Chester Clinic

Actavis.ie2

Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 Summary of Product Characteristics
NAME OF THE MEDICINAL PRODUCT

Docetaxel Actavis 20 mg/ml concentrate for solution for infusion

2.
QUALITATIVE AND QUANTITATIVE COMPOSITION

Each single dose vial contains docetaxel 20 mg/ml
Each 1 ml single dose vial contains 20 mg docetaxel
Each 4 ml single dose vial contains 80 mg docetaxel
Each 7 ml single dose vial contains 140 mg docetaxel
Each 8 ml single dose vial contains 160 mg docetaxel
Excipient with known effect: Ethanol absolute 400 mg/ml
For the full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM

Concentrate for solution for infusion
The concentrate is a clear, pale yellow solution.
4.
CLINICAL PARTICULARS
Therapeutic indications

Breast cancer

Docetaxel Actavis in combination with doxorubicin and cyclophosphamide is indicated for the
adjuvant treatment of patients with:
• operable node-positive breast cancer • operable node-negative breast cancer For patients with operable node-negative breast cancer, adjuvant treatment should be restricted to patients eligible to receive chemotherapy according to internationally established criteria for primary therapy of early breast cancer (see section 5.1). Docetaxel Actavis in combination with doxorubicin is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this condition. Docetaxel Actavis monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have included an anthracycline or an alkylating agent. Docetaxel Actavis in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer whose tumors over express HER2 and who previously have not received chemotherapy for metastatic disease.

Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025
Docetaxel Actavis in combination with capecitabine is indicated for the treatment of patients with
locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy
should have included an anthracycline.
Non-small cell lung cancer

Docetaxel Actavis is indicated for the treatment of patients with locally advanced or metastatic non-
small cell lung cancer after failure of prior chemotherapy.
Docetaxel Actavis in combination with cisplatin is indicated for the treatment of patients with
unresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have not
previously received chemotherapy for this condition.
Prostate cancer

Docetaxel Actavis in combination with prednisone or prednisolone is indicated for the treatment of
patients with hormone refractory metastatic prostate cancer.
Gastric Adenocarcinoma

Docetaxel Actavis in combination with cisplatin and 5-fluorouracil is indicated for the treatment of
patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal
junction, who have not received prior chemotherapy for metastatic disease.
Head and neck cancer

Docetaxel Actavis in combination with cisplatin and 5-fluorouracil is indicated for the induction
treatment of patients with locally advanced squamous cell carcinoma of the head and neck.
4.2
Posology and method of administration

The use of docetaxel should be confined to units specialised in the administration of cytotoxic
chemotherapy and it should only be administered under the supervision of a physician qualified in the
use of anticancer chemotherapy (see section 6.6).
Recommended dosage

For breast, non-small cell lung, gastric, and head and neck 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 docetaxel administration, unless contraindicated, can be used (see section 4.4). Prophylactic
G-CSF may be used to mitigate the risk of hematological toxicities.
For prostate cancer, given the concurrent use of prednisone or prednisolone the recommended
premedication regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel
infusion (see section 4.4).
Docetaxel is administered as a one-hour infusion every three weeks.
Breast cancer
In the adjuvant treatment of operable node-positive and node-negative breast cancer, the
recommended dose of docetaxel is 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and
cyclophosphamide 500 mg/m2 every 3 weeks for 6 cycles (TAC regiment) (see also Dosage
adjustments during treatment).

Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 For the treatment of patients with locally advanced or metastatic breast cancer, the recommended dosage of docetaxel is 100 mg/m2 in monotherapy. In first-line treatment, docetaxel 75 mg/m2 is given in combination therapy with doxorubicin (50 mg/m2). In combination with trastuzumab the recommended dose of docetaxel is 100 mg/m2 every three weeks, with trastuzumab administered weekly. In the pivotal study the initial docetaxel infusion was started the day following the first dose of trastuzumab. The subsequent docetaxel doses were administered immediately after completion of the trastuzumab infusion, if the preceding dose of trastuzumab was well tolerated. For trastuzumab dosage and administration, see trastuzumab summary of product characteristics. In combination with capecitabine, the recommended dose of docetaxel is 75 mg/m2 every three weeks, combined with capecitabine at 1250 mg/m2 twice daily (within 30 minutes after a meal) for 2 weeks followed by 1-week rest period. For capecitabine dose calculation according to body surface area, see capecitabine summary of product characteristics. Non-small cell lung cancer In chemotherapy naïve patients treated for non-small cell lung cancer, the recommended dose regimen is docetaxel 75 mg/m2 immediately followed by cisplatin 75 mg/m2 over 30-60 minutes. For treatment after failure of prior platinum-based chemotherapy, the recommended dose is 75 mg/m² as a single agent. Prostate cancer The recommended dose of docetaxel is 75 mg/m2. Prednisone or prednisolone 5 mg orally twice daily is administered continuously (see section 5.1). Gastric adenocarcinoma The recommended dose of docetaxel is 75 mg/m2 as a 1 hour infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour infusion (both on day 1 only), followed by 5-fluorouracil 750 mg/m2 per day given as a 24-hour continuous 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. Prophylactic G-CSF should be used to mitigate the risk of hematological toxicities (See also Dosage adjustments during treatment). Head and neck cancer Patients must receive premedication with antiemetics and appropriate hydration (prior to and after cisplatin administration). Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities. All patients on the docetaxel-containing arm of the TAX 323 and TAX 324 studies, received prophylactic antibiotics. - Induction chemotherapy followed by radiotherapy (TAX 323) For the induction treatment of inoperable locally advanced squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of docetaxel is 75 mg/m2 as a 1 hour infusion followed by cisplatin 75 mg/m2 over 1 hour, on day one, followed by 5-fluorouracil as a continuous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy. Induction chemotherapy followed by chemoradiotherapy (TAX 324) For the induction treatment of patients with locally advanced (technically unresectable, low probability of surgical cure, and aiming at organ preservation) squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of docetaxel is 75 mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30-minute to

Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 3 hour infusion, followed by 5-fluorouracil 1000 mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy.
For cisplatin and 5-fluorouracil dose modifications, see the corresponding summary of product
characteristics.
Dose adjustments during treatment

General
Docetaxel should be administered when the neutrophil count is ≥ 1,500 cells/mm3. In patients who
experienced either febrile neutropenia, neutrophil < 500 cells/mm3 for more than one week, severe or
cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel therapy, the dose of
docetaxel should be reduced from 100 mg/m2 to 75 mg/m2 and/or from 75 to 60 mg/m². If the patient
continues to experience these reactions at 60 mg/m², the treatment should be discontinued.
Adjuvant therapy for breast cancer
Primary G-CSF prophylaxis should be considered in patients who receive docetaxel, doxorubicin and
cyclophosphamide (TAC) adjuvant therapy for breast cancer. Patients who experience febrile
neutropenia and/or neutropenic infections should have their docetaxel dose reduced to 60 mg/m2 in all
subsequent cycles (see sections 4.4 and 4.8). Patients who experience Grade 3 or 4 stomatitis should
have their dose decreased to 60 mg/m².
In combination with cisplatin
For patients who are dosed initially at docetaxel 75 mg/m2 in combination with cisplatin and whose
nadir of platelet count during the previous course of therapy is < 25,000 cells/mm3, or in patients who
experience febrile neutropenia, or in patients with serious non-hematologic toxicities, the docetaxel
dosage in subsequent cycles should be reduced to 65 mg/m2. For cisplatin dosage adjustments, see
manufacturer's summary of product characteristics.
In combination with capecitabine
• For capecitabine dose modifications, see capecitabine summary of product characteristics.
• For patients developing the first appearance of Grade 2 toxicity, which persists at the time of the
next docetaxel/capecitabine treatment, delay treatment until resolved to Grade 0-1, and resume at
100% of the original dose.
• For patients developing the second appearance of Grade 2 toxicity, or the first appearance of a Grade
3 toxicity, at any time during the treatment cycle, delay treatment until resolved to Grade 0-1, then
resume treatment with docetaxel 55 mg/m².
• For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the docetaxel
dose.
For trastuzumab dose modifications, see trastuzumab summary of product characteristics
In combination with cisplatin and 5-fluorouracil
If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-
CSF
use, the docetaxel dose should be reduced from 75 to 60 mg/m2. If subsequent episodes of
complicated neutropenia occur the docetaxel dose should be reduced from 60 to 45 mg/m2. In case of
Grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 to 60 mg/m2. Patients
should not be retreated with subsequent cycles of docetaxel until neutrophils recover to a level >
1,500 cells/mm3 and platelets recover to a level > 100,000 cells/mm3. Discontinue treatment if these
toxicities persist. (See section 4.4).

Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 Recommended dose modifications for gastrointestinal toxicities in patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (5-FU): Toxicity
Dosage adjustment
Diarrhoea grade 3 First episode: reduce 5-FU dose by 20%. Second episode: then reduce docetaxel dose by 20%. Diarrhoea grade 4 First episode: reduce docetaxel and 5-FU doses by 20%. Second episode: discontinue treatment. Stomatitis/mucositis First episode: reduce 5-FU dose by 20%. Second episode: stop 5-FU only, at all subsequent cycles. Third episode: reduce docetaxel dose by 20%. Stomatitis/mucositis First episode: stop 5-FU only, at all subsequent cycles. Second episode: reduce docetaxel dose by 20%.
For cisplatin and 5-fluorouracil dose adjustments, see the corresponding summary of product
characteristics.
In the pivotal SCCHN studies patients who experienced complicated neutropenia (including
prolonged neutropenia, febrile neutropenia, or infection), it was recommended to use G-CSF to
provide prophylactic coverage (eg, day 6-15) in all subsequent cycles.
Special populations

Patients with hepatic impairment
Based on pharmacokinetic data with docetaxel at 100 mg/m² as single agent, patients who have both
elevations of transaminase (ALT and/or AST) greater than 1.5 times the upper limit of the normal
range (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of
docetaxel is 75 mg/m2 (see sections 4.4 and 5.2). For those patients with serum bilirubin > ULN
and/or ALT and AST > 3.5 times the ULN associated with alkaline phosphatase > 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 trial 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.
This medicinal product contains 400 mg ethanol per ml concentrate. This has to be taken into account
in high-risk groups such as patients with liver disease.
Paediatric population
The safety and efficacy of Docetaxel Actavis 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 Actavis 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.
Elderly
Based on a population pharmacokinetic analysis, there are no special instructions for use in the
elderly.
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)

Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Docetaxel must not be used in patients with baseline neutrophil count of < 1,500 cells/mm3.
Docetaxel must not be used in patients with severe liver impairment since there is no data available
(see sections 4.2 and 4.4).
Contraindications for other medicinal products also apply, when combined with docetaxel.
4.4
Special warnings and precautions for use

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 docetaxel
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 docetaxel infusion (see section 4.2).
Hematology
Neutropenia is the most frequent adverse reaction of docetaxel. Neutrophil nadirs occurred at a
median of 7 days but this interval may be shorter in heavily pre-treated patients. Frequent monitoring
of complete blood counts should be conducted on all patients receiving docetaxel. Patients should be
retreated with docetaxel when neutrophils recover to a level ≥ 1,500 cells/mm3 (see section 4.2). In the case of severe neutropenia (< 500 cells/mm3 for seven days or more) during a course of docetaxel therapy, a reduction in dose for subsequent courses of therapy or the use of appropriate symptomatic measures are recommended (see section 4.2). 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, (see sections 4.2 and 4.8). 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 prohphylaxis. 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 (see section 4.2 and 4.8). Hypersensitivity reactions Patients should be observed closely for hypersensitivity reactions especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of docetaxel, thus facilities for the treatment of hypotension and bronchospasm should be available. If hypersensitivity reactions occur, minor symptoms such as flushing or localized cutaneous reactions do not require interruption of therapy. However, severe reactions, such as severe hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactions should not be re-challenged with 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. Severe symptoms such as eruptions followed by

Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 desquamation which lead to interruption or discontinuation of docetaxel treatment were reported (see section 4.2). Fluid retention Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be monitored closely. 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. Patients with liver 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 (see section 4.2). 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. Patients with renal impairment There are no data available in patients with severely impaired renal function treated with docetaxel. Nervous system The development of severe peripheral neurotoxicity requires a reduction of dose (see section 4.2). Since Docetaxel Actavis contains ethanol (400 mg ethanol per ml concentrate), consideration should be given to possible central nervous system and other effects. 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 (see section 4.8). 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.

Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025
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 (see section
4.8).

Others
Contraceptive measures must be taken by both men and women during treatment and for men at least
6 months after cessation of therapy (see section 4.6).
The concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole,
clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and
voriconazole) should be avoided (see section 4.5).
Ethanol
Docetaxel Actavis contains 400 mg ethanol per ml concentrate.
Harmful for those patients suffering from alcoholism.
To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as
patients with liver disease or epilepsy.
The amount of alcohol in this medicinal product may alter the effects of other medicinal products.
The amount of alcohol in this medicinal product may impair the patients 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 (see section 4.2).
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 (see sections 4.8 and 5.1).
Leukaemia
In the docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed
myelodysplasia or myeloid leukaemia requires hematological 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 (see section 5.1).
Elderly patients
Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 There are limited data available in patients > 70 years of age on docetaxel use in combination with doxorubicin and cyclophosphamide. Of the 333 patients treated with docetaxel every three weeks in a prostate cancer study, 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 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 edema occurred at rates ≥ 10% higher in patients who were 75 years of age or greater versus less than 65 years. Among the 300 (221 patients in the phase III part of the study and 79 patients in the phase II part) patients treated with docetaxel in combination with cisplatin and 5-fluorouracil in the gastric cancer study, 74 were 65 years of age or older and 4 patients were 75 years of age or older. The incidence of serious adverse events 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.
During the post marketing experience a high number of delayed infusion site adverse reactions were
reported for docetaxel, concentrate for solution for infusion. Although the mechanism of these
reactions is not known at present it was observed that they occur close to the infusion site, several
days of the last docetaxel cycle and have a "burn-like" appearance. In some cases, vesicles and vein
hyperpigmentation were reported. No correlation with docetaxel cycle number was noted and re-
occurrence was not always seen with re-exposure. In most of the cases the patients recovered or were
recovering at the time of reporting.
4.5
Interaction with other medicinal products and other forms of interaction
In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds which induce, inhibit or are metabolised by (and thus may inhibit the enzyme competitively) cytochrome P450-3A such as ciclosporine, ketoconazole and erythromycin. As a result, caution should be exercised when treating patients with these medicinal products as concomitant therapy since there is a potential for a significant interaction. In case of combination with CYP3A4 inhibitors, the occurrence of docetaxel adverse reactions may increase, as a result of reduced metabolism. If the concomitant use of a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) cannot be avoided, a close clinical surveillance is warranted and a dose-adjustment of docetaxel may be suitable during the treatment with the strong CYP3A4 inhibitor (see section 4.4). In a pharmacokinetic study with 7 patients, the co-administration of docetaxel with the strong CYP3A4 inhibitor ketoconazole leads to a significant decrease in docetaxel clearance by 49%. Docetaxel pharmacokinetics in the presence of prednisone was studied in patients with metastatic prostate cancer. Docetaxel is metabolised by CYP3A4 and prednisone is known to induce CYP3A4. No statistically significant effect of prednisone on the pharmacokinetics of docetaxel was observed. Docetaxel is highly protein bound (> 95%). Although the possible in vivo interaction of docetaxel with concomitantly administered medication has not been investigated formally, in vitro interactions with tightly protein-bound agents such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein binding of docetaxel. In addition, dexamethasone did not affect protein binding of docetaxel. Docetaxel did not influence the binding of digitoxin. Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025
The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their
coadministration. Limited data from a single uncontrolled study were suggestive of an interaction
between docetaxel and carboplatin. When combined to docetaxel, the clearance of carboplatin was
about 50% higher than values previously reported for carboplatin monotherapy.
Docetaxel Actavis contains 400 mg ethanol per ml concentrate. In higher doses (7.5 ml concentrate
(150 mg) contains 3 g ethanol) the amount of alcohol may alter the effects of other medicines.
4.6
Fertility, pregnancy and lactation

Pregnancy
There is no information on the use of docetaxel in pregnant women. Docetaxel has been shown to be
both embryotoxic and foetotoxic in rabbits and rats, and to reduce fertility in rats. As with other
cytotoxic medicinal products, docetaxel may cause foetal harm when administered to pregnant
women. Therefore, docetaxel must not be used during pregnancy unless clearly indicated.
Women of childbearing age receiving docetaxel should be advised to avoid becoming pregnant, and to
inform the treating physician immediately should this occur.
Breastfeeding
Docetaxel is a lipophilic substance but it is not known whether it is excreted in human milk.
Consequently, because of the potential for adverse reactions in nursing infants, breast feeding must be
discontinued for the duration of docetaxel therapy.
Contraception in males and females
An effective method of contraception should be used during treatment.
Fertility
In non clinical studies, docetaxel has genotoxic effects and may alter male fertility (see section 5.3).
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.

4.7
Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.
Docetaxel Actavis contains 400 mg ethanol per ml concentrate. In higher doses (7.5 ml concentrate
(150 mg docetaxel) contains 3 g ethanol) the amount of alcohol may impair the ability to drive or use
machines.
4.8
Undesirable effects
Summary of the safety profile for all indications The adverse reactions considered to be possibly or probably related to the administration of docetaxel have been obtained in: • 1312 and 121 patients who received 100 mg/m² and 75 mg/m² of docetaxel as a single agent • 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). Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 • 1276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively)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),the COSTART and the MedDRA 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), not known (cannot be estimated from available data).
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 study 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 (see sections 4.2 and
4.4). 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 (see sections 4.2 and 4.4). 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 (see section 4.4).
Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025

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 fever or chills.
Severe reactions were characterised by hypotension and/or bronchospasm or generalized
rash/erythema (see section 4.4).

