken, as needed.

In two reports of overdose, one patient received 150 mg/m and the other received 200 mg/m as 1-hour infusions.

Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident.

In mice, lethality was observed following single intravenous doses that were ≥154 mg/kg (about 4.5 times the human dose of 100 mg/m on a mg/m 2 basis); neurotoxicity associated with paralysis, non-extension of hind limbs, and myelin degeneration was observed in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m 2 basis).

In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m on a mg/m 2 basis) and was associated with abnormal mitosis and necrosis of multiple organs.

• neutrophil counts of <1500 cells/mm 3.

• a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80.

Severe reactions, including anaphylaxis, have occurred.

• Hypersensitivity to docetaxel or polysorbate 80.

• Neutrophil counts of <1500 cells/mm 3.

For all indications, toxicities may warrant dosage adjustments.

Administer in a facility equipped to manage possible complications (e.g., anaphylaxis).

Administer intravenously (IV) over 1 hour every 3 weeks.

PVC equipment is not recommended.

Use only a 21 gauge needle to withdraw Docetaxel Injection from the vial.

• BC locally advanced or metastatic: 60 mg/m to 100 mg/m 2 single agent.

• BC adjuvant: 75 mg/m 2 administered 1 hour after doxorubicin 50 mg/m and cyclophosphamide 500 mg/m 2 every 3 weeks for 6 cycles.

• NSCLC: after platinum therapy failure: 75 mg/m 2 single agent.

• NSCLC: chemotherapy-naïve: 75 mg/m 2 followed by cisplatin 75 mg/m 2.

• CRPC: 75 mg/m with 5 mg prednisone twice a day continuously.

• GC: 75 mg/m 2 followed by cisplatin 75 mg/m 2 (both on day 1 only) followed by fluorouracil 750 mg/m 2 per day as a 24-hour IV (days 1–5), starting at end of cisplatin infusion.

• SCCHN: 75 mg/m 2 followed by cisplatin 75 mg/m 2 IV (day 1), followed by fluorouracil 750 mg/m 2 per day as a 24-hour IV (days 1–5), starting at end of cisplatin infusion; for 4 cycles.

• SCCHN: 75 mg/m 2 followed by cisplatin 100 mg/m 2 IV (day 1), followed by fluorouracil 1000 mg/m 2 per day as a 24-hour IV (days 1–4); for 3 cycles For all patients:

• Premedicate with oral corticosteroids.

• Adjust dose as needed 2.1 Breast Cancer.

• For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of Docetaxel Injection is 60 mg/m to 100 mg/m 2 administered intravenously over 1 hour every 3 weeks.

• For the adjuvant treatment of operable node-positive breast cancer, the recommended Docetaxel Injection dose is 75 mg/m 2 administered 1 hour after doxorubicin 50 mg/m and cyclophosphamide 500 mg/m 2 every 3 weeks for 6 courses.

G-CSF may be used to mitigate the risk of hematological toxicities. 2.2 Non-small Cell Lung Cancer.

• For treatment after failure of prior platinum-based chemotherapy, docetaxel was evaluated as monotherapy, and the recommended dose is 75 mg/m 2 administered intravenously over 1 hour every 3 weeks.

A dose of 100 mg/m in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized controlled trials.

• For chemotherapy-naïve patients, docetaxel was evaluated in combination with cisplatin.

The recommended dose of Docetaxel

Injection is 75 mg/m 2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m 2 over 30–60 minutes every 3 weeks. 2.3 Prostate Cancer.

• For metastatic castration-resistant prostate cancer, the recommended dose of Docetaxel Injection is 75 mg/m 2 every 3 weeks as a 1 hour intravenous infusion.

Prednisone 5 mg orally twice daily is administered continuously. 2.4 Gastric Adenocarcinoma.

• For gastric adenocarcinoma, the recommended dose of Docetaxel Injection is 75 mg/m as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m 2, as a to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m 2 per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion.

Treatment is repeated every three weeks.

Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration. 2.5 Head and Neck Cancer Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration).

Prophylaxis for neutropenic infections should be administered.

All patients treated on the Docetaxel Injection containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.

Induction Chemotherapy Followed by

Radiotherapy (TAX323) For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m as a 1 hour intravenous infusion followed by cisplatin 75 mg/m 2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m 2 per day for five days.

This regimen is administered every 3 weeks for 4 cycles.

Following chemotherapy, patients should receive radiotherapy.

Chemoradiotherapy (TAX324) For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m 2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m 2 /day as a continuous infusion from day to day 4.

This regimen is administered every 3 weeks for 3 cycles.

Following chemotherapy, patients should receive chemoradiotherapy. 2.6 Premedication Regimen All patients should be premedicated with oral corticosteroids such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to Docetaxel Injection administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions.

For metastatic castration-resistant prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg at 12 hours, 3 hours, and 1 hour before the Docetaxel Injection infusion. 2.7 Dosage Adjustments during Treatment Breast Cancer Patients who are dosed initially at 100 mg/m and who experience either febrile neutropenia, neutrophils <500 cells/mm for more than 1 week, or severe or cumulative cutaneous reactions during Docetaxel Injection therapy should have the dosage adjusted from 100 mg/m to 75 mg/m 2.

