4.4     Special warnings and precautions for use

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).

Leukaemia

In the docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed myelodysplasia or myeloid leukaemia requires haematological follow‑up.

 

4.8     Undesirable effects

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.

Nervous system disorders

Paraesthesia; Headache; Dysgeusia; Hypoaesthesia

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 and 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.

 

Post-marketing experience

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

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

 

 

 

Section 4.2 title added:-

 

Posology

 

Section 4.2 title removed:-

 

Recommended dose

 

Wording changed in paragraph:-

 

Prophylactic G CSF may be used to mitigate the risk of haematological toxicities.

 

Method of administration

 

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

 

Section 4.4 added:-

 

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).

 

Section 4.7 wording added into paragraph:-

 

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 added and reworded.:-

 

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

 

Have been reported including enterocolitis

Section 4.4 added:-

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.

Section 4.4 removed:-

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 (see section 4.7).

Section 4.5 added:-

The amount of alcohol in this medicinal product may alter the effects of other medicinal products.

Section 4.7 added:-

alcohol in this medicinal product

Section  4.7 removed:-

ethanol Taxotere

Section 4.8 added:-

Hypersensitivity reactions (frequency not known) have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel

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).

4.4

Added:-

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. 

 

4.8

Deletions and additions as follows:-

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.

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 and 1 patient in TAC arm died because of dilated cardiomyopathy, and CHF was observed to be ongoing in 1 patient (0.2%) in FAC arm.

(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. 

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 (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 in 19 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%)

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.

Type II CCDS V31- the change concerns the update of section 4.8 of the SPC to update the safety information related to electrolyte imbalance under the section metabolism and nutrition disorders. The PIL will be updated accordingly.

Update to reference permanent alopecia - frequency unknown

SPC updated to further warn about the risks with alcohol content.

Section 4.4 updated to include new information under the heading 'Excipients'.
Section 4.7 updated to include information about the amount of ethanol which may impair the ability to drive or use machines.

Type II to update SPC sections 4.8 and 5.1 to reflect the results of study GEICAM 9805 after 10-year follow-up (v115).

EMEA/H/C/000073/II/0114: Bulk Type II variation to update sections 4.4 & 4.5 of the SmPC in order to add a warning and update the safety information on interactions with CYP3A4 inhibitors further to the PRAC assessment of a signal.  At the same time inconsistencies on the number and grade of alopecia adverse reactions have been corrected in section 4.8 and the list of local representatives has been updated in the Leaflet.

CCDS v28. Update of section 4.4 to add a warning on cystoid macular oedema based on the results of safety cumulative reviews conducted by the MAH and section 4.8 of the SmPC to include cystoid macular oedema and hyponatraemia in the list of adverse reactions. The package leaflet is updated accordingly.
In addition the product information is revised in line with the QRD template version 9 and the local representative for Croatia is added in the Package Leaflet.

Type IIC Bulk - CCDS v27 (v110) to add a warning related to respiratory disorders and include Interstitial pneumonitis, Interstritial lung disease and pulmonary fibrosis as new adverse reactions.

Section 6.3, the shelf-life has been extended from 2 to 3 years.

Ammendment of the SPC following assessment of PSUR 23-28.

Section 4.1 Addition of a new indication
Section 4.2 inclusion of the new indication
Section 4.4 In patients treated with Docetaxel in combination with doxorubicin & cyclophoshamide special warning added for neutropenia
Section 4.8 Geicam study information added & new indication side effects (medra classification)
Section 5.1 Clinical data added for new indication

None provided