Tabulated list of adverse reactions in breast cancer for docetaxel 100 mg/m² single agent:
MedDRA System
Very common
Common adverse
Uncommon adverse
Organ classes
adverse reactions
reactions
reactions
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: Blood and lymphatic Neutropenia (G4: Thrombocytopenia 8.9%); Febrile neutropenia Peripheral sensory neuropathy (G3: 4.1%); Peripheral motor neuropathy (G3/4: 4%) Dysgeusia (severe 0.07%) Respiratory, thoracic Dyspnoea (severe Gastrointestinal Stomatitis (G3/4: Constipation (severe Oesophagitis (severe: Diarrhoea (G3/4: Nausea (G3/4: 4%); Gastrointestinal Vomiting (G3/4: 3%) Haemorrhage (severe 0.3%) subcutaneous tissue Skin reaction (G3/4: 5.9%); Nail disorders (severe 2.6%) Musculoskeletal and Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 connective tissue disorders Metabolism and nutrition disorders
Infections and
Infections (G3/4: Infection associated with G4 neutropenia pneumonia, fatal in Vascular disorders Hypertension; Haemorrhage General disorders and Fluid retention Infusion site reaction; administration site Non-cardiac chest Asthenia (severe Hypersensitivity
Description of selected adverse reactions in breast cancer for docetaxel 100 mg/m2 single agent:

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.
Tabulated list of adverse reactions in non-small cell lung cancer for docetaxel 75mg/m² single
agent:
MedDRA System Organ
Very common adverse
Common adverse reactions
reactions
G3/4 Blood bilirubin increased (<2%) Cardiac disorders Arrhythmia (no severe); Blood and lymphatic system Neutropenia (G4: 54.2%); Febrile neutropenia Anaemia (G3/4: 10.8%); Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 Thrombocytopenia (G4: 1.7%) Nervous system disorders Peripheral sensory neuropathy Peripheral motor neuropathy Gastrointestinal disorders Nausea (G3/4: 3.3%); Stomatitis (G3/4: 1.7%); Vomiting (G3/4: 0.8%); Diarrhoea (G3/4: 1.7%) Skin and subcutaneous tissue Nail disorders (severe 0.8%) Skin reaction (G3/4: 0.8%) Musculoskeletal and connective tissue disorders Metabolism and nutrition disorders
Infections and infestations
Infections (G3/4: 5%) Vascular disorders General disorders and Asthenia (severe 12.4%); administration site conditions Fluid retention (severe 0.8%); Immune system disorders Hypersensitivity (no severe)
Tabulated list of adverse reactions in breast cancer for docetaxel 75mg/m² in combination with
doxorubicin:

MedDRA System
Very common adverse Common adverse
Uncommon adverse
Organ classes
reactions
reactions
reactions
G3/4 Blood bilirubin G3/4 AST increased increased (<2.5%); G3/4 Blood alkaline G3/4 ALT increased phosphatase increased Cardiac disorders Cardiac failure; Arrhythmia (no severe) Blood and lymphatic Neutropenia (G4: system disorders Anaemia (G3/4: 9.4%); Febrile neutropenia; Thrombocytopenia (G4: 0.8%) Peripheral sensory Peripheral motor neuropathy (G3: 0.4%) neuropathy (G3/4: 0.4%) Gastrointestinal Nausea (G3/4: 5%); Stomatitis (G3/4: 7.8%); Diarrhoea (G3/4: 6.2%); Vomiting (G3/4: 5%); Constipation Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 Skin and subcutaneous tissue disorders Nail disorders (severe 0.4%); Skin reaction (no severe) Musculoskeletal and connective tissue disorders

Metabolism and
nutrition disorders Infections and Infection (G3/4: 7.8%) Vascular disorders General disorders and Asthenia (severe 8.1%); Infusion site reaction administration site Fluid retention (severe Hypersensitivity (G3/4:
Tabulated list of adverse reactions in non-small cell lung cancer for docetaxel 75mg/m² in
combination with cisplatin:

MedDRA System
Very common adverse
Common adverse
Uncommon adverse
Organ classes
reactions
reactions
reactions
G3/4 Blood bilirubin G3/4 AST increased increased (2.1%); G3/4 ALT increased G3/4 Blood alkaline phosphatase increased Cardiac disorders Arrhythmia (G3/4: Blood and lymphatic Neutropenia (G4: Febrile neutropenia system disorders Anaemia (G3/4: 6.9%); Thrombocytopenia (G4:0.5%) Peripheral sensory neuropathy (G3: 3.7%); Peripheral motor neuropathy (G3/4: 2%) Gastrointestinal Nausea (G3/4: 9.6%); Vomiting (G3/4: 7.6%);
Diarrhoea (G3/4:
Stomatitis (G3/4: 2%) Skin and subcutaneous tissue disorders Nail disorders (severe Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 0.7%); Skin reaction Musculoskeletal and Myalgia (severe 0.5%) connective tissue disorders Metabolism and nutrition disorders Infection (G3/4: 5.7%) Vascular disorders Hypotension (G3/4: General disorders and Asthenia (severe 9.9%); Infusion site reaction; administration site Fluid retention (severe Fever (G3/4: 1.2%) Hypersensitivity (G3/4:
Tabulated list of adverse reactions in breast cancer for docetaxel 100mg/m² in combination with
trastuzumab:

MedDRA System Organ
Very common adverse
Common adverse reactions
reactions
Weight increased Cardiac disorders Blood and lymphatic system Neutropenia (G3/4: 32%); Febrile neutropenia (includes neutropenia associated with fever and antibiotic use) or neutropenic sepsis Nervous system disorders Paresthesia; Headache; Dysgeusia; Hypoaesthesia Lacrimation increased; Respiratory, thoracic and Epistaxis; Pharyngolaryngeal mediastinal disorders pain; Nasopharyngitis ; Dyspnoea; Cough; Rhinorrhoea Gastrointestinal disorders Nausea; Diarrhoea; Vomiting; Constipation; Stomatitis; Dyspepsia; Abdominal pain Skin and subcutaneous tissue Alopecia; Erythema; Rash; Nail Musculoskeletal and connective Myalgia; Arthralgia; Pain in tissue disorders extremity; Bone pain; Back pain Metabolism and nutrition disorders
Vascular disorders
General disorders and Asthenia; Oedema peripheral; Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 administration site conditions Pyrexia; Fatigue; Mucosal inflammation; Pain; Influenza like illness; Chest pain; Chills Psychiatric disorders
Description of selected adverse reactions in breast cancer for docetaxel 100 mg/m² in combination
with trastuzumab

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 lymphatic system disorders
Very common: Hematological 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).
Tabulated list of adverse reactions in breast cancer for docetaxel 75mg/m² in combination with
capecitabine:
MedDRA System Organ
Very common adverse
Common adverse reactions
reactions
Weight decreased; G3/4 Blood bilirubin increased (9%) Blood and lymphatic system Neutropenia (G3/4: 63%); Thrombocytopenia (G3/4: 3%) Anaemia (G3/4: 10%) Nervous system disorders Dysgeusia (G3/4: <1%); Paraesthesia (G3/4: <1%) Headache (G3/4: <1%); Neuropathy peripheral Lacrimation increased Respiratory, thoracic and Pharyngolaryngeal pain Dyspnoea (G3/4: 1%); mediastinal disorders Cough (G3/4: <1%); Epistaxis (G3/4: <1%) Gastrointestinal disorders Stomatitis (G3/4: 18%); Abdominal pain upper; Diarrhoea (G3/4: 14%); Nausea (G3/4: 6%); Vomiting (G3/4: 4%); Constipation (G3/4: 1%); Abdominal pain (G3/4: 2%); Dyspepsia Skin and subcutaneous tissue Hand-foot syndrome (G3/4: Rash erythematous (G3/4: Alopecia (G3/4: 6%); <1%); Nail discolouration; Nail disorders (G3/4: 2%) Onycholysis (G3/4: 1%) Musculoskeletal and connective Myalgia (G3/4: 2%); Pain in extremity (G3/4: <1%); Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 tissue disorders Arthralgia (G3/4: 1%) Back pain (G3/4: 1%); Metabolism and nutrition Anorexia (G3/4: 1%); Dehydration (G3/4: 2%); Decreased appetite Infections and infestations Oral candidiasis (G3/4: <1%) General disorders and Asthenia (G3/4: 3%); administration site conditions Pyrexia (G3/4: 1%); Fatigue/ weakness (G3/4: 5%); Oedema peripheral (G3/4: 1%);
Tabulated list of adverse reactions in prostate cancer for docetaxel 75mg/m² in combination with
prednisone or prednisolone:
MedDRA System Organ
Very common adverse
Common adverse reactions
reactions
Cardiac disorders Cardiac left ventricular function decrease (G3/4: 0.3%) Blood and lymphatic system Neutropenia (G3/4: 32%); Thrombocytopenia; (G3/4: Anaemia (G3/4: 4.9%) Febrile neutropenia Nervous system disorders Peripheral sensory neuropathy Peripheral motor neuropathy Dysgeusia (G3/4: 0%) Lacrimation increased (G3/4: 0.6%) Respiratory, thoracic and Epistaxis (G3/4: 0%); mediastinal disorders 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 Exfoliative rash (G3/4: 0.3%) Nail disorders (no severe) Musculoskeletal and connective Arthralgia (G3/4: 0.3%); tissue disorders Myalgia (G3/4: 0.3%) Metabolism and nutrition Anorexia (G3/4: 0.6%) disorders
Infections and infestations
Infection (G3/4: 3.3%) General disorders and Fatigue (G3/4: 3.9%); administration site conditions Fluid retention (severe 0.6%) Immune system disorders Hypersensitivity (G3/4: 0.6%)
Tabulated list of adverse reactions in breast cancer for adjuvant therapy with docetaxel 75mg/m² in
combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX316) and
node negative (GEICAM9805) breast cancer – pooled data:
MedDRA System
Very common adverse Common adverse
Uncommon adverse
Organ classes
reactions
reactions
reactions
Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 Infection (G3/4: 2.4%); Neutropenic infection (G3/4: 2.6%) Blood and lymphatic Anaemia (G3/4: 3%); system disorders Neutropenia (G3/4: 59.2%); Thrombocytopenia (G3/4: 1.6%); Febrile neutropenia (G3/4: NA) Hypersensitivity (G3/4: Anorexia (G3/4: 1.5%) nutrition disorders Nervous system Dysgeusia (G3/4: Peripheral motor Syncope (G3/4: 0%) neuropathy (G3/4: Neurotoxicity (G3/4): Peripheral sensory neuropathy (G3/4: Conjuctivitis (G3/4: Lacrimation increased (G3/4: <0.1%); Cardiac disorders Arrhythmia (G3/4: Vascular disorders Hot flush (G3/4: 0.5%) Hypotension (G3/4: Lymphoedema (G3/4: Phlebitis (G3/4: 0%) Respiratory, thoracic Cough (G3/4: 0%) mediastinal disorders Gastrointestinal Nausea (G3/4: 5.0%); Abdominal pain (G3/4: Stomatitis (G3/4: Vomiting (G3/4: 4.2%); Diarrhoea (G3/4: 3.4%); Constipation (G3/4: 0.5%) Skin and subcutaneous Alopecia (persisting tissue disorders Skin disorder (G3/4: 0.6%); Nail disorders (G3/4: 0.4%) Musculoskeletal and Myalgia (G3/4: 0.7%); connective tissue Arthralgia (G3/4: 0.2%) Reproductive system Amenorrhoea (G3/4: and breast disorders General disorders and administration site Fever (G3/4: NA); Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 Oedema peripheral (G3/4: 0.2%) Weight increased (G3/4: 0%; Weight decreased (G3/4: 0.2%)
Description of selected adverse reactions for adjuvant therapy with docetaxel 75 mg/m² in
combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and
node-negative (GEICAM 9805) breast cancer
Cardiac disorders
In study TAX316, 26 patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm
experienced congestive heart failure. All except one patient in each arm were diagnosed with CHF
more than 30 days after the treatment period. Two patients in the TAC arm and 4 patients in the FAC
arm died because of cardiac failure.
In GEICAM 9805 study, 3 patients (0.6 %) in TAC arm and 3 patients (0.6 %) in FAC arm developed
congestive heart failure during the follow-up period. One patient in TAC arm died because of dilated
cardiomyopathy.