If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m to 55 mg/m 2 or the treatment should be discontinued.

Conversely, patients who are dosed initially at 60 mg/m and who do not experience febrile neutropenia, neutrophils <500 cells/mm for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during Docetaxel Injection therapy may tolerate higher doses.

Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection treatment discontinued entirely.

Combination Therapy with Docetaxel Injection in the Adjuvant Treatment of Breast Cancer Docetaxel Injection in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1500 cells/mm 3.

Patients who experience febrile neutropenia should receive G-CSF in all subsequent cycles.

Patients who continue to experience this reaction should remain on G-CSF and have their Docetaxel Injection dose reduced to 60 mg/m 2.

Patients who experience grade 3 or 4 stomatitis should have their Docetaxel Injection dose decreased to 60 mg/m 2.

Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection therapy should have their dosage of Docetaxel Injection reduced from 75 mg/m to 60 mg/m 2.

If the patient continues to experience these reactions at 60 mg/m 2, treatment should be discontinued.

Non-small Cell Lung Cancer Monotherapy with Docetaxel Injection for NSCLC Treatment after Failure of Prior Platinum-Based Chemotherapy Patients who are dosed initially at 75 mg/m and who experience either febrile neutropenia, neutrophils <500 cells/mm for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during Docetaxel Injection treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m 2.

Combination Therapy with Docetaxel Injection for

Chemotherapy-Naïve NSCLC For patients who are dosed initially at Docetaxel Injection 75 mg/m in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm 3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the Docetaxel Injection dosage in subsequent cycles should be reduced to 65 mg/m 2.

In patients who require a further dose reduction, a dose of 50 mg/m is recommended.

For cisplatin dosage adjustments, see manufacturers' prescribing information.

Prostate Cancer Combination Therapy with Docetaxel Injection for Metastatic Castration-Resistant Prostate Cancer Docetaxel Injection should be administered when the neutrophil count is ≥1500 cells/mm 3.

Patients who experience either febrile neutropenia, neutrophils <500 cells/mm for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection therapy should have the dosage of Docetaxel Injection reduced from 75 mg/m to 60 mg/m 2.

If the patient continues to experience these reactions at 60 mg/m 2, the treatment should be discontinued.

Gastric or Head and Neck Cancer Docetaxel Injection in Combination with Cisplatin and Fluorouracil in Gastric Cancer or Head and Neck Cancer Patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines.

In both studies, G-CSF was recommended during the second and/or subsequent cycles in case of febrile neutropenia, or documented infection with neutropenia, or neutropenia lasting more than 7 days.

If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the Docetaxel Injection dose should be reduced from 75 mg/m to 60 mg/m 2.

If subsequent episodes of complicated neutropenia occur the Docetaxel Injection dose should be reduced from 60 mg/m to 45 mg/m 2.

In case of grade 4 thrombocytopenia the Docetaxel Injection dose should be reduced from 75 mg/m to 60 mg/m 2.

Do not retreat patients with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1500 cells/mm 3.

Avoid retreating patients until platelets recover to a level >100,000 cells/mm 3.

Discontinue treatment if these toxicities persist.

Recommended dose modifications for toxicities in patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil are shown in Table 1.

Table 1: Recommended Dose Modifications for Toxicities in Patients Treated with Docetaxel Injection in Combination with Cisplatin and Fluorouracil Toxicity Dosage Adjustment Diarrhea grade 3 First episode: reduce fluorouracil dose by 20%.

Second episode: then reduce Docetaxel Injection dose by 20%.

Diarrhea grade 4 First episode: reduce Docetaxel Injection and fluorouracil doses by 20%.

Second episode: discontinue treatment.

Stomatitis/mucositis grade 3 First episode: reduce fluorouracil dose by 20%.

Second episode: stop fluorouracil only, at all subsequent cycles.

Third episode: reduce Docetaxel Injection dose by 20%.

Stomatitis/mucositis grade 4 First episode: stop fluorouracil only, at all subsequent cycles.

Second episode: reduce Docetaxel Injection dose by 20%.

Liver dysfunction.

Injection, USP is supplied in single-dose or multiple-dose vials as a sterile, pyrogen-free, non-aqueous colorless to pale yellow solution.

Discard unused portion of the single-dose vial.

The following strengths are available in a one-vial formulation: Unit of Sale Concentration NDC 0409-2026-01 Carton of 1 single-dose vial 20 mg/2 mL (10 mg/mL) NDC 0409-0016-01 Carton of 1 multiple-dose vial 160 mg/16 mL (10 mg/mL) 16.2 Storage Store at 20°C to 25°C (68°F to 77°F). .

Retain in the original package to protect from light.

Freezing does not adversely affect the product.

