DOCETAX Infusion (Docetaxel)

Table of Content

Black Box Warning: Toxic Deaths, Hepatotoxicity, Neutropenia, Hypersensitivity Reactions, And Fluid Retention

The incidence of treatment-related mortality associated with Docetaxel therapy is increased in patients with abnormal liver function, in patients receiving higher doses, and in patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who receive Docetaxel as a single agent at a dose of 100 mg/m2.

Docetaxel should not be given to patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated elevations of transaminase >1.5 × ULN also had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic death. Bilirubin, AST or ALT, and alkaline phosphatase values should be obtained prior to each cycle of Docetaxel therapy.

Docetaxel therapy should not be given to patients with neutrophil counts of <1500 cells/mm3. In order to monitor the occurrence of neutropenia, which may be severe and result in infection, frequent blood cell counts should be performed on all patients receiving Docetaxel.

Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who received a 3-day dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the Docetaxel infusion and administration of appropriate therapy. Docetaxel must not be given to patients who have a history of severe hypersensitivity reactions to Docetaxel or to other drugs formulated with polysorbate 80.

Severe fluid retention occurred in 6.5% of patients despite use of a 3-day dexamethasone premedication regimen. It was characterized by one or more of the following events: poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnoea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites).

Composition

DOCETAX-20 Infusion

Each single dose vial contains:
Docetaxel ... 20 mg
Polysorbate 80 IP.........0.5 ml

Each solvent vial contains
Alcohol IP (95% v/v) ........ 13%w/v
(Absolute Alcohol content 15.25%v/v)
Water for injection IP q.s. ..... 1.5 ml

DOCETAX-80 Infusion

Each single dose vial contains:
Docetaxel …. 80 mg
Polysorbate 80 IP.........2.0 ml

Each solvent vial contains
Alcohol IP (95% v/v)........ 13%w/v
(Absolute Alcohol content 15.25%v/v)
Water for injection IP q.s. ..... 6.0 ml

DOCETAX-120 Infusion

Each single dose vial contains:
Docetaxel ….... 120 mg
Polysorbate 80 IP.........3.0 ml

Each solvent vial contains
Alcohol IP (95%v/v)........ 13%w/v
(Absolute Alcohol content 15.25%v/v)
Water for injection IP q.s. ..... 9.0 ml

Dosage Form

I.V. Infusion

Pharmacology

Pharmacodynamics

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.

Pharmacokinetics

Absorption
The pharmacokinetics of Docetaxel has been evaluated in cancer patients after administration of 20 mg/m2 to 115 mg/m2 in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m2 to 115 mg/m2 with infusion times of 1 to 2 hours. Docetaxel's pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with half-lives for the α, β, and γ phases of 4 min, 36 min, and 11.1 hr, respectively. Mean total body clearance was 21 L/h/m2 .

Distribution
The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of Docetaxel from the peripheral compartment. Mean steady state volume of distribution was 113 L. In vitro studies showed that Docetaxel is about 94% protein bound, mainly to ?1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the In vitro binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding of Docetaxel.

Metabolism
In vitro drug interaction studies revealed that Docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4.

Elimination
A study of 14C-Docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as 1 major and 3 minor metabolites with very small amounts (less than 8%) of unchanged drug.

Effect of Age
A population pharmacokinetic analysis was carried out after Docetaxel treatment of 535 patients dosed at 100 mg/m2 . 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.

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

Hepatic Impairment
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. 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/m2 to 90 mg/m2 was similar to that of European/American populations dosed at 100 mg/m2 , suggesting no significant difference in the elimination of Docetaxel in the two populations.

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/m2 intravenous) alone or Docetaxel (10 mg/m2 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 co-administration with ketoconazole.

Effect of Combination Therapies
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 hormone-refractory metastatic 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/m2 ), doxorubicin (50 mg/m2 ), and cyclophosphamide (500 mg/m2 ) when administered in combination. The co administration of Docetaxel had no effect on the pharmacokinetics of doxorubicin and cyclophosphamide when the three drugs were given in combination compared to co administration 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.

Indications

DOCETAX Infusion is indicated for the treatment of patients with locally advanced metastatic breast cancer and non small cell lung cancer

Dosage and Administration

Breast Cancer

  • For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of DOCETAX Infusion is 60 mg/m2 to 100 mg/m2 administered intravenously over 1 hour every 3 weeks.
  • For the adjuvant treatment of operable node-positive breast cancer, the recommended DOCETAX Infusion dose is 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 courses. Prophylactic G-CSF may be used to mitigate the risk of haematological toxicities.

Non-Small Cell Lung Cancer

  • For treatment after failure of prior platinum-based chemotherapy, DOCETAX Infusion was evaluated as monotherapy, and the recommended dose is 75 mg/m2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m2 in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized, controlled trials.
  • For chemotherapy-naive patients, DOCETAX Infusion was evaluated in combination with cisplatin. The recommended dose of DOCETAX Infusion is 75 mg/m2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m2 over 30-60 minutes every 3 weeks.

Premedication Regimen

All patients should be premedicated with oral corticosteroids such as dexamethasone 16 mg per day (e.g., 8 mg BID) for 3 days starting 1 day prior to DOCETAX administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions.

Dosage Adjustments During Treatment

Breast Cancer
Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, or severe or cumulative cutaneous reactions during DOCETAX therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2 . If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during DOCETAX therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have DOCETAX treatment discontinued entirely

Combination Therapy with DOCETAX in the Adjuvant Treatment of Breast Cancer
DOCETAX Infusion in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm3. 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 DOCETAX Infusion dose reduced to 60 mg/m2. Patients who experience grade 3 or 4 stomatitis should have their DOCETAX Infusion dose decreased to 60 mg/m2. Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during DOCETAX Infusion therapy should have their dosage of DOCETAX Infusion reduced from 75 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, treatment should be discontinued.