Nervous system disorders
Peripheral sensory neuropathy was observed to be ongoing during follow-up in10 patients out of the
84 patients with peripheral sensory neuropathy at the end of the chemotherapy in the node positive
breast cancer study (TAX316).
Skin and subcutaneous tissue disorders
In study TAX316, alopecia persisting into the follow-up period after the end of chemotherapy was
reported in 687 of 744 TAC patients and 645 of 736 FAC patients. At the end of the follow-up period
(actual median follow-up time of 96 months), alopecia was observed to be ongoing in 29 TAC
patients (3.9%) and 16 FAC patients (2.2%).
In GEICAM 9805 study, alopecia persisted into the follow-up period (median follow-up time of 10
years and 5 months) and was observed to be ongoing in 49 patients (9.2 %) in TAC arm and 35
patients (6.7 %) in FAC arm. Alopecia related to study drug started or worsened during the follow-up
period in 42 patients (7.9 %) in TAC arm and 30 patients (5.8 %) in FAC arm.
General disorders and administration site conditions
In study TAX316, peripheral oedema was observed to be ongoing in 19 patients out of the 119
patients with peripheral oedema in the TAC arm and 4 patients out of the 23 patients with peripheral
oedema in the FAC arm. In study GEICAM 9805, lymphoedema was observed to be ongoing in 4 of
the 5 patients in TAC arm and in 1 of the 2 patients in FAC arm at the end of the chemotherapy, and
did not resolve during the follow-up period (median follow-up time of 10 years and 5 months).
Asthenia persisted into the follow-up period (median follow-up time of 10 years and 5 months) and
was observed to be ongoing in 12 patients (2.3 %) in TAC arm and 4 patients (0.8 %) in FAC arm.

Reproductive system and breast disorders
Amenorrhoea was observed to be ongoing during follow-up in 121 patients out of the 202 patients
with amenorrhoea at the end of the chemotherapy in study TAX316.
In GEICAM 9805 study, amenorrhoea persisted into the follow-up period (median follow-up time of
10 years and 5 months) and was observed to be ongoing in 18 patients (3.4 %) in TAC arm and 5
patients (1.0 %) in FAC arm.
Acute leukaemia / Myelodysplastic syndrome
Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 After 10 years of follow up in study TAX316, acute leukaemia was reported in 4 of 744 TAC patients and in 1 of 736 FAC patients. Myelodysplastic syndrome was reported in 2 of 744 TAC patients and in 1 of 736 FAC patients. After 10 years of follow-up in GEICAM 9805 study, acute leukaemia occurred in 1 of 532 (0.2%) patients in TAC arm No cases were reported in patients in FAC arm. No patient was diagnosed with myelodysplastic syndrome in either treatment groups. Neutropenic complications Table below shows that the incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic infection was decreased in patients who received primary G-CSF prophylaxis after it was made mandatory in the TAC arm – GEICAM study. Neutropenic complications in patients receiving TAC with or without primary G-CSF prophylaxis Without primary G_CSF
With primary G-CSF
prophylaxis
prophylaxis
Neutropenia (Grade 4) Febrile neutropenia Neutropenic infection Neutropenic infection (Grade 3- 4)
Tabulated list of adverse reactions in gastric adenocarcinoma cancer for docetaxel 75mg/m² in
combination with cisplatin and 5-fluorouracil


MedDRA System Organ
Very common adverse
Common adverse reactions
reactions

Cardiac disorders
Arrhythmia (G3/4: 1.0%). Blood and lymphatic system Anaemia (G3/4: 20.9%); Neutropenia (G3/4: 83.2%); Thrombocytopenia (G3/4: Febrile neutropenia. Nervous system disorders Peripheral sensory neuropathy Dizziness (G3/4: 2.3%); Peripheral motor neuropathy (G3/4: 1.3%). Lacrimation increased (G3/4: 0%). Ear and labyrinth disorders Hearing impaired (G3/4: 0%). Gastrointestinal disorders Diarrhoea (G3/4: 19.7%); Constipation (G3/4: 1.0 %); Nausea (G3/4: 16%); Gastrointestinal pain (G3/4: Stomatitis (G3/4: 23.7%); Vomiting (G3/4: 14.3%). hagia (G3/4: 0.7%). Skin and subcutaneous tissue Alopecia (G3/4: 4.0%). Rash pruritus (G3/4: 0.7%); Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 Nail disorders (G3/4: 0.7%); Skin exfoliation (G3/4: 0%). Metabolism and nutrition Anorexia (G3/4: 11.7%). disorders
Infections and infestations
Neutropenic infection; Infection (G3/4: 11.7%). General disorders and Lethargy (G3/4: 19.0%); administration site conditions Fever (G3/4: 2.3%); Fluid retention (severe/life threatening: 1%). Immune system disorders Hypersensitivity (G3/4: 1.7).
Description of selected adverse reactions in gastric adenocarcinoma cancer for docetaxel 75 mg/m2
in combination with cisplatin and 5-fluorouracil
Blood and 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, (see section 4.2).
Tabulated list of adverse reactions in head and neck cancer for docetaxel 75mg/m² in combination
with cisplatin and 5-fluorouracil

• Induction chemotherapy followed by radiotherapy (TAX 323)
MedDRA System
Very common adverse
Common adverse
Uncommon adverse
Organ classes
reactions
reactions
reactions
Weight increased Cardiac disorders Myocardial ischemia Blood and lymphatic Febrile neutropenia Anaemia (G3/4:9.2) Thrombocytopenia (G3/4:5.2%) Dysgeusia/Parosmia Peripheral sensory neuropathy (G3/4:0.6%) Lacrimation increased Ear and labyrinth Hearing impaired Gastrointestinal Nausea (G3/4:0.6%) Stomatitis (G3/4;4.0%) Esophagitis/dysphagia/ Diarrhoea (G3/4:2.9%) Vomiting (G3/4:0.6%) Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 Dyspepsia Gastrointestinal haemorrhage (G3/4:0.6%) Skin and subcutaneous Alopecia (G3/4:10.9%). Rash pruritic tissue disorders Dry skin Skin exfoliative (G3/4:0.6%) Musculoskeletal and Myalgia (G3/4:0.6%) connective tissue disorders Metabolism and Anorexia (G3/4:0.6%) nutrition disorders
Infections and
Infection (G3/4:6.3%) Neutropenic infection Neoplasms benign, Cancer pain (G3/4: (incl cysts and polyps) Vascular disorders General disorders and Lethargy (G3/4:3.4%) administration site Pyrexia (G3/4:0.6%) Fluid retention Oedema Hypersensitivity (no • Induction chemotherapy followed by chemoradiotherapy (TAX 324)
MedDRA System
Very common adverse
Common adverse
Uncommon adverse
Organ classes
reactions
reactions
reactions
Weight decreased Weight increased Cardiac disorders Ischemia myocardial Blood and lymphatic Anaemia (G3/4:12.4%) Thrombocytopenia (G3/4:4.0%) Febrile neutropenia Dysgeusia/Parosmia Peripheral sensory Peripheral motor neuropathy (G3/4:1.2%) Lacrimation increased Ear and labyrinth Hearing impaired Gastrointestinal Nausea (G3/4: 13.9%); Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 Gastrointestinal pain Vomiting (G3/4:8.4%); Diarrhoea (G3/4: 6.8%); Gastrointestinal Esophagitis/dysphagia/ Constipation (G3/4:0.4%) Skin and subcutaneous Alopecia (G3/4:4.0%); tissue disorders Musculoskeletal and Myalgia (G3/4:0.4%) connective tissue disorders Metabolism and Anorexia (G3/4:12.0%) nutrition disorders
Infections and
Infection (G3/4:3.6%) Neutropenic infection infestations Neoplasms benign, Cancer pain (G3/4: (incl cysts and polyps) Vascular disorders General disorders and Lethargy (G3/4:4.0%) administration site Pyrexia (G3/4:3.6%) Fluid retention (G3/4:1.2) Oedema (G3/4:1.2%) Hypersensitivity disorders

Post-Marketing Experience:

Cardiac disorders
Rare cases of myocardial infarction have been reported.

