DOCETAXEL ACTAVIS 20 MG / ML CONCENTRATE FOR SOLUTION FOR INFUSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Docetaxel Actavis 20mg/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

Each single dose vial contains 40 % (w/v) ethanol absolute Each 1 ml single dose vial contains 400 mg ethanol absolute.

Each 4 ml single dose vial contains 1600 mg ethanol absolute. Each 7 ml single dose vial contains 2800 mg ethanol absolute. Each 8 ml single dose vial contains 3200 mg ethanol absolute.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion

The concentrate is a clear, pale yellow solution.

4.1 Therapeutic indications

Breast cancer

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion 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 20mg/ml Concentrate for Solution for Infusion 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 20mg/ml Concentrate for Solution for Infusion 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 20mg/ml Concentrate for Solution for Infusion in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer whose tumours over express HER2 and who previously have not received chemotherapy for metastatic disease.

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion 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 20mg/ml Concentrate for Solution for Infusion is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior chemotherapy.

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion 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 20mg/ml Concentrate for Solution for Infusion in combination with prednisone or prednisolone is indicated for the treatment of patients with castration-resistant metastatic prostate cancer.

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion in combination with androgen-deprivation therapy (ADT), with or without prednisone or prednisolone, is indicated for the treatment of patients with metastatic hormonesensitive prostate cancer.

Gastric adenocarcinoma

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion 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 20mg/ml Concentrate for Solution for Infusion 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).

Posology

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. 8mg BID) for 3 days starting 1 day prior to docetaxel administration, unless contraindicated, can be used (see section 4.4).

For metastatic castration-resistant prostate cancer, given the concurrent use of prednisone or prednisolone the recommended premedication regimen is oral dexamethasone 8mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.4).

For metastatic hormone-sensitive prostate cancer, irrespective of the concurrent use of prednisone or prednisolone, the recommended premedication regimen is oral dexamethasone 8 mg 12 hours, 3 hours, and 1 hour before docetaxel infusion (see section 4.4).

Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities. 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 75mg/m2 administered 1-hour after doxorubicin 50mg/m2 and cyclophosphamide 500mg/m2 every 3 weeks for 6 cycles (TAC regimen) (see also Dose adjustments during treatment).

For the treatment of patients with locally advanced or metastatic breast cancer, the recommended dose of docetaxel is 100 mg/m2 in monotherapy. In first-line treatment, docetaxel 75mg/m2 is given in combination therapy with doxorubicin (50mg/m2).

2

In combination with trastuzumab the recommended dose of docetaxel is 100mg/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 dose and administration, see trastuzumab summary of product characteristics.

In combination with capecitabine, the recommended dose of docetaxel is 75mg/m2 every three weeks, combined with capecitabine at 1250mg/m2 twice daily (within 30 minutes after a meal) for 2 weeks followed by a 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 75mg/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 75mg/m2 as a single agent.

Prostate cancer

Metastatic castration-resistant prostate cancer

The recommended dose of docetaxel is 75mg/m2. Prednisone or prednisolone 5mg orally twice daily is administered continuously (see section 5.1).

Metastatic hormone-sensitive prostate cancer

The recommended dose of docetaxel is 75 mg/m2 every 3 weeks for 6 cycles. Prednisone or prednisolone 5 mg orally twice daily may be administered continuously.

Gastric adenocarcinoma

The recommended dose of docetaxel is 75mg/m2 as a 1 hour infusion, followed by cisplatin 75mg/m2, as a 1 to 3 hour infusion (both on day 1 only), followed by 5-fluorouracil 750mg/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 haematological toxicities (see also Dose 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 haematological 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 75mg/m2 as a 1 hour infusion followed by cisplatin 75mg/m2 over 1 hour, on day one, followed by 5-fluorouracil as a continuous infusion at 750mg/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 75mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100mg/m2 administered as a 30-minute to 3 hour infusion, followed by 5-fluorouracil 1000mg/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 > 1,500cells/mm3­. In

3 patients who experienced either febrile neutropenia, neutrophil count < 500cells/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 100mg/m2 to 75mg/m2 and/or from 75 to 60mg/m2 If the patient continues to experience these reactions at 60mg/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 infection should have their docetaxel dose reduced to 60mg/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 60mg/m2.