Non-Small Cell Lung Cancer
Monotherapy with DOCETAX Infusion for NSCLC treatment after failure of prior platinum-based chemotherapy 

Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during DOCETAX Infusion treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2 . Patients who develop ≥grade 3 peripheral neuropathy should have DOCETAX Infusion treatment discontinued entirely.

Combination therapy with DOCETAX  Infusion for chemotherapy-naive NSCLC 
For patients who are dosed initially at DOCETAX Infusion 75 mg/m2in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the DOCETAX Infusion dosage in subsequent cycles should be reduced to 65 mg/m2. In patients who require a further dose reduction, a dose of 50 mg/m2is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information

Administration Precautions

Solvent for Docetaxel Injection Concentrate is clear colourless solution. It is supplied as an aqueous solution for preparing a premix solution of Docetaxel Injection Concentrate and this premix solution is intended for further dilution with either 0.9% Sodium Chloride Injection IP or 5% Dextrose Injection IP.

DOCETAX Infusion is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing DOCETAX solutions. The use of gloves is recommended.

If DOCETAX Infusion Injection Concentrate, initial diluted solution, or final dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If DOCETAX Infusion Injection Concentrate, initial diluted solution, or final dilution for infusion should come into contact with mucosa, immediately and thoroughly wash with water.

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

DO NOT use the two-vial formulation (Injection Concentrate and diluent) with the one-vial formulation. Use 1.5 ml solvent vial for DOCETAX-20, 6 ml solvent vial for DOCETAX-80 and 9 ml solvent vial for DOCETAX-120.

Two-vial formulation (Injection Concentrate and Diluent)
DOCETAX Injection Concentrate requires two dilutions prior to administration. Please follow the preparation instructions provided below. Note: Both the DOCETAX Injection Concentrate and the diluent vials contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with the entire contents of the accompanying diluent, there is an initial diluted solution containing 10 mg/mL Docetaxel.

The table below provides the fill range of the Diluent, the approximate extractable volume of Diluent when the entire contents of the diluent vial are withdrawn, and the concentration of the initial diluted solution for DOCETAX 20 mg, DOCETAX 80 mg and DOCETAX 120.

Table Initial Dilution of DOCETAX Injection Concentrate
Product
Diluent 13% (w/w) ethanol in water for injection Fill Range(mL)
Approximate extractable volume of Diluent when entire contents are withdrawn(mL)
Concentration of the initial diluted solution(mg/mL Docetaxel)
DOCETAX 20 mg/0.5 mL 1.88 – 2.08 mL   1.8 ml 10 mg/mL
DOCETAX 80 mg/2 mL 6.96 - 7.70 mL 7.1 mL 10 mg/mL
DOCETAX 120 mg/3 mL 9.9 - 10.3 mL 9.5 mL 10 mg/mL

Preparation and Administration

Two-vial formulation (Injection Concentrate and Diluent)

A. Initial Diluted Solution

The initial diluted solution may be used immediately or stored either in the refrigerator or at room temperature for a maximum of 8 hours.

  1. DOCETAX Infusion vials should be stored between 2°C and 25°C (36°F and 77°F). If the vials are stored under refrigeration, allow the appropriate number of vials of DOCETAX Infusion Injection Concentrate and diluent (13% ethanol in water for injection) vials to stand at room temperature for approximately 5 minutes.
  2. Aseptically withdraw the entire contents of the appropriate diluent vial (approximately 1.8 mL for DOCETAX Infusion 20 mg and approximately 7.1 mL for DOCETAX Infusion 80 mg) into a syringe by partially inverting the vial, and transfer it to the appropriate vial of DOCETAX Infusion Injection Concentrate. If the procedure is followed as described, an initial diluted solution of 10 mg DOCETAX Infusion/mL will result.
  3. Mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full mixture of the concentrate and diluent. Do not shake. Rotate the vial gently and allow the initial diluted solution to stand for 5 min.
  4. The initial diluted DOCETAX Infusion solution (10 mg Docetaxel/mL) should be clear; however, there may be some foam on top of the solution due to the polysorbate 80. Allow the solution to stand for a few minutes to allow any foam to dissipate. It is not required that all foam dissipate prior to continuing the preparation process.

B. Final Dilution for Infusion

  1. Aseptically withdraw the required amount of initial diluted DOCETAX Infusion solution (10 mg Docetaxel/mL) with a calibrated syringe and inject into a 250 mL infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 to 0.74 mg/mL. If a dose greater than 200 mg of DOCETAX Infusion is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL DOCETAX Infusion is not exceeded.
  2. Thoroughly mix the infusion by manual rotation.
  3. As with all parenteral products, DOCETAX Infusion should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the DOCETAX Infusion initial diluted solution or final dilution for intravenous infusion is not clear or appears to have precipitation, these should be discarded.

The final DOCETAX Infusion dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature and lighting conditions.

Contraindications

  • Docetaxel Infusion is contraindicated in patients who have a history of severe hypersensitivity reactions to Docetaxel Infusion or to other drugs formulated with polysorbate 80. Severe reactions, including anaphylaxis, have occurred
  • Docetaxel Infusion should not be used in patients with neutrophil counts of <1500 cells/mm3

Warnings and Precautions

General

For breast and non-small cell lung cancers, premedication consisting of an oral corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to DOCETAX Infusion administration, unless contraindicated, can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions. For prostate cancer, the premedication is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the DOCETAX Infusion.

Drug Interactions

Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of Docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4.

In vivo studies showed that the exposure of Docetaxel increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of Docetaxel. Concomitant use of Docetaxel and drugs that inhibit CYP3A4 may increase exposure to Docetaxel and should be avoided. In patients receiving treatment with Docetaxel, close monitoring for toxicity and a Docetaxel dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided

Toxic Deaths

Breast Cancer
Docetaxel administered at 100 mg/m2 was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients dosed at 60 mg/m2 , mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function. Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths.

Non-Small Cell Lung Cancer
Docetaxel administered at a dose of 100 mg/m2 in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies). There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m2 dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m2 dose level, 3 of 5 patients had an ECOG PS of 2 at study entry.

Haematology

Perform frequent peripheral blood cell counts on all patients receiving Docetaxel. Patients should not be retreated with subsequent cycles of Docetaxel until neutrophils recover to a level >1500 cells/mm3 and platelets recover to a level > 100,000 cells/mm3.

A 25% reduction in the dose of Docetaxel is recommended during subsequent cycles following severe neutropenia (<500 cells/mm3) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a Docetaxel cycle

Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 mg/m2 to 100 mg/m2 of Docetaxel and grade 4 neutropenia (<500 cells/mm3) occurs in 85% of patients given 100 mg/m2 and 75% of patients given 60 mg/m2 . Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. Docetaxel should not be administered to patients with neutrophils <1500 cells/mm3.

Febrile neutropenia occurred in about 12% of patients given 100 mg/m2 but was very uncommon in patients given 60 mg/m2 . Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related.

Three breast cancer patients with severe liver impairment (bilirubin >1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia. In gastric cancer patients treated with Docetaxel in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not. Patients receiving TCF should be closely monitored during the first and subsequent cycles for febrile neutropenia and neutropenic infection in patients treated with Docetaxel in combination with cisplatin and 5-fluorouracil (TCF), febrile neutropenia and neutropenic infection occurred at lower rates when patients received prophylactic G-CSF. Patients treated with TCF should receive prophylactic G-CSF to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TCF should be closely monitored.

In patients treated with Docetaxel in combination with doxorubicin and cyclophosphamide (TAC), febrile neutropenia and/or neutropenic infection occurred at lower rates when patients received primary G-CSF prophylaxis. Primary G-CSF prophylaxis should be considered in patients who receive adjuvant therapy with TAC for breast cancer to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TAC should be closely monitored.

Hypersensitivity Reactions

Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the Docetaxel infusion and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with Docetaxel.

Hypersensitivity reactions may occur within a few minutes following initiation of a Docetaxel infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of Docetaxel.

Cutaneous Reactions 

Localised skin erythema of the extremities (palms of the hands and soles of the feet) with oedema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended. Severe symptoms such as eruptions followed by desquamation which lead to interruption or discontinuation of Docetaxel treatment were reported.

Fluid Retention

Patients should be premedicated with oral corticosteroids prior to each Docetaxel administration to reduce the incidence and severity of fluid retention. Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be monitored closely. When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg. Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).

Respiratory Disorders 

Acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung disease, pulmonary fibrosis and respiratory failure have been reported and may be associated with fatal outcome. Cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

If new or worsening pulmonary symptoms develop, patients should be closely monitored, promptly investigated, and appropriately treated. Interruption of Docetaxel therapy is recommended until diagnosis is available. Early use of supportive care measures may help improve the condition. The benefit of resuming Docetaxel treatment must be carefully evaluated.

Neurologic Reactions

Severe neurosensory symptoms (e.g. paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued. Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks). Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965).

Asthenia

Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease.

Cardiac Toxicity

Heart failure has been observed in patients receiving Docetaxel in combination with trastuzumab, particularly following anthracycline (doxorubicin or epirubicin)-containing chemotherapy. This may be moderate to severe and has been associated with death.

When patients are candidates for treatment with Docetaxel in combination with trastuzumab, they should undergo baseline cardiac assessment. Cardiac function should be further monitored during treatment (e.g. every three months) to help identify patients who may develop cardiac dysfunction. For more details see summary of product characteristics of trastuzumab.

Eye Disorders

Cystoid macular oedema (CMO) has been reported in patients treated with Docetaxel. Patients with impaired vision should undergo a prompt and complete ophthalmologic examination. In case CMO is diagnosed, Docetaxel treatment should be discontinued and appropriate treatment initiated.

Solvent

The solvent is not to be injected as such. It is only to be used as diluent for Docetaxel Injection Concentrate.

Women of childbearing potential /contraception:
Women of childbearing age receiving Docetaxel should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur.

An effective method of contraception should be used during treatment.

In non clinical studies, Docetaxel has genotoxic effects and may alter male fertility. Therefore, men being treated with Docetaxel are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment.

Patients with Renal Impairment

There are no data available in patients with severely impaired renal function treated with Docetaxel.

Patients with Hepatic Impairment

In patients treated with Docetaxel at 100 mg/m2 as single agent who have serum transaminase levels (ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels greater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as toxic deaths including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of Docetaxel in those patients with elevated liver function test (LFTs) is 75 mg/m2 and LFTs should be measured at baseline and before each cycle.

For patients with serum bilirubin levels > ULN and/or ALT and AST > 3.5 times the ULN concurrent with serum alkaline phosphatase levels > 6 times the ULN, no dose-reduction can be recommended and Docetaxel should not be used unless strictly indicated.

In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric adenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST > 1.5 × ULN associated with alkaline phosphatase > 2.5 × ULN, and bilirubin > 1 x ULN; for these patients, no dose-reductions can be recommended and Docetaxel should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by Docetaxel in combination in the other indications.

Pregnancy 

Pregnancy Category D
Based on its mechanism of action and findings in animals, Docetaxel can cause foetal harm when administered to a pregnant woman. If Docetaxel is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the foetus.

Docetaxel can cause foetal harm when administered to a pregnant woman. Studies in both rats and rabbits at doses ≥0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on a mg/m2 basis), administered during the period of organogenesis, have shown that Docetaxel is embryotoxic and foetotoxic (characterized by intrauterine mortality, increased resorption, reduced foetal weight, and foetal ossification delay). The doses indicated above also caused maternal toxicity.

Lactation

Docetaxel is a lipophilic substance but it is not known whether it is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Docetaxel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Paediatric Population

The safety and efficacy of Docetaxel in nasopharyngeal carcinoma in children aged 1 month to less than 18 years have not yet been established.

There is no relevant use of Docetaxel in the paediatric population in the indications breast cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma and head and neck cancer, not including type II and III less differentiated nasopharyngeal carcinoma.

Geriatric Use

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.

There are limited data available in patients >70 years of age on Docetaxel use in combination with doxorubicin and cyclophosphamide.

In patients treated with Docetaxel every three weeks in a prostate cancer study, the incidence of related nail changes occurred at a rate ≥10% higher in patients who were 65 years of age or greater compared to younger patients. The incidence of related fever, diarrhoea, anorexia, and peripheral oedema occurred at rates ≥10% higher in patients who were 75 years of age or greater versus less than 65 years.

The incidence of serious adverse events in patients treated with Docetaxel in combination with cisplatin and 5-fluorouracil in the gastric cancer study was higher in the elderly patients compared to younger patients. The incidence of the following adverse events (all grades): lethargy, stomatitis, 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.

In combination with capecitabine, for patients 60 years of age or more, a starting dose reduction of capecitabine to 75% is recommended (see capecitabine summary of product characteristics).

Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. The ethanol content of this medicinal product may impair the ability to drive or use machines.

Additional Cautions for Use in Adjuvant Treatment of Breast Cancer

Complicated neutropenia
For patients who experience complicated neutropenia (prolonged neutropenia, febrile neutropenia or infection), G-CSF and dose reduction should be considered.

Gastrointestinal reactions
Symptoms such as early abdominal pain and tenderness, fever, diarrhoea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly.

Congestive heart failure (CHF)
Patients should be monitored for symptoms of congestive heart failure during therapy and during the follow up period. In patients treated with the TAC regimen for node positive breast cancer, the risk of CHF has been shown to be higher during the first year after treatment.

Leukaemia
Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. In the Docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed myelodysplasia or myeloid leukaemia requires haematological follow-up.

Patients with 4+ nodes
As the benefit observed in patient with 4+ nodes was not statistically significant on disease-free survival (DFS) and overall survival (OS), the positive benefit/risk ratio for TAC in patients with 4+ nodes was not fully demonstrated at the final analysis.

Undesirable Effects

The most serious adverse reactions from Docetaxel are:

  • Toxic Deaths
  • Hepatotoxicity
  • Neutropenia
  • Hypersensitivity
  • Fluid Retention

The most common adverse reactions across all Docetaxel indications are infections, neutropenia, anaemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhoea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the indication.

Responding patients may not experience an improvement in performance status on therapy and may experience worsening. The relationship between changes in performance status, response to therapy, and treatment-related side effects has not been established.

The adverse reactions considered to be possibly or probably related to the administration of Docetaxel have been obtained in:

  • 2 and 75 mg/m2 of Docetaxel as a single agent respectively
  • 258 patients who received Docetaxel in combination with doxorubicin
  • 406 patients who received Docetaxel in combination with cisplatin
  • 92 patients treated with Docetaxel in combination with trastuzumab,
  • 255 patients who received Docetaxel in combination with capecitabine,
  • 332 patients who received Docetaxel in combination with prednisone or prednisolone (clinically important treatment related adverse events are presented).
  • 744 patients who received Docetaxel in combination with doxorubicin and cyclophosphamide (clinically important treatment related adverse events are presented).
  • 300 gastric adenocarcinoma patients (221 patients in the phase III part of the study and 79 patients in the phase II part) who received Docetaxel in combination with cisplatin and 5-fluorouracil (clinically important treatment related adverse events are presented).
  • 174 and 251 head and neck cancer patients who received docetaxel in combination with cisplatin and 5-fluorouracil (clinically important treatment related adverse events are presented).

These reactions were described using the NCI Common Toxicity Criteria (grade 3 = G3; grade3-4 = G3/4; grade 4 = G4) and the COSTART terms. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). 

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The most commonly reported adverse reactions of Docetaxel alone are: Neutropenia (which was reversible and not cumulative; the median day to nadir was 7 days and the median duration of severe neutropenia (< 500 cells/mm3) was 7 days), anaemia, alopecia, nausea, vomiting, stomatitis, diarrhoea and asthenia. The severity of adverse events of Docetaxel may be increased when Docetaxel is given in combination with other chemotherapeutic agents.

For combination with trastuzumab, adverse events (all grades) reported in ≥ 10% are displayed. There was an increased incidence of SAEs (40% vs. 31%) and Grade 4 AEs (34% vs. 23%) in the trastuzumab combination arm compared to Docetaxel monotherapy.

For combination with capecitabine, the most frequent treatment-related undesirable effects (≥ 5%) reported in a phase III trial in breast cancer patients failing anthracycline treatment are presented (see capecitabine summary of product characteristics).

