Marketing Authorization Holder “Aventis Pharma S.A – 20 Avenue Raymond Aron – F- 92165- Antony Cedex France” to the new Marketing Authorization Holder “Sanofi Mature IP – 54 rue La Boétie – 75008- Paris

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.

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.