In combination with cisplatin

For patients who are dosed initially at docetaxel 75mg/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-haematologic toxicities, the docetaxel dosa in subsequent cycles should be reduced to 65mg/m2. For cisplatin dose adjustments, see the corresponding 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 Grade 3 toxicity, at any time during the treatment cycle, delay treatment until resolved to Grade 0–1, and then resume treatment with docetaxel 55mg/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 60mg/m2. If subsequent episodes of complicated neutropenia occur the docetaxel dose should be reduced from 60 to 45mg/m2. In case of Grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 to 60mg/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).

Recommended dose modifications for toxicities in patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (5-FU):

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 100mg/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 study excluded patients with ALT and/or AST > 1.5 x ULN associated with alkaline phosphatase > 2.5 x 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.

Paediatric population

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

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

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).

Method of administration

For instructions on preparation and administration of the product, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with baseline neutrophil count of < 1,500 cells/mm3.

Patients with severe liver impairment (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 16mg per day (e.g. 8mg 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 8mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.2).

Haematology

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 prophylaxis. Primary G-CSF prophylaxis should be considered in patients who receive adjuvant therapy with TAC for breast cancer to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TAC should be closely monitored (see sections 4.2 and 4.8).

Gastrointestinal reactions

Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications. Although majority of cases occurred during the first or second cycle of docetaxel containing regimen, enterocolitis could develop at any time, and could lead to death as early as on the first day of onset. Patients should be closely monitored for early manifestations of serious gastrointestinal toxicity (see sections 4.2, 4.4 Haematology, 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 localised 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.

Patients who have previously experienced a hypersensitivity reaction to paclitaxel may be at risk to develop hypersensitivity reaction to docetaxel, including more severe hypersensitivity reaction. These patients should be closely monitored during initiation of docetaxel therapy.

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 desquamation which lead to interruption or discontinuation of docetaxel treatment were reported (see section 4.2).

Severe Cutaneous Adverse Reactions (SCARs) such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP) have been reported with docetaxel treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and closely monitored. If signs and symptoms suggestive of these reactions appear discontinuation of docetaxel should be considered.

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 100mg/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 75mg/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 dosereduction 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 x ULN associated with alkaline phosphatase > 2.5 x 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 20mg/ml Concentrate for Solution for Infusion contains ethanol (400mg 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.

Ventricular arrhythmia including ventricular tachycardia (sometimes fatal) has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/ or cyclophosphamide (see section 4.8).

Baseline cardiac assessment is recommended.

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).

Second primary malignancies

Second primary malignancies have been reported when docetaxel was given in combination with anticancer treatments known to be associated with second primary malignancies. Second primary malignancies (including acute myeloid leukemia, myelodysplastic syndrome and non-Hodgkin lymphoma) may occur several months or years after docetaxel-containing therapy. Patients should be monitored for second primary malignancies (see section 4.8).

Tumour Lysis Syndrome

Tumour lysis syndrome has been reported with docetaxel after the first or the second cycle (see section 4.8). Patients at risk of tumour lysis syndrome (e.g. with renal impairment, hyperuricemia, bulky tumour, rapid progression) should be closely monitored. Correction of dehydration and treatment of high uric acid levels are recommended prior to initiation of treatment.

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).

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).

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

Cautions for use in adjuvant treatment of breast cancer

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

Cautions for use in castration-resistant prostate cancer

Of the 333 patients treated with docetaxel every three weeks in a prostate cancer study(TAX 327), 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 oedema occurred at rates > 10% higher in patients who were 75 years of age or greater versus less than 65 years.

Cautions for use in hormone-sensitive prostate cancer

Of the 545 patients treated with docetaxel every 3 weeks in a hormone-sensitive prostate cancer study (STAMPEDE), 296 patients were 65 years of age or older, and 48 patients were 75 years of age or older. More patients aged >65 years in the docetaxel arm reported hypersensitivity reaction, neutropenia, anaemia, fluid retention, dyspnea, and nail changes when compared to the patients aged less than 65 years. None of these increases in frequency reached 10% difference with the control arm. In patients who were 75 years of age or older, when compared to younger patients, neutropenia, anaemia, diarrhea, dyspnea and upper respiratory tract infection were reported with a greater incidence (at least 10% higher).

Cautions for use in gastric adenocarcinoma cancer

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.

Delayed infusion site adverse reactions

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.

Excipients

Ethanol

This medicinal product contains 400mg ethanol (alcohol) per ml concentrate(40 % (w/v)).

A dose of 100 mg/m2 of this medicine administered to an adult weighing 70 kg would result in exposure to 51 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 8.6 mg/100 ml.

For comparison, for an adult drinking a glass of wine or 500 ml of beer, the BAC is likely to be about 50 mg/100 ml.

Because this medicine is usually given slowly over 1 hour, the effects of alcohol may be reduced.

Co-administration with medicines containing e.g. propylene glycol or ethanol may lead to accumulation of ethanol and induce adverse effects, in particular in young children with low or immature metabolic capacity.

Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women and children. Consideration should be given to possible effects on the central nervous system.

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 medicinal product 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.

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 20mg/ml Concentrate for Solution for Infusion contains 400 mg ethanol per ml concentrate. The amount of alcohol in this medicinal product may alter the effects of other medicinal products.

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.

The amount of alcohol in this medicinal product and the side effects of the product may impair the ability to drive or use machines (see sections 4.4 and 4.8). Therefore, patients should be warned of the potential impact of the amount of alcohol and the side effects of this medicinal product on the ability to drive or use machines, and be advised not to drive or use machines if they experience these side effects during treatment.

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 100mg/m2 and 75mg/m2 of docetaxel as a single agent respectively

258 patients who received docetaxel in combination with doxorubicin

406 patients who received docetaxel in combination with cisplatin

92 patients treated with docetaxel in combination with trastuzumab,

255 patients who received docetaxel in combination with capecitabine,

332 patients (TAX327) who received docetaxel in combination with prednisone or prednisolone (clinically important treatment related adverse events are presented).

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).

545 patients (STAMPEDE study) who received docetaxel in combination with

prednisone or prednisolone and ADT.

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 the 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).

For combination with ADT and with prednisone or prednisolone (STAMPEDE study), adverse events occurring over the 6 cycles of treatment with docetaxel and having at least 2% higher incidence in the docetaxel treatment arm by comparison to the control arm, are presented, using the CTCAE grading scale.

The following adverse reactions are frequently observed with docetaxel:

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).

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 paraesthesia, 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).

Tabulated list of adverse reactions in breast cancer for docetaxel 100 mg/m2 single agent:

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 100mg/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

2 The median cumulative dose to treatment discontinuation was more than 1,000mg/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: 818.9mg/m2) in patients with premedication compared with patients without premedication (median cumulative dose: 489.7mg/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:

Tabulated list of adverse reactions in breast cancer for docetaxel 75mg/m2 in combination with doxorubicin:

Tabulated list of adverse reactions in non-small cell lung cancer for docetaxel 75mg/m2 in combination with cisplatin:

Tabulated list of adverse reactions in breast cancer for docetaxel 100mg/m2 in combination with trastuzumab:

Description of selected adverse reactions in breast cancer for docetaxel 100 mg/m2 in combination with trastuzumab

Blood and lymphatic system disorders

Very common: Haematological toxicity was increased in patients receiving trastuzumab and docetaxel, compared with docetaxel alone (32% grade 3/4 neutropenia versus 22%, using NCI-CTC criteria). Note that this is likely to be an underestimate since docetaxel alone at a dose of 100mg/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).

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.

Tabulated list of adverse reactions in breast cancer for docetaxel 75mg/m2 in combination with capecitabine:

Tabulated list of adverse reactions in metastatic castration-resistant prostate cancer for docetaxel 75mg/m2 in combination with prednisone or prednisolone:

Tabulated list of adverse reactions in high-risk locally advanced or metastatic hormonesensitive prostate cancer for docetaxel 75 mg/m2 in combination with prednisone or prednisolone and ADT (STAMPEDE study)

a From the GETUG AFU15 study

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

Description of selected adverse reactions for adjuvant therapy with docetaxel 75 mg/m2 in combination with doxorubicin and cyclophosphamide in patients with nodepositive (TAX 316) and node-negative (GEICAM 9805) breast cancer

Nervous system disorders

In study TAX316 peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2 %) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm.

In GEICAM 9805 study peripheral sensory neuropathy that started during the treatment period persisted into the follow-up period in 10 patients (1.9%) in TAC arm and 4 patients (0.8 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), peripheral sensory neuropathy was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

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. At the end of the follow-up period (actual median follow-up time of 10 years and 5 months), no patients had CHF in TAC arm and1 patient in TAC arm died because of dilated cardiomyopathy, and CHF was observed to be ongoing in 1 patient (0.2%) in FAC arm.

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 (92.3%) and 645 of 736 FAC patients (87.6%). At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In GEICAM 9805 study, alopecia that started during the treatment period and persisted into the follow-up period 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. At the end of the follow-up period (median follow-up time of 10 years and 5 months), alopecia was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Reproductive system and breast disorders

In TAX316 amenorrhoea that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 202 of 744 TAC patients (27.2%) and 125 of 736 FAC patients (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%).

In GEICAM 9805 study amenorrhoea that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 18 patients (3.4 %) in TAC arm and 5 patients (1.0 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), amenorrhoea was observed to be ongoing in 7 patients (1.3%) in TAC arm, and in 4 patients (0.8%) in FAC arm.

General disorders and administration site conditions

In study TAX316, peripheral oedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16.0%) and 23 of 736 FAC patients (3.1%). At the end of the follow-up period (actual median follow-up time of 8 years), peripheral oedema was ongoing in19 TAC patients (2.6%) and 4 FAC patients (0.5%).

In study TAX316 lymphoedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1.5%) and 1 of 736 FAC patients (0.1%). At the end of the follow-up period (actual median follow-up time of 8 years), lymphoedema was observed to be ongoing in 6 TAC patients (0.8%) and 1 FAC patient (0.1%).

In study TAX316 asthenia that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 236 of 744 TAC patients (31.7%) and 180 of 736 FAC patients (24.5%). At the end of the follow-up period (actual median follow-up time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In study GEICAM 9805 peripheral oedema that started during the treatment period persisted into the follow-up period in 4 patients (0.8%) in TAC arm and in 2 patients (0.4%) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), no patients (0%) in TAC arm had peripheral oedema and it was observed to be ongoing in 1 patient (0.2%) in FAC arm. Lymphoedema that started during the treatment period persisted into the follow-up period in 5 patients (0.9%) in TAC arm and 2 patients (0.4 %) in FAC arm. At the end of the follow-up period, lymphoedema was observed to be ongoing in 4 patients (0.8%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Asthenia that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 12 patients (2.3 %) in TAC arm and 4 patients (0.8 %) in FAC arm. At the end of the follow-up period, asthenia was observed to be ongoing in 2 patients (0.4%) in TAC arm, and in 2 patients (0.4%) in FAC arm.

Acute leukaemia / Myelodysplastic syndrome

After 10 years of follow up in study TAX316, acute leukaemia was reported in 3 of 744 TAC patients (0.4%) and in 1 of 736 FAC patients (0.1%). One TAC patient (0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of 8 years). Myelodysplastic syndrome was reported in 2 of 744 TAC patients (0.3%) and in 1 of 736 FAC patients (0.1%).

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 (GEICAM 9805)

Tabulated list of adverse reactions in gastric adenocarcinoma cancer for docetaxel 75mg/m2 in combination with cisplatin and 5-fluorouracil:

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)

Induction chemotherapy followed by chemoradiotherapy (TAX 324)

Post-Marketing Experience:

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Second primary malignancies (frequency not known), including non-Hodgkin lymphoma have been reported in association with docetaxel when used in combination with other anticancer treatments known to be associated with second primary malignancies. Acute myeloid leukemia and myelodysplastic syndrome have been reported (frequency uncommon) in pivotal clinical studies in breast cancer with TAC regimen.

Blood and lymphatic system disorders

Bone marrow suppression and other haematologic adverse reactions have been reported. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported.

Immune system disorders

Some cases of anaphylactic shock, sometimes fatal, have been reported. Hypersensitivity reactions (frequency not known) have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.

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 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.

Cardiac disorders

Rare cases of myocardial infarction have been reported. Ventricular arrhythmia including ventricular tachycardia (frequency not known), sometimes fatal, has been

reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/ or cyclophosphamide.

Vascular disorders

Venous thromboembolic events have rarely 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 cases of enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, have been reported with a potential fatal outcome (frequency not known).

Rare occurrences of dehydration have been reported as a consequence of gastrointestinal events including enterocolitis and gastrointestinal perforation. Rare cases of ileus and intestinal obstruction have been reported.

Hepato-biliary disorders

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

Skin and subcutaneous tissue disorders

Cases of cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme and severe cutaneous adverse reactions such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP), 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 permanent alopecia (frequency not known) have 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 gastrointestinal disorders.

General disorders and administration site conditions

Radiation recall phenomena have rarely been reported.

Injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) has been observed at the site of previous extravasation (frequency not known).

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 electrolyte imbalance have been reported. Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and pneumonia.

Hypokalaemia, hypomagnesaemia, and hypocalcaemia were observed, usually in association with gastrointestinal disorders and in particular with diarrhoea. Tumour lysis syndrome, potentially fatal, has been reported (frequency not known).

Musculoskeletal disorder

Myositis has been reported with docetaxel (frequency not known).

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 the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties5.1   Pharmacodynamic properties

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

6.1 List of excipients

Citric acid

Povidone

Polysorbate 80

Ethanol absolute

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 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 × 1 ml single dose vial

1 × 4 ml single dose vial

1 × 7 ml single dose vial 1 × 8 ml single dose vial

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion is an antineoplastic agent and, as with other potentially toxic compounds, caution should be exercised when handling it and preparing Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion solutions. Cytotoxic agents should be prepared for administration only by personnel who have been trained in the safe handling of such preparations. Pregnant personnel should not handle cytotoxic agents. Refer to local cytotoxic guidelines before commencing. The use of gloves is recommended. If Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion concentrate or infusion solution should come into contact with skin, wash immediately and thoroughly with soap and water. If Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion concentrate or infusion solution should come into contact with mucous membranes, wash immediately and thoroughly with water. In the event of spillage, trained personnel wearing appropriate personal protective equipment should remove the maximum amount of material by use of a cytotoxic drug spill kit or designated absorbent materials. The area should be rinsed with copious amounts of water. All contaminated cleaning materials should be disposed of in accordance with local requirements.

Preparation of the solution for infusion

More than one vial of Docetaxel Actavis 20mg/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 20mg/ml Concentrate for Solution for Infusion.

For doses below 192 mg of docetaxel, inject the required volume of Docetaxel Actavis 20mg/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.

Reykjavikurvegur 76–78,

220 Hafnarfjôrôur

Iceland

8 MARKETING AUTHORISATION NUMBER(S)

PL 30306/0261

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/08/2010