Blood and lymphatic system disorders
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.

Nervous system disorders
Rare cases of convulsion or transient loss of consciousness have been observed with docetaxel
administration. These reactions sometimes appear during the infusion of the medicinal product.

Eye disorders
Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically
occurring during infusion of the medicinal product and in association with hypersensitivity reactions
have been reported. These were reversible upon discontinuation of the infusion. Cases of lacrimation
Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025
with or without conjunctivitis, as cases of lacrimal duct obstruction resulting in excessive tearing have
been rarely reported.
Cases of cystoid macular oedema (CMO) have been reported in patients treated with docetaxel.

Ear and labyrinth disorders
Rare cases of ototoxicity, hearing impaired and/or hearing loss have been reported.

Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome and cases of interstitial pneumonia/ pneumonitis, interstitial lung
disease, pulmonary fibrosis and respiratory failure sometimes fatal have rarely been reported. Rare
cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

Gastrointestinal disorders
Rare occurrences of dehydration as a consequence of gastrointestinal events, gastrointestinal
perforation, colitis ischaemic, colitis and neutropenic enterocolitis have been reported. Rare cases of
ileus and intestinal obstruction have been reported.

Skin and subcutaneous tissue disorders
Very rare cases of cutaneous lupus erythematosus and bullous eruptions such as erythema multiforme,
Stevens-Johnson syndrome, toxic epidermal necrolysis, have been reported with docetaxel. In some
cases concomitant factors may have contributed to the development of these effects. Sclerodermal-
like changes usually preceded by peripheral lymphoedema have been reported with docetaxel. Cases
of persisting alopecia have been reported.

Neoplasms benign, malignant and unspecified (incl cysts and polyps)
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.
Vascular disorders
Venous thromboembolic events have rarely been reported.
Renal and urinary disorders
Renal insufficiency and renal failure have been reported. In about 20% of these cases there were no
risk factors for acute renal failure such as concomitant nephrotoxic medicinal products and gastro-
intestinal disorders.

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
Cases of delayed infusion site adverse reactions with a "burn-like" appearance have been reported
with unknown frequency.
Metabolism and nutrition disorders
Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and
pneumonia.
Immune system disorders
Some cases of anaphylactic shock, sometimes fatal, have been reported.
Hepato-biliary disorders
Very rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders,
have been reported.
Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance,
Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website:
www.hpra.ie; E-mail: [email protected].
4.9
Overdose

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.
5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, ATC Code: L01CD 02
Preclinical data

Mechanism of action
Docetaxel is an antineoplastic agent which acts by promoting the assembly of tubulin into stable
microtubules and inhibits their disassembly which leads to a marked decrease of free tubulin. The
binding of docetaxel to microtubules does not alter the number of protofilaments.
Docetaxel has been shown in vitro to disrupt the microtubular network in cells which is essential for
vital mitotic and interphase cellular functions.
Pharmacodynamic effects
Docetaxel was found to be cytotoxic in vitro against various murine and human tumour cell lines and
against freshly excised human tumour cells in clonogenic assays. Docetaxel achieves high
intracellular concentrations with a long cell residence time. In addition, docetaxel was found to be
active on some but not all cell lines over expressing the p-glycoprotein which is encoded by the
multidrug resistance gene. In vivo, docetaxel is schedule independent and has a broad spectrum of
experimental antitumour activity against advanced murine and human grafted tumours.

Clinical efficacy and safety

Breast cancer

Docetaxel in combination with doxorubicin and cyclophosphamide: adjuvant therapy
Patients with operable node-positive breast cancer (TAX 316)

Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 Data from a multicenter open label randomized study support the use of docetaxel for the adjuvant treatment of patients with operable node-positive breast cancer and KPS ≥ 80%, between 18 and 70 years of age. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclosphosphamide 500 mg/m2 (FAC arm). Both regimens were administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion, all other medicinal products were given as intravenous bolus on day one. G-CSF was administered as secondary prophylaxis to patients who experienced complicated neutropenia (febrile neutropenia, prolonged neutropenia, or infection). Patients on the TAC arm received antibiotic prophylaxis with ciprofloxacin 500 mg orally twice daily for 10 days starting on day 5 of each cycle, or equivalent. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC. Two interim analyses and one final analysis were performed. The first interim analysis was planned 3 years after the date when half of study enrollment was done. The second interim analysis was done after 400 DFS events had been recorded overall, which led to a median follow-up of 55 months. The final analysis was performed when all patients had reached their 10-year follow-up visit (unless they had a DFS event or were lost to follow- up before). Disease-free survival (DFS) was the primary efficacy endpoint and Overall survival (OS) was the secondary efficacy endpoint. A final analysis was performed with an actual median follow up of 96 months. Significantly longer disease-free survival for the TAC arm compared to the FAC arm was demonstrated. Incidence of relapses at 10 years was reduced in patients receiving TAC compared to those who received FAC (39% versus 45%, respectively) i.e. an absolute risk reduction by 6% (p=0.0043). Overall survival at 10 years was also significantly increased with TAC compared to FAC (76% versus 69%, respectively) i.e. an absolute reduction of the risk of death by 7% (p = 0.002). As the benefit observed in patients with 4+ nodes was not statistically significant on DFS and OS, the positive benefit/risk ratio for TAC in patients with 4+ nodes was not fully demonstrated at the final analysis.Overall, the study results demonstrate a positive benefit risk ratio for TAC compared to FAC. TAC-treated patient subsets according to prospectively defined major prognostic factors were analyzed. Disease Free Survival
Overall Survival
patients
No of positive
0.68-0.93 0.0043 *a hazard ratio of less than 1 indicates that TAC is associated with a longer disease-free survival and overall survival compared to FAC Patients with operable node-negative breast cancer eligible to receive chemotherapy (GEICAM 9805) Data from a multicenter open label randomized trial support the use of docetaxel for the adjuvant treatment of patients with operable node-negative breast cancer eligible to receive chemotherapy. 1060 patients were randomized to receive either docetaxel 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (539 patients in TAC arm), or doxorubicin Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclosphosphamide 500 mg/m2 (521 patients in FAC arm), as adjuvant treatment of operable node-negative breast cancer patients with high risk of relapse according to 1998 St. Gallen criteria (tumour size >2 cm and/or negative ER and PR and/or high histological/nuclear grade (grade 2 to 3) and /or age <35 years). Both regimens were administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion, all other drugs were given intraveinously on day 1 every three weeks. Primary prophylactic G-CSF was made mandatory in TAC arm after 230 patients were randomized. The incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic infection was decreased in patients who received primary G-CSF prophylaxis (see section 4.8). In both arms, after the last cycle of chemotherapy, patients with ER+ and/or PgR+ tumours received tamoxifen 20 mg once a day for up to 5 years. Adjuvant radiation therapy was administered according to guidelines in place at participating institutions and was given to 57.3% of patients who received TAC and 51.2% of patients who received FAC. One primary analysis and one updated analysis were performed. The primary analysis was done when all patients had a follow-up of greater than 5 years (median follow-up time of 77 months). The updated analysis was performed when all patients had reached their 10-year (median follow up time of 10 years and 5 months) follow-up visit (unless they had a DFS event or were lost to follow-up previously). Disease-free survival (DFS) was the primary efficacy endpoint and Overall survival (OS) was the secondary efficacy endpoint. At the median follow-up time of 77 months, significantly longer disease-free survival for the TAC arm compared to the FAC arm was demonstrated. TAC-treated patients had a 32% reduction in the risk of relapse compared to those treated with FAC (hazard ratio = 0.68, 95% CI (0.49-0.93), p = 0.01). At the median follow up time of 10 years and 5 months, TAC treated patients had a 16,5% reduction in the risk of relapse compared to those treated with FAC (hazard ratio = 0.84, 95% CI (0.65-1.08), p=0.1646). DFS data were not statistically significant but were still associated with a positive trend in favour of TAC. At the median follow-up time of 77 months, overall survival (OS) was longer in the TAC arm with TAC-treated patients having a 24% reduction in the risk of death compared to FAC (hazard ratio = 0.76, 95% CI (0.46-1.26, p = 0.29). However, the distribution of OS was not significantly different between the 2 groups. At the median follow up time of 10 years and 5 months, TAC-treated patients had a 9% reduction in the risk of death compared to FAC-treated patients (hazard ratio = 0.91, 95% CI (0.63-1.32)). The survival rate was 93.7% in the TAC arm and 91.4 % in the FAC arm, at the 8-year follow-up timepoint, and 91.3 % in the TAC arm and 89 % in the FAC arm, at the 10-year follow-up timepoint. The positive benefit risk ratio for TAC compared to FAC remained unchanged. TAC-treated patient subsets according to prospectively defined major prognostic factors were analyzed in the primary analysis (at the median follow-up time of 77 months) (see table below): Subset analyses-Adjuvant Therapy in Patients with Node-negative Breast Cancer Study (Intent-tp-Treat Analysis)
Patieth subset
Number of patients in
Disease Free Survival
TAC group
Hazard ratio*
Age category 1
Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025
Age category 2
Hormonal receptor
Tumour size
Histological grade
Grade 1 (includes grade Menopausal status
*a hazard ratio (TAC/FAC) of less than 1 indicates that TAC is associated with a longer disease free survival compared to FAC, Exploratory subgroup analyses for disease-free survival for patients who meet the 2009 St. Gallen chemotherapy criteria – (ITT population) were performed and presented here below. Meeting relative indication for chemotherapya No 0.606 (0.42-0.877) 0.0072 TAC = docetaxel, doxorubicin and cyclophosphamide FAC = 5-fluorouracil, doxorubin and cyclophosphamide CI = confidence interval; ER= estrogen receptor PR = progesterone receptor aER/PR-negative or Grade 3 or tumour size >5 cm The estimated hazard ratio was using Cox proportional hazard model with treatment group as the factor. Docetaxel as single agent Two randomised phase III comparative studies, involving a total of 326 alkylating or 392 anthracycline failure metastatic breast cancer patients, have been performed with docetaxel at the recommended dose and regimen of 100 mg/m² every 3 weeks. In alkylating-failure patients, docetaxel was compared to doxorubicin (75 mg/m² every 3 weeks). Without affecting overall survival time (docetaxel 15 months vs. doxorubicin 14 months, p=0.38) or time to progression (docetaxel 27 weeks vs. doxorubicin 23 weeks, p=0.54), docetaxel increased response rate (52% vs. 37%, p=0.01) and shortened time to response (12 weeks vs. 23 weeks, Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 p=0.007). Three docetaxel patients (2%) discontinued the treatment due to fluid retention, whereas 15 doxorubicin patients (9%) discontinued due to cardiac toxicity (three cases of fatal congestive heart failure). In anthracycline-failure patients, docetaxel was compared to the combination of Mitomycin C and Vinblastine (12 mg/m² every 6 weeks and 6 mg/m² every 3 weeks). Docetaxel increased response rate (33% vs. 12%, p < 0.0001), prolonged time to progression (19 weeks vs. 11 weeks, p=0.0004) and prolonged overall survival (11 months vs. 9 months, p=0.01). During these two phase III studies, the safety profile of docetaxel was consistent with the safety profile observed in phase II studies (see section 4.8). An open-label, multicenter, randomized phase III study was conducted to compare docetaxel monotherapy and paclitaxel in the treatment of advanced breast cancer in patients whose previous therapy should have included an anthracycline. A total of 449 patients were randomized to receive either docetaxel monotherapy 100 mg/m² as a 1 hour infusion or paclitaxel 175 mg/m² as a 3 hour infusion. Both regimens were administered every 3 weeks. Without affecting the primary endpoint, overall response rate (32% vs 25%, p=0.10), docetaxel prolonged median time to progression (24.6 weeks vs 15.6 weeks; p < 0.01) and median survival (15.3 months vs 12.7 months; p=0.03). More grade 3/4 adverse events were observed for docetaxel monotherapy (55.4%) compared to paclitaxel (23.0%). Docetaxel in combination with doxorubicin One large randomized phase III study, involving 429 previously untreated patients with metastatic disease, has been performed with doxorubicin (50 mg/m²) in combination with docetaxel (75 mg/m²) (AT arm) versus doxorubicin (60 mg/m²) in combination with cyclophosphamide (600 mg/m²) (AC arm). Both regimens were administered on day 1 every 3 weeks. • Time to progression (TTP) was significantly longer in the AT arm versus AC arm, p=0.0138. The median TTP was 37.3 weeks (95%CI :33.4 - 42.1) in AT arm and 31.9 weeks (95%CI : 27.4 - 36.0) in AC arm. • Overall response rate (ORR) was significantly higher in the AT arm versus AC arm, p=0.009. The ORR was 59.3% (95%CI : 52.8 - 65.9) in AT arm versus 46.5% (95%CI : 39.8 - 53.2) in AC arm. In this study, AT arm showed a higher incidence of severe neutropenia (90% versus 68.6%), febrile neutropenia (33.3% versus 10%), infection (8% versus 2.4%), diarrhoea (7.5% versus 1.4%), asthenia (8.5% versus 2.4%), and pain (2.8% versus 0%) than AC arm. On the other hand, AC arm showed a higher incidence of severe anaemia (15.8% versus 8.5%) than AT arm, and, in addition, a higher incidence of severe cardiac toxicity: congestive heart failure (3.8% versus 2.8%), absolute LVEF decrease ≥ 20% (13.1 % versus 6.1%), absolute LVEF decrease ≥ 30% (6.2% versus 1.1%). Toxic deaths occurred in 1 patient in the AT arm (congestive heart failure) and in 4 patients in the AC arm (1 due to septic shock and 3 due to congestive heart failure). In both arms, quality of life measured by the EORTC questionnaire was comparable and stable during treatment and follow-up. Docetaxel in combination with trastuzumab Docetaxel in combination with trastuzumab was studied for the treatment of patients with metastatic breast cancer whose tumors overexpress HER2, and who previously had not received chemotherapy for metastatic disease. One hundred eighty six patients were randomized to receive docetaxel (100 mg/m2) with or without trastuzumab; 60% of patients received prior anthracycline based adjuvant chemotherapy. Docetaxel plus trastuzumab was efficacious in patients whether or not they had received prior adjuvant anthracyclines. The main test method used to determine HER2 positivity in Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 this pivotal study was immunohistochemistry (IHC). A minority of patients were tested using fluorescence in-situ hybridization (FISH). In this trial, 87% of patients had disease that was IHC 3+, and 95% of patients entered had disease that was IHC 3+ and/or FISH positive. Efficacy results are summarized in the following table: Parameter Docetaxel plus trastuzumab1 Median duration of response Median TTP (months) Median survival (months) TTP=time to progression; "ne" indicates that it could not be estimated or it was not yet reached.
1Full analysis set (intent-to-treat)
2 Estimated median survival
Docetaxel in combination with capecitabine
Data from one multicenter, randomised, controlled phase III clinical study support the use of
docetaxel in combination with capecitabine for treatment of patients with locally advanced or
metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this
study, 255 patients were randomised to treatment with docetaxel (75 mg/m2 as a 1 hour intravenous
infusion every 3 weeks) and capecitabine (1250 mg/m2 twice daily for 2 weeks followed by 1-week
rest period). 256 patients were randomised to treatment with docetaxel alone (100 mg/ m2 as a 1 hour
intravenous infusion every 3 weeks). Survival was superior in the docetaxel +capecitabine
combination arm (p=0.0126). Median survival was 442 days (docetaxel + capecitabine) vs. 352 days
(docetaxel alone). The overall objective response rates in the all-randomised population (investigator
assessment) were 41.6% (docetaxel + capecitabine) vs. 29.7% (docetaxel alone); p = 0.0058. Time to
progressive disease was superior in the docetaxel + capecitabine combination arm (p < 0.0001). The
median time to progression was 186 days (docetaxel + capecitabine) vs. 128 days (docetaxel alone).
Non-small cell lung cancer

Patients previously treated with chemotherapy with or without radiotherapy
In a phase III study, in previously treated patients, time to progression (12.3 weeks versus 7 weeks)
and overall survival were significantly longer for docetaxel at 75 mg/m² compared to Best Supportive
Care. The 1-year survival rate was also significantly longer in docetaxel (40%) versus BSC (16%).
There was less use of morphinic analgesic (p < 0.01), non-morphinic analgesics (p < 0.01), other
disease related medications (p=0.06) and radiotherapy (p < 0.01) in patients treated with docetaxel at
75 mg/m² compared to those with BSC.
The overall response rate was 6.8% in the evaluable patients, and the median duration of response was
26.1 weeks.
Docetaxel in combination with platinum agents in chemotherapy-naïve patients
In a Phase III study, 1218 patients with unresectable stage IIIB or IV NSCLC, with KPS of 70% or
greater, and who did not receive previous chemotherapy for this condition, were randomised to either
docetaxel (T) 75 mg/m2 as a 1 hour infusion immediately followed by cisplatin (Cis) 75 mg/ m2 over
30-60 minutes every 3 weeks, docetaxel 75 mg/ m2 as a 1 hour infusion in combination with
carboplatin (AUC 6 mg/ml•min) over 30-60 minutes every 3 weeks, or vinorelbine (V) 25 mg/ m2
Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/ m2 administered on day 1 of cycles repeated every 4 weeks. Survival data, median time to progression and response rates for two arms of the study are illustrated in the following table: Statistical Analysis Overall Survival (Primary end-point): Median Survival (months) Hazard Ratio: 1.122 [97.2% CI: 0.937; 1.342]* 1-year Survival (%) Treatment difference: [95% CI: -1.1; 12.0] 2-year Survival (%) Treatment difference: 6.2% [95% CI: 0.2; 12.3] Hazard Ratio: 1.032 [95% CI: 0.876; 1.216] Overall Response Rate Treatment difference: [95% CI: 0.7; 13.5] *: Corrected for multiple comparisons and adjusted for stratification factors (stage of disease and
region of treatment), based on evaluable patient population.
Secondary end-points included change of pain, global rating of quality of life by EuroQoL-5D, Lung
Cancer Symptom Scale, and changes in Karnosfky performance status. Results on these end-points
were supportive of the primary end-points results.
For docetaxel/carboplatin combination, neither equivalent nor non-inferior efficacy could be proven
compared to the reference treatment combination VCis.
Prostate cancer