The following adverse reactions are frequently observed with Docetaxel:
Nervous system disorders
The development of severe peripheral neurotoxicity requires a reduction of dose. Mild to moderate neuro-sensory signs are characterised by paresthesia, dysesthesia or pain including burning. Neuro-motor events are mainly characterised by weakness.

Skin and subcutaneous tissue disorders
Reversible cutaneous reactions have been observed and were generally considered as mild to moderate. Reactions were characterised by a rash including localised eruptions mainly on the feet and hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequently associated with pruritus. Eruptions generally occurred within one week after the Docetaxel infusion. Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead to interruption or discontinuation of Docetaxel treatment were reported. Severe nail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis.

General disorders and administration site conditions
Infusion site reactions were generally mild and consisted of hyper pigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein. Fluid retention includes events such as peripheral oedema and less frequently pleural effusion, pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the lower extremities and may become generalised with a weight gain of 3 kg or more. Fluid retention is cumulative in incidence and severity.

Immune system disorders
Hypersensitivity reactions have generally occurred within a few minutes following the start of the infusion of Docetaxel and were usually mild to moderate. The most frequently reported symptoms were flushing, rash with or without pruritus, chest tightness, back pain, dyspnoea and drug fever or chills. Severe reactions were characterised by hypotension and/or bronchospasm or generalized rash/Erythema.

Docetaxel 100 mg/m2 single agent:
MedDRA System Organ classes Very common adverse reactions

≥1/10

Common adverse reactions

≥1/100, <1/10

Uncommon adverse reactions

≥1/1000, <1/100

Investigations G3/4 Blood bilirubin increased (<5%);

G3/4 Blood alkaline phosphatase increased (<4%);

G3/4 AST increased (<3%);

G3/4 ALT increased (<2%)

Cardiac disorders Arrhythmia (G3/4: 0.7%) Cardiac failure
Blood and the lymphatic system disorders Neutropenia (G4: 76.4%);

Anaemia (G3/4: 8.9%);

Febrile neutropenia

Thrombocytopenia (G4: 0.2%)
Nervous system disorders Peripheral sensory neuropathy (G3: 4.1%);

Peripheral motor neuropathy (G3/4: 4%)

Dysgeusia (severe 0.07%)

Respiratory, thoracic and mediastinal disorders Dyspnoea (severe 2.7%)
Gastrointestinal disorders Stomatitis (G3/4: 5.3%);

Diarrhoea (G3/4: 4%);

Nausea (G3/4: 4%);

Vomiting (G3/4: 3%)

Constipation (severe 0.2%);

Abdominal pain (severe 1%);

Gastrointestinal Haemorrhage (severe 0.3%)

Oesophagitis (severe: 0.4%)
Skin and subcutaneous tissue disorders Alopecia;

Skin reaction (G3/4: 5.9%);

Nail disorders (severe 2.6%)

Musculoskeletal and connective tissue disorders. Myalgia (severe 1.4%) Arthralgia
Metabolism and nutrition disorders Anorexia
Infections and infestations Infections (G3/4: 5.7%; including sepsis and pneumonia, fatal in 1.7%) Infection associated with G4 neutropenia (G3/4: 4.6%)
Vascular disorders Hypotension;

Hypertension;

Haemorrhage

General disorders and administration site conditions Fluid retention (severe: 6.5%)

Asthenia (severe 11.2%);

Pain

Infusion site reaction;

Non-cardiac chest pain (severe 0.4%)

Immune system disorders Hypersensitivity (G3/4: 5.3%)

Blood and Lymphatic system disorders
Rare: bleeding episodes associated with grade 3/4 thrombocytopenia

Nervous system disorders
Reversibility data are available among 35.3% of patients who developed neurotoxicity following Docetaxel treatment at 100 mg/m2 as single agent. The events were spontaneously reversible within 3 months.

Skin and subcutaneous tissue disorders
Very rare: one case of alopecia non-reversible at the end of the study. 73% of the cutaneous reactions were reversible within 21 days.

General disorders and administration site conditions
The median cumulative dose to treatment discontinuation was more than 1,000 mg/m2 and the median time to fluid retention reversibility was 16.4 weeks (range 0 to 42 weeks). The onset of moderate and severe retention is delayed (median cumulative dose: 818.9 mg/m2 ) in patients with premedication compared with patients without premedication (median cumulative dose: 489.7 mg/m2 ); however, it has been reported in some patients during the early courses of therapy.

Docetaxel 75 mg/m2 single agent:
MedDRA System Organ classes
Very common
adverse reactions

≥ 1/10

Common
adverse reactions

≥ 1/100, <1/10

Investigations G3/4 Blood bilirubin Increased (<2%)
Cardiac disorders Arrhythmia (no severe);
Blood and the lymphatic system disorders Neutropenia (G4: 54.2%);

Anaemia (G3/4: 10.8%);

Thrombocytopenia (G4:1.7%)

Febrile neutropenia
Nervous system disorders Peripheral sensory neuropathy (G3/4: 0.8%) Peripheral motor neuropathy (G3/4: 2.5%)
Gastrointestinal disorders Nausea (G3/4: 3.3%);

Stomatitis (G3/4: 1.7%);

Vomiting (G3/4: 0.8%);

Diarrhea (G3/4: 1.7%)

Constipation
Skin and subcutaneous tissue disorders Alopecia;

Skin reaction (G3/4: 0.8%)