After first use and following multiple needle entries and product withdrawals, Docetaxel Injection multiple-dose vials are stable for up to 28 days when stored between 2°C and 8°C (36°F and 46°F) and protected from light. 16.3 Handling and Disposal Docetaxel Injection is a hazardous drug.

Follow applicable special handling and disposal procedures.

Store at 20°C to 25°C (68°F to 77°F). .

Retain in the original package to protect from light.

Freezing does not adversely affect the product.

After first use and following multiple needle entries and product withdrawals, Docetaxel Injection multiple-dose vials are stable for up to 28 days when stored between 2°C and 8°C (36°F and 46°F) and protected from light.

Based on findings in animal reproduction studies and its mechanism of action, Docetaxel Injection can cause fetal harm when administered to a pregnant woman.

Available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Injection contains alcohol which can interfere with neurobehavioral development.

In animal reproductive studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused an increased incidence of embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Injection contains alcohol.

Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development.

Data Animal data

Intravenous administration of ≥0.3 and 0.03 mg/kg/day docetaxel to pregnant rats and rabbits, respectively, during the period of organogenesis caused an increased incidence of intrauterine mortality, resorptions, reduced fetal weights, and fetal ossification delays.

Maternal toxicity was also observed at these doses, which were approximately 0.02 and 0.003 times the daily maximum recommended human dose based on body surface area, respectively.

The alcohol content of Docetaxel

Injection should be taken into account when given to pediatric patients.

The efficacy of docetaxel in pediatric patients as monotherapy or in combination has not been established.

The overall safety profile of docetaxel in pediatric patients receiving monotherapy or TCF was consistent with the known safety profile in adults.

Docetaxel has been studied in a total of 289 pediatric patients: 239 in 2 trials with monotherapy and in combination treatment with cisplatin and 5-fluorouracil (TCF).

Docetaxel monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12.5 years, range 1–22 years) with a variety of refractory solid tumors.

The recommended dose was 125 mg/m as a 1-hour intravenous infusion every 21 days.

The primary dose limiting toxicity was neutropenia.

The recommended dose for docetaxel monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1–26 years) with a variety of recurrent/refractory solid tumors.

Efficacy was not established with tumor response rates ranging from one complete response (CR) (0.6%) in a patient with undifferentiated sarcoma to four partial responses (2.2%) seen in one patient each with Ewing Sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma.

Docetaxel was studied in combination with cisplatin and 5-fluorouracil (TCF) versus cisplatin and 5-fluorouracil (CF) for the induction treatment of nasopharyngeal carcinoma (NPC) in pediatric patients prior to chemoradiation consolidation.

Seventy-five patients (median age 16 years, range to 21 years) were randomized (2:1) to docetaxel (75 mg/m 2 ) in combination with cisplatin (75 mg/m 2 ) and 5-fluorouracil (750 mg/m 2 ) (TCF) or to cisplatin (80 mg/m 2 ) and 5-fluorouracil (1000 mg/m 2 /day) (CF).

The primary endpoint was the CR rate following induction treatment of NPC.

One patient out of in the

TCF group (2%) had a complete response while none of the 25 patients in the CF group had a complete response.

Pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials.

Following docetaxel administration at 55 mg/m to 235 mg/m in a 1-hour intravenous infusion every 3 weeks in 25 patients aged to 20 years (median 11 years), docetaxel clearance was 17.3±10.9 L/h/m 2.

Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF), at dose levels of 75 mg/m in a 1-hour intravenous infusion day in 28 patients aged to 21 years (median 16 years, 17 patients were older than 16).

Docetaxel clearance was 17.9±8.75 L/h/m 2, corresponding to an AUC of 4.20±2.57 μg∙h/mL.

In summary, the body surface area adjusted clearance of docetaxel monotherapy and TCF combination in children were comparable to those in adults.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients.

In a study conducted in chemotherapy-naïve patients with NSCLC (TAX326), 148 patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater.

There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater.

In the docetaxel+cisplatin group, patients less than 65 years of age had a median survival of 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% CI: 9.3 months, 14 months).

In patients 65 years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%).

Patients treated with docetaxel+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively).

When docetaxel was combined with carboplatin for the treatment of chemotherapy-naïve, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with docetaxel+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin.

Of the 333 patients treated with docetaxel every three weeks plus prednisone in the prostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years.

In patients treated with docetaxel every three weeks, the following treatment-emergent adverse reactions occurred at rates ≥10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs. 59%), infection (37% vs. 24%), nail changes (34% vs. 23%), anorexia (21% vs. 10%), weight loss (15% vs. 5%), respectively.

In the adjuvant breast cancer trial (TAX316), docetaxel in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater.

The number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients.

Among the 221 patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years.

In this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients.

However, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients.

The incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients.

Elderly patients treated with

TCF should be closely monitored.

Among the and 251 patients who received the induction treatment with Docetaxel Injection in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively.

These clinical studies of Docetaxel

Injection in combination with cisplatin and fluorouracil in patients with SCCHN did not include sufficient numbers of patients aged and over to determine whether they respond differently from younger patients.

Other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients.