1.  Introduction

Docetaxel is an antineoplastic agent belongs to the taxoid family [1], frequently used to treat different kinds of cancer, including cancers of the breast, prostate, stomach, head and neck cancers, and non-small-cell lung cancer [2].  Most common adverse reactions across all Docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia [3].

2.  Patient and Methods

As a response to many statements from the medical oncology service of UHE-Oran; concerning the appearance of serious side effects linked to the use of Docetaxel such as: Medullary Aplasia (M.A), toxic shock and death, we carried out a Pharmacovigilance investigation. The statements were about six patients using Docetaxel, with five fatal evolutions; their information is illustrated in the following table (Table 1)

3.   Results

The results of imputability estimation according to the updated French method are resumed in (Table 2).

4.  Discussion

4.1   Drug interactions

Docetaxel is metabolized by the CYP 3A4 isoenzyme. About 80 % Docetaxel is eliminated in faeces during the first 48 hours as inactive metabolites.

An association between docetaxeland a powerful inhibitor of 3A4 cytochrome will reduce Docetaxel metabolism, which will lead to an elevation of its blood concentration and thus increasing its toxicity [4]. The main inhibitors of the CYP3A4 are:

 ·         Grapefruit Juice

·         Amiodaron

·         Calcic Channels Antagonistic (Diltiazem, Verapamil),

·         Antifungal Drugs (Ketoconazol, Itraconazol, Fluconazol, Miconazol, Posaconazol, Voriconazole),

·         Delavirdin,

·         Proteases Inhibitors (Ritonavir, Nelfinavir, Amprénavir, Indinavir, Atazanavir),

·         Imatinib,

·         Macrolide (Erythromycin, Clarithromycin, Josamycin, Telithromycin),

·         Association Quinupristin + Dalfopristin,

·         Stiripentol.

On the other hand, the incidence of the febrile neutropenia accompanied or not with sepsis is higher in patients treated with Trastuzumab and Docetaxel than it is with Docetaxel [5].

 4.2   ANSM investigation

On March 2017, a signal of colitis and septic shocks has been confirmed with Docetaxel (originator and generics). To improve knowledge of the safety profile of Docetaxel, another study has been performed on all the adverse drug reactions. Moreover, a same study has been performed for paclitaxel, alternative to Docetaxel in the treatment of breast cancer [6].

Adverse drug reactions reported between 1995 and 03/04/2017 were:

 ·         Skin disorders (26%)

·         General disorders: malaises, asthenia, fever, pain, oedema, mucositis (12%)

·         Gastro-intestinal disorders (11%)

·         Blood disorders (10%)

·         Respiratory disorders (7%)

·         Musculoskeletal disorders (6%)

·         Nervous system disorders (5%)

·         Infections (4%)

·         Vascular disorders (3%)

·         Immune system disorders (3%)

·         Cardiac disorders (2%)

These results show that increase of “Serious” or “Fatal” adverse drug reactions since 2010:

 concerns all taxanes and not only Docetaxel

mainly concerns dose dependant toxicities, suggesting a problem of concentration

Occurrence or complications for some adverse drug reactions could be limited by a simple surveillance (blood numeration, gastrointestinal symptoms, and hepatic surveillance), dose adaptation for the next treatment and a systematic use of G-CSF that is currently recommended only if there are risk factors [6].

5.  Conclusion and Perspectives

The Pharmacovigilance team plans to lead a prospective study in order to survey and prevent serious side effects. This study will start in October 2017. Monitoring Docetaxel plasmatic level by chromatographic method will be the main aim of our team, to optimize the treatment’s quality.   

Table 1: Six Patients Using Docetaxel, With Five Fatal Evolutions; Their Information.

Table 2: Imputability Estimation According to the updated French method. 

1. A stability-indicating HPLC assay method for Docetaxel. Nieuweboer Cancer Treatment Reviews 2015
2. FDA Drug Safety Communication: FDA warns that cancer drug Docetaxel may cause symptoms of alcohol intoxication after treatment 2014.
3. Full prescribing information. Reference ID: 3101735. 
4. Guide prescribes des interactions medicament uses 2016.
5. Cancer du sein, Docetaxel, neutropenia: 5 décès, pourquoi? Revue francophone des laboratoires -Avril 2017 -n°491.
6. Equate de Pharmacovigilance Profile de tolerance du Docetaxel: analyse des données de la base national de Pharmacovigilance. Comité technique de Pharmacovigilance du 04/07/2017-ANSM