Nail disorders (severe 0.8%)
Musculoskeletal and connective tissue disorders. Myalgia
Metabolism and nutrition disorders Anorexia
Infections and infestations Infections (G3/4: 5%)
Vascular disorders Hypotension
General disorders and administration site conditions Asthenia (severe 12.4%);

Fluid retention (severe 0.8%); Pain

Immune system disorders Hypersensitivity (no severe)
Docetaxel 75 mg/m2 in combination with doxorubicin
MedDRA System Organ classes Very common adverse reactions
≥ 1/10
Common adverse reactions
≥ 1/100, <1/10
Uncommon adverse reactions
≥ 1/1,000, <1/100
Investigations G3/4 Blood bilirubin increased (<2.5%);
G3/4 Blood alkaline phosphatase increased (<2.5%)
G3/4 AST increased (<1%);
G3/4 ALT increased (<1%)
Cardiac disorders Cardiac failure;
Arrhythmia (no severe)
Blood and the lymphatic system disorders Neutropenia (G4: 91.7%);
Anaemia (G3/4: 9.4%);
Febrile neutropenia;
Thrombocytopenia (G4: 0.8%)
Nervous system disorders Peripheral motor neuropathy (G3/4: 0.4%)
Gastrointestinal disorders Nausea (G3/4: 5%);
Stomatitis (G3/4: 7.8%);
Diarrhoea (G3/4: 6.2%);
Vomiting (G3/4: 5%);
Constipation
Skin and subcutaneous tissue disorders Alopecia;
Nail disorders (severe 0.4%);
Skin reaction (no severe)
Musculoskeletal and connective tissue disorders. Myalgia
Metabolism and nutrition disorders Anorexia
Infections and infestations Infection (G3/4: 7.8%)
Vascular disorders Hypotension
General disorders and administration site conditions Asthenia (severe 8.1%);
Fluid retention (severe 1.2%); Pain
Immune system disorders Hypersensitivity (G3/4: 1.2%)
Docetaxel 75 mg/m2 in combination with cisplatin
MedDRA System Organ classes Very common adverse reactions

≥ 1/10

Common adverse reactions

≥ 1/100, <1/10

Uncommon adverse reactions

≥ 1/1,000, <1/100

Investigations G3/4 Blood bilirubin increased (2.1%);

G3/4 ALT increased (1.3%)


G3/4 Blood alkaline Phosphatise increased (0.3%)
Cardiac disorders Arrhythmia (G3/4: 0.7%) Cardiac failure
Blood and the lymphatic system disorders Neutropenia (G4: 51.5%);

Anaemia (G3/4: 6.9%);

Thrombocytopenia (G4:0.5%)

Febrile neutropenia
Nervous system disorders Peripheral sensory neuropathy (G3: 3.7%);

Peripheral motor neuropathy (G3/4: 2%)

Gastrointestinal disorders Nausea (G3/4: 9.6%);

Vomiting (G3/4:7.6%);

Diarrhoea (G3/4:6.4%);

Stomatitis (G3/4:2%)

Constipation
Skin and subcutaneous tissue disorders Alopecia;

Nail disorders (severe 0.7%);

Skin reaction (G3/4: 0.2%)

Musculoskeletal and connective tissue disorders. Myalgia (severe 0.5%)
Metabolism and nutrition disorders Anorexia
Infections and infestations Infection (G3/4: 5.7%)
Vascular disorders Hypotension (G3/4:0.7%)
General disorders and administration site conditions Asthenia (severe 9.9%);

Fluid retention (severe 0.7%);

Fever (G3/4: 1.2%)

Infusion site reaction;

Pain

Immune system disorders Hypersensitivity (G3/4: 2.5%)
Docetaxel 100 mg/m2 in combination with trastuzumab:
MedDRA System Organ classes
Very common
adverse reactions

≥ 1/10 

Common
adverse reactions

≥ 1/100, <1/10

Investigations Weight increased
Cardiac disorders Cardiac failure
Blood and the lymphatic system disorders Neutropenia (G3/4: 32%); Febrile neutropenia (includes neutropenia associated with fever and antibiotic use) or neutropenic sepsis
Nervous system disorders Paresthesia; Headache; Dysgeusia; Hypoaesthesia
Eye disorders Lacrimation increased; Conjunctivitis
Respiratory, thoracic and mediastinal disorders Epistaxis; Pharyngolaryngeal pain; Nasopharyngitis ; Dyspnoea; Cough; Rhinorrhoea
Gastrointestinal disorders Nausea; Diarrhoea; Vomiting; Constipation; Stomatitis; Dyspepsia; Abdominal pain
Skin and subcutaneous tissue disorders Alopecia; Erythema; Rash; Nail disorders
Musculoskeletal and connective tissue disorders. Myalgia; Arthralgia; Pain in extremity; Bone pain; Back pain
Metabolism and nutrition disorders Anorexia
Vascular disorders Lymphoedema
General disorders and administration site conditions Asthenia; Oedema peripheral; Pyrexia; Fatigue; Mucosal inflammation; Pain; Influenza like illness; Chest pain; Chills Lethargy
Psychiatric disorders Insomnia

Cardiac disorders
Symptomatic cardiac failure was reported in 2.2% of the patients who received Docetaxel plus trastuzumab compared to 0% of patients given Docetaxel alone. In the Docetaxel plus trastuzumab arm, 64% had received a prior anthracycline as adjuvant therapy compared with 55% in the Docetaxel arm alone.