The safety and efficacy of docetaxel in combination with prednisone or prednisolone in patients with
hormone refractory metastatic prostate cancer were evaluated in a randomized multicenter Phase III
study. A total of 1006 patients with KPS ≥ 60 were randomized to the following treatment groups: Docetaxel 75 mg/m2 every 3 weeks for 10 cycles. Docetaxel 30 mg/m2 administered weekly for the first 5 weeks in a 6 week cycle for 5 cycles. Mitoxantrone 12 mg/m2 every 3 weeks for 10 cycles. All 3 regimens were administered in combination with prednisone or prednisolone 5 mg twice daily, continuously. Patients who received docetaxel every three weeks demonstrated significantly longer overall survival compared to those treated with mitoxantrone. The increase in survival seen in the docetaxel weekly arm was not statistically significant compared to the mitoxantrone control arm. Efficacy endpoints for the docetaxel arms versus the control arm are summarized in the following table: Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 Endpoint Docetaxel Docetaxel Mitoxantrone every 3 weeks every week every 3 weeks Number of patients Median survival (17.0-21.2) (15.7-19.0) (14.4-18.6) Hazard ratio (0.619-0.936) (0.747-1.113) p-value†* Number of patients PSA** response rate (%) (39.5-51.3) (41.9-53.9) (26.4-37.3) <0.0001 Number of patients Pain response rate (%) (27.1-42.7) (24.0-39.1) (15.5-28.9) Number of patients Tumor response rate (%) (7.2-18.6) (4.2-14.2) (3.0-12.1) †Stratified log rank test *Threshold for statistical significance=0.0175 **PSA: Prostate-Specific Antigen Given the fact that docetaxel every week presented a slightly better safety profile than docetaxel every 3 weeks, it is possible that certain patients may benefit from docetaxel every week. No statistical differences were observed between treatment groups for Global Quality of Life. Gastric adenocarcinoma A multicenter, open-label, randomized study, was conducted to evaluate the safety and efficacy of docetaxel for the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for metastatic disease. A total of 445 patients with KPS>70 were treated with either docetaxel (T) (75 mg/m2 on day 1) in combination with cisplatin (C) (75 mg/m2 on day 1) and 5-fluorouracil (F) (750 mg/m2 per day for 5 days) or cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (1000 mg/m2 per day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF arm. The median number of cycles administered per patient was 6 (with a range of 1-16) for the TCF arm compared to 4 (with a range of 1-12) for the CF arm. Time to progression (TTP) was the primary endpoint. The risk reduction of progression was 32.1% and was associated with a significantly longer TTP (p=0.0004) in favor of the TCF arm. Overall survival was also significantly longer (p=0.0201) in favor of the TCF arm with a risk reduction of mortality of 22.7%. Efficacy results are summarized in the following table: Efficacy of docetaxel in the treatment of patients with gastric adenocarcinoma
Endpoint
Median TTP (months) Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 Median survival (months) 2-year estimate (%) Overall Response Rate (CR+PR) (%) Progressive Disease as Best Overall *Unstratified logrank test Subgroup analyses across age, gender and race consistently favored the TCF arm compared to the CF arm. A survival update analysis conducted with a median follow-up time of 41.6 months no longer showed a statistically significant difference although always in favour of the TCF regimen and showed that the benefit of TCF over CF is clearly observed between 18 and 30 months of follow up. Overall, quality of life (QoL) and clinical benefit results consistently indicated improvement in favor of the TCF arm. Patients treated with TCF had a longer time to 5% definitive deterioration of global health status on the QLQ-C30 questionnaire (p=0.0121) and a longer time to definitive worsening of Karnofsky performance status (p=0.0088) compared to patients treated with CF. Head and neck cancer • Induction chemotherapy followed by radiotherapy (TAX323) The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a phase III, multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO perfomance status 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m2 followed by cisplatin (P) 75 mg/m2 followed by 5-fluorouracil (F) 750 mg/m2 per day as a continuous infusion for 5 days. This regimen was administered every three weeks for 4 cycles in case at least a minor response (≥ 25% reduction in bidimensionally measured tumour size) was observed after 2 cycles. At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines for 7 weeks (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m2 followed by 5-fluorouracil (F) 1000 mg/m2 per day for 5 days. This regimen was administered every three weeks for 4 cycles in case at least a minor response (≥ 25% reduction in bidimensionally measured tumour size) was observed after 2 cycles. At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines for 7 weeks (PF/RT). Locoregional therapy with radiation was delivered either with a conventional fraction (1.8 Gy - 2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy), or accelerated/hyperfractionated regimens of radiation therapy (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week). A total of 70 Gy was recommended for accelerated regimens and 74 Gy for hyperfractionated schemes. Surgical resection was allowed following chemotherapy, before or after radiotherapy. Patients on the TPF arm received antibiotic prophylaxis Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025
with ciprofloxacin 500 mg orally twice daily for 10 days starting on day 5 of each cycle, or
equivalent. The primary endpoint in this study, progression-free survival (PFS), was significantly
longer in the TPF arm compared to the PF arm, p = 0.0042 (median PFS: 11.4 vs. 8.3 months
respectively) with an overall median follow up time of 33.7 months. Median overall survival was also
significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.5
months respectively) with a 28% risk reduction of mortality, p = 0.0128. Efficacy results are
presented in the table below:
Efficacy of docetaxel in the induction treatment of patients with inoperable locally advanced
SCCHN (Intent-to-Treat Analysis)
Endpoint
Docetaxel+
Cis+5-FU
Cis+5-FU
Median progression free survival (months) Adjusted Hazard ratio Median survival (months) Best overall response to chemotherapy (%)(95%CI) Best overall response to study treatment [chemotherapy +/- radiotherapy] (%) (95%CI) ***p-value Median duration of response to chemotherapy ± radiotherapy (months) A Hazard ratio of less than 1 favors docetaxel+Cisplatin+5-FU *Cox model (adjustment for Primary tumor site, T and N clinical stages and PSWHO) *** Chi-square test Quality of life parameters Patients treated with TPF experienced significantly less deterioration of their Global health score compared to those treated with PF (p=0.01, using the EORTC QLQ-C30 scale). Clinical benefit parameters The performance status scale, for head and neck (PSS-HN) subscales designed to measure understandability of speech, ability to eat in public, and normalcy of diet, was significantly in favor of TPF as compared to PF. Median time to first deterioration of WHO performance status was significantly longer in the TPF arm compared to PF. Pain intensity score improved during treatment in both groups Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 indicating adequate pain management. • Induction chemotherapy followed by chemoradiotherapy (TAX324) The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced
squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a randomized, multicenter
open-label, phase III, study (TAX324). In this study, 501 patients, with locally advanced SCCHN, and
a WHO performance status of 0 or 1, were randomized to one of two arms. The study population
comprised patients with technically unresectable disease, patients with low probability of surgical
cure and patients aiming at organ preservation. The efficacy and safety evaluation solely addressed
survival endpoints and the success of organ preservation was not formally addressed. Patients on the
docetaxel arm received docetaxel (T) 75 mg/m² by intravenous infusion on day 1 followed by
cisplatin (P) 100 mg/m² administered as a 30-minute to three-hour intravenous infusion, followed by
the continuous intravenous infusion of 5-fluorouracil (F) 1000 mg/m²/day from day 1 to day 4. The
cycles were repeated every 3 weeks for 3 cycles. All patients who did not have progressive disease
were to receive chemoradiotherapy (CRT) as per protocol (TPF/CRT). Patients on the comparator arm
received cisplatin (P) 100 mg/m² as a 30-minute to three-hour intravenous infusion on day 1 followed
by the continuous intravenous infusion of 5-fluorouracil (F) 1000 mg/m²/day from day 1 to day 5. The
cycles were repeated every 3 weeks for 3 cycles. All patients who did not have progressive disease
were to receive CRT as per protocol (PF/CRT).
Patients in both treatment arms were to receive 7 weeks of CRT following induction chemotherapy
with a minimum interval of 3 weeks and no later than 8 weeks after start of the last cycle (day 22 to
day 56 of last cycle). During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour
intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment
using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks, for a total dose of 70-72
Gy). Surgery on the primary site of disease and/or neck could be considered at anytime following
completion of CRT. All patients on the docetaxel-containing arm of the study received prophylactic
antibiotics. The primary efficacy endpoint in this study, overall survival (OS) was significantly longer
(log-rank test, p = 0.0058) with the docetaxel-containing regimen compared to PF (median OS: 70.6
versus 30.1 months respectively), with a 30% risk reduction in mortality compared to PF (hazard ratio
(HR) = 0.70, 95% confidence interval (CI) = 0.54-0.90) with an overall median follow up time of 41.9
months. The secondary endpoint, PFS, demonstrated a 29% risk reduction of progression or death and
a 22 month improvement in median PFS (35.5 months for TPF and 13.1 for PF). This was also
statistically significant with an HR of 0.71; 95% CI 0.56-0.90; log-rank test
p = 0.004. Efficacy results are presented in the table below:
Efficacy of docetaxel in the induction treatment of patients with locally advanced SCCHN
(Intent-to-Treat Analysis)
Endpoint
Docetaxel + Cis + 5-U
Cis + 5-FU
Median overall survival (months) Median PFS (months) Best overall response (CR+PR) to chemotherapy (%) Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 Best overall response (CR+PR) to study treatment [chemotherapy +/- chemoradiotherapy] (%) A Hazard ratio of less than 1 favors docetaxel + cisplation + fluorouracil *un-adjusted log-rank test **un-adjusted log-rank test, not adjusted for multiple comparisons ***Chi square test, not adjusted for multiple comparisons NA – not applicable Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with
docetaxel in all subsets of the paediatric population in breast cancer, non-small cell lung cancer,
prostated cancer, gastric carcinoma and head and neck cancer, not including type II and III less
differentiated nasopharyngeal carcinoma (see section 4.2 for information on paediatric use).
5.2
Pharmacokinetic properties