Blood and the lymphatic system disorders
Very common: Haematological toxicity was increased in patients receiving trastuzumab and Docetaxel, compared with Docetaxel alone (32% grade 3/4 neutropenia versus 22%, using NCI-CTC criteria). Note that this is likely to be an underestimate since Docetaxel alone at a dose of 100 mg/m2 is known to result in neutropenia in 97% of patients, 76% grade 4, based on nadir blood counts. The incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with Herceptin plus Docetaxel (23% versus 17% for patients treated with Docetaxel alone).

Docetaxel 75mg/m2 in combination with capecitabine with cisplatin and 5-fluorouracil for gastric adenocarcinoma cancer:
MedDRA System Organ classes
Very common
adverse reactions

≥ 1/10

Common
adverse reactions

≥ 1/100, <1/10

Investigations Weight decreased;
G3/4 Blood bilirubin increased (9%)
Blood and the lymphatic system disorders Neutropenia (G3/4: 63%);
Anaemia (G3/4: 10%)
Thrombocytopenia (G3/4: 3%)
Nervous system disorders Dysgeusia (G3/4: <1%);
Paraesthesia (G3/4: <1%)
Dizziness;
Headache (G3/4: <1%);
Neuropathy peripheral
Eye disorders Lacrimation increased
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain (G3/4: 2%) Dyspnoea (G3/4: 1%);
Cough (G3/4: <1%);
Epistaxis (G3/4: <1%)
Gastrointestinal disorders Stomatitis (G3/4: 18%);
Diarrhoea (G3/4: 14%);
Nausea (G3/4: 6%);
Vomiting (G3/4: 4%);
Constipation (G3/4: 1%);
Abdominal pain (G3/4: 2%);
Dyspepsia
Abdominal pain upper;
Dry mouth
Skin and subcutaneous tissue disorders Hand-foot syndrome (G3/4: 24%)
Alopecia (G3/4: 6%);
Nail disorders (G3/4: 2%)
Dermatitis;
Rash erythematous (G3/4: <1%);
Nail discolouration;
Onycholysis (G3/4: 1%)
Musculoskeletal and connective tissue disorders. Myalgia (G3/4: 2%);
Arthralgia (G3/4: 1%)
Pain in extremity (G3/4: <1%);
Back pain (G3/4: 1%);
Metabolism and nutrition disorders Anorexia (G3/4: 1%);
Decreased appetite
Dehydration (G3/4: 2%);
Infections and infestations Oral candidiasis (G3/4: <1%)
General disorders and administration site conditions Asthenia (G3/4: 3%);
Pyrexia (G3/4: 1%);
Fatigue/ weakness (G3/4: 5%);
Oedema peripheral (G3/4: 1%);
Lethargy;
Pain
Docetaxel 75mg/m2 in combination with prednisone or prednisolone
MedDRA System Organ classes
Very common
adverse reactions

≥ 1/10

Common
adverse reactions

≥ 1/100,

Cardiac disorders Cardiac left ventricular
Function decrease (G3/4: 0.3%)
Blood and the lymphatic system disorders Neutropenia (G3/4: 32%);
Anaemia (G3/4: 4.9%)
Thrombocytopenia; (G3/4: 0.6%);
Febrile neutropenia
Nervous system disorders Peripheral sensory neuropathy (G3/4: 1.2%);
Dysgeusia (G3/4: 0%)
Peripheral motor neuropathy (G3/4: 0%)
Eye disorders Lacrimation increased (G3/4: 0.6%)
Respiratory, thoracic and mediastinal disorders Epistaxis (G3/4: 0%);
Dyspnoea (G3/4: 0.6%);
Cough (G3/4: 0%)
Gastrointestinal disorders Nausea (G3/4: 2.4%);
Diarrhoea (G3/4: 1.2%);
Stomatitis/Pharyngitis (G3/4: 0.9%);
Vomiting (G3/4: 1.2%)
Skin and subcutaneous tissue disorders Alopecia;
Nail disorders (no severe)
Exfoliative rash (G3/4:0.3%)
Musculoskeletal and connective tissue disorders. Arthralgia (G3/4: 0.3%);
Myalgia (G3/4: 0.3%)
Metabolism and nutrition disorders Anorexia (G3/4: 0.6%)
Infections and infestations Infection (G3/4: 3.3%)
General disorders and administration site conditions Fatigue (G3/4: 3.9%);
Fluid retention (severe 0.6%)
Immune system disorders Hypersensitivity (G3/4:0.6%)
Docetaxel 75mg/m2 in combination with doxorubicin and cyclophosphamide with cisplatin and 5-fluorouracil for Head and Neck cancer:
MedDRA System Organ classes Very common adverse reactions

≥1/10

Common adverse reactions

≥1/100, <1/10

Uncommon adverse reactions

≥1/1000, <1/100

Investigations Weight increased or decreased (G3/4: 0.3%)
Cardiac disorders Arrhythmia (G3/4: 0.1%);
Congestive heart failure
Blood and the lymphatic system disorders Anaemia (G3/4: 4.3%);
Neutropenia (G3/4: 65.5%);
Thrombocytopenia (G3/4: 2.0%);
Febrile neutropenia
Nervous system disorders Dysgeusia (G3/4: 0.7%);
Peripheral sensory neuropathy (G3/4: 0%)
Peripheral motor neuropathy (G3/4: 0%);
Neurocortical (G3/4: 0.3%);
Neurocerebella (G3/4: 0.1%)
Syncope (G3/4: 0%)
Eye disorders Lacrimation disorder (G3/4: 0.1%);
Conjunctivitis (G3/4: 0.3%)
Respiratory, thoracic and mediastinal disorders Cough (G3/4:0%)
Gastrointestinal disorders Nausea (G3/4: 5.1%);
Stomatitis (G3/4: 7.1%);
Vomiting (G3/4: 4.3%);
Diarrhoea (G3/4: 3.2%);
Constipation (G3/4: 0.4%)
Abdominal pain (G3/4:0.5%)