Absorption
The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20-
115 mg/m2 in Phase I studies. The kinetic profile of docetaxel is dose independent and 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 h, respectively. The late phase is due, in part, to a relatively slow efflux of docetaxel from
the peripheral compartment.
Distribution
Following the administration of a 100 mg/m2 dose given as a one hour infusion a mean peak plasma
level of 3.7 µg/ml was obtained with a corresponding AUC of 4.6 h.µg/ml. Mean values for total body
clearance and steady-state volume of distribution were 21 l/h/m2 and 113 l, respectively. Inter
individual variation in total body clearance was approximately 50%. Docetaxel is more than 95%
bound to plasma proteins.
Elimination
A study of 14C-docetaxel has been conducted in three cancer patients. Docetaxel was eliminated in
both the urine and faeces following cytochrome P450-mediated oxidative metabolism of the tert-butyl
ester group, within seven days, the urinary and faecal excretion accounted for about 6% and 75% of
the administered radioactivity, respectively. About 80% of the radioactivity recovered in faeces is
excreted during the first 48 hours as one major inactive metabolite and 3 minor inactive metabolites
and very low amounts of unchanged medicinal product.
Special populations

Age and gender
A population pharmacokinetic analysis has been performed with docetaxel in 577 patients.
Pharmacokinetic parameters estimated by the model were very close to those estimated from Phase I
studies. The pharmacokinetics of docetaxel were not altered by the age or sex of the patient.
Hepatic impairment
Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025 In a small number of patients (n=23) with clinical chemistry data suggestive of mild to moderate liver function impairment (ALT, AST ≥ 1.5 times the ULN associated with alkaline phosphatase ≥ 2.5 times the ULN), total clearance was lowered by 27% on average (see section 4.2). Fluid retention Docetaxel clearance was not modified in patients with mild to moderate fluid retention and there are no data available in patients with severe fluid retention. Combination therapy Doxorubicin
When used in combination, docetaxel does not influence the clearance of doxorubicin and the plasma
levels of doxorubicinol (a doxorubicin metabolite). The pharmacokinetics of docetaxel, doxorubicin
and cyclophosphamide were not influenced by their coadministration.
Capecitabine
Phase I study evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice
versa showed no effect by capecitabine on the pharmacokinetics of docetaxel (Cmax and AUC) and no
effect by docetaxel on the pharmacokinetics of a relevant capecitabine metabolite 5'-DFUR.
Cisplatin
Clearance of docetaxel in combination therapy with cisplatin was similar to that observed following
monotherapy. The pharmacokinetic profile of cisplatin administered shortly after docetaxel infusion is
similar to that observed with cisplatin alone.
Cisplatin and 5-fluorouracil
The combined administration of docetaxel, cisplatin and 5-fluorouracil in 12 patients with solid
tumors had no influence on the pharmacokinetics of each individual medicinal product.
Prednisone and dexamethasone
The effect of prednisone on the pharmacokinetics of docetaxel administered with standard
dexamethasone premedication has been studied in 42 patients.
Prednisone
No effect of prednisone on the pharmacokinetics of docetaxel was observed.

5.3
Preclinical safety data

The carcinogenic potential of docetaxel has not been studied.
Docetaxel has been shown to be mutagenic in the in vitro micronucleus and chromosome aberration
test in CHO-K1 cells and in the in vivo micronucleus test in the mouse. However, it did not induce
mutagenicity in the Ames test or the CHO/HGPRT gene mutation assay. These results are consistent
with the pharmacological activity of docetaxel.
Undesirable effects on the testis observed in rodent toxicity studies suggest that docetaxel may impair
male fertility.

6.
PHARMACEUTICAL PARTICULARS
List of excipients
Citric acid anhydrous Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025
Povidone
Polysorbate 80
Ethanol absolute
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
6.6.
6.3 Shelf life

Unopened vial:
24 months.
After opening of the vial:
Each vial is for single use and should be used immediately after opening. If not used immediately, in-
use storage times and conditions are the responsibility of the user.
Once added to the infusion bag:
From a microbiological point of view, reconstitution/dilution must take place in controlled and aseptic
conditions and the medicinal product should be used immediately. If not used immediately, in-use
storage times and conditions are the responsibility of the user.
Once added as recommended into the infusion bag, the docetaxel infusion solution, if stored below
25°C, in non-PVC bags, is stable for 8 hours. It should be used within 8 hours (including the one hour
infusion intravenous administration).
In addition, physical and chemical in-use stability of the infusion solution prepared as recommended
has been demonstrated for 3 days when stored between 2 to 8°C protected from light.
Docetaxel infusion solution is supersaturated, therefore may crystallize over time. If crystals appear,
the solution must no longer be used and shall be discarded.
6.4 Special precautions for storage
Store below 25°C.
Store in the original package in order to protect from light.
Do not refrigerate or freeze.
For storage conditions after opening of the vials and of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Colourless glass vial (type I) closed with a bromobutyl rubber stopper (type I) sealed with aluminium
cap with polypropylene disc. Vial will be packed with or without a protective plastic overwrap.
Pack sizes:
1 x 1 ml single dose vial
1 x 4 ml single dose vial
1 x 7 ml single dose vial
1 x 8 ml single dose vial
Not all pack sizes may be marketed.
Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025

6.6 Special precautions for disposal and other handling
Docetaxel Actavis is an antineoplastic agent and, as with other potentially toxic compounds, caution
should be exercised when handling it and preparing Docetaxel Actavis solutions. Cytotoxic agents
should be prepared for administration only by personnel who have been trained in the safe handling of
such preparations. Refer to local cytotoxic guidelines before commencing. The use of gloves is
recommended. If Docetaxel Actavis concentrate or infusion solution should come into contact with
skin, wash immediately and thoroughly with soap and water. If Docetaxel Actavis concentrate or
infusion solution should come into contact with mucous membranes, wash immediately and
thoroughly with water.

Preparation of the solution for infusion
More than one vial of Docetaxel Actavis 20 mg/ml concentrate for solution for infusion may be
necessary to obtain the required dose for individual patients. Based on the required dose for the
patient expressed in mg, aseptically withdraw the corresponding volume of 20 mg/ml docetaxel from
the appropriate number of vials using graduated syringes fitted with a needle. For example, a dose of
140 mg docetaxel would require 7 ml of Docetaxel Actavis 20 mg/ml concentrate for solution for
infusion.
For doses below 192 mg of docetaxel, inject the required volume of Docetaxel Actavis 20 mg/ml
concentrate for solution for infusion into a 250 ml infusion bag or bottle containing either 250 ml of
50 mg/ml (5%) glucose solution for infusion or 9 mg/ml (0.9%) sodium chloride solution for infusion.
For doses exceeding 192 mg of docetaxel more than 250 ml of the infusion solution is required, as the
maximum concentration of docetaxel is 0.74 mg per ml of infusion solution.
Mix the infusion bag or bottle manually using a rocking motion. The diluted solution should be used
within 8 hours and should be aseptically administered as a 1-hour infusion at room temperature and
normal lighting conditions.
Administration
For instructions on administration see Section 4.2.
As with all parenteral products, this medicinal product should be visually inspected prior to use and
solutions containing a precipitate should be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf.
Reykjavikurvegi 76-78
220 Hafnarfjordur
Iceland

8. MARKETING AUTHORISATION NUMBER

PA1380/84/1

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorization: 24th September 2010
Docetaxel Actavis 20 mg/ml concentrate for solution for infusion V025
10. DATE OF REVISION OF THE TEXT
November 2015

Source: http://actavis.ie/NR/rdonlyres/66E840E4-7B7F-4570-BF87-BB32A5C4FEC6/34823/ieDocetaxelSmPCv10_20160421.pdf