Gastrointestinal Haemorrhage (severe 0.3%)

Colitis/enteritis/ large intestine perforation
Skin and subcutaneous tissue disorders Alopecia;
Skin toxicity (G3/4: 0.7%);
Nail disorders (G3/4: 0.4%)
Musculoskeletal and connective tissue disorders. Myalgia (G3/4: 0.8%);
Arthralgia (G3/4:0.4%)
Metabolism and nutrition disorders Anorexia (G3/4: 2.2%)
Infections and infestations Infection (G3/4: 3.2%);
Neutropenic infection.
There were no septic deaths.
Vascular disorders Vasodilatation (G3/4: 0.9%) Hypotension (G3/4: 0% Phlebitis (G3/4: 0%);
Lymphoedema (G3/4: 0%)
General disorders and administration site conditions Asthenia (G3/4: 11%);
Fever (G3/4: 1.2%);
Oedema peripheral (G3/4: 0.4%)
Infusion site reaction;

Non-cardiac chest pain (severe 0.4%)

Immune system disorders Hypersensitivity (G3/4: 1.1%)
Reproductive system and breast disorders Amenorrhoea

Cardiac disorders
Congestive Heart Failure (CHF) (2.3% at 70 months median follow-up) has also been reported. One patient in each treatment arm died due to cardiac failure.

Nervous system disorders
Peripheral sensory neuropathy was observed to be ongoing at the median follow-up time of 55 months in 9 patients out of the 73 patients with peripheral sensory neuropathy at the end of the chemotherapy.

Skin and subcutaneous tissue disorders
Alopecia was observed to be ongoing at the median follow-up time of 55 months in 22 patients out of the 687 patients with alopecia at the end of the chemotherapy.
General disorders and administration site condition
Oedema peripheral was observed to be ongoing at the median follow-up time of 55 months in 18 patients out of the 112 patients with oedema peripheral at the end of the chemotherapy.

Reproductive system and breast disorders
Amenorrhoea was observed to be ongoing at the median follow-up time of 55 months in 133 patients out of the 233 patients with amenorrhoea at the end of the chemotherapy.

Blood and the lymphatic system disorders
Febrile neutropenia and neutropenic infection occurred in 17.2% and 13.5% of patients respectively, regardless of G-CSF use. G-CSF was used for secondary prophylaxis in 19.3% of patients (10.7% of the cycles). Febrile neutropenia and neutropenic infection occurred respectively in 12.1% and 3.4% of patients when patients received prophylactic G-CSF, in 15.6% and 12.9% of patients without prophylactic G-CSF.

Post-Marketing Experiences

The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.

Body as a whole: Diffuse pain, chest pain, radiation recall phenomenon.

Cardiovascular: Atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction.

Cutaneous: Very rare cases of cutaneous lupus erythematosus and rare cases of bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Scleroderma-like changes usually preceded by peripheral Lymphoedema. In some cases multiple factors may have contributed to the development of these effects. Severe hand and foot syndrome has been reported.

Gastrointestinal: Abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal haemorrhage, gastrointestinal perforation, ischemic colitis, colitis, intestinal obstruction, ileus, neutropenic enterocolitis and dehydration as a consequence to gastrointestinal events have been reported.

Hematologic: Bleeding episodes. Bone marrow suppression and other hematologic adverse reactions have been reported. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported. Cases of acute myeloid leukemia and myelodysplasic syndrome have been reported in association with Docetaxel when used in combination with other chemotherapy agents and/or radiotherapy.

Hypersensitivity: Rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication.

Hepatic: rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.

Neurologic: Confusion, rare cases of seizures or transient loss of consciousness have been observed, sometimes appearing during the infusion of the drug.

Ophthalmologic: Conjunctivitis, lacrimation or lacrimation with or without conjunctivitis. Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion.

Hearing: Rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs.

Respiratory: Dyspnea, acute pulmonary edema, acute respiratory distress syndrome, interstitial pneumonia. Pulmonary fibrosis and interstitial lung disease has been rarely reported. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

Renal: Renal insufficiency and renal failure have been reported, the majority of these cases were associated with concomitant nephrotoxic drugs.

Neoplasms benign, malignant and unspecified (including cysts and polyps): Very rare cases of acute myeloid leukaemia and myelodysplastic syndrome have been reported in association with Docetaxel when used in combination with other chemotherapy agents and/or radiotherapy.

Metabolism and nutrition disorders: Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and pneumonia.

Vascular disorders: Venous thromboembolic events have rarely been reported.

General disorders and administration site conditions: Radiation recall phenomena have rarely been reported. Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Dehydration and pulmonary oedema have rarely been reported.

Overdosage

There were a few reports of overdose. There is no known antidote for Docetaxel overdose. In case of overdose, the patient should be kept in a specialised unit and vital functions closely monitored. In cases of overdose, exacerbation of adverse events may be expected. The primary anticipated complications of overdose would consist of 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.

Stability

DOCETAX Infusion final dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F) is stable for 4 hours. DOCETAX Infusion final dilution for infusion (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 1 hour intravenous administration).

Storage and Handling Instructions

Store below 25°C. Protect from light.

Packaging Information

DOCETAX Infusion 20: Vial of 5 ml with solvent vial of 5 ml.
DOCETAX Infusion 80: Vial of 15 ml with solvent vial of 15 ml.
DOCETAX Infusion 120: Vial of 20 ml with solvent vial of 20 ml.