Journal of Pharmacovigilance and Pharmacotherapeutics (ISSN: 2688-6464)

Article / case report

"Fatal Medullar Aplasia: Is DOCETAXEL Responsible? About Six Cases"

Houari Toumi1*, H Belmekki1, Z Mansouri1, INH Bekhti1, N Amara1, M Baira1, A Berradia1, F Bechir1, A Boukli1, H Zitouni1, Fz Mekaouche1, S Djeddid1, Bessayeh2, Yammouni2             

1Department of Pharmacovigilance, University Hospital of Oran, Algeria

2Department of Oncology, University Hospital of Oran, Algeria

*Corresponding author: Houari Toumi, Department of Pharmacovigilance, University Hospital of Oran, Algeria. Tel: +21341705112; Email: toumi54@live.fr

Received Date: 27 September, 2017; Accepted Date: 17 October, 2017; Published Date:  23 October, 2017

Docetaxel is a frequently used chemotherapeutic agent in the treatment of solid cancers.  The medical oncology service of UHE-Oran has notified serious adverse reactions such as: Medullary Aplasia (M.A) and toxic shock linked to the use of Docetaxel, this study is about six patients with five fatal evolutions. The Pharmacovigilance team led an investigation in order to analyze the cases and estimate the imputability. Pharmacological studies revealed that Docetaxel is metabolized by the CYP3A4 isoenzyme, so its metabolism may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4. To improve the safety profile of Docetaxel usage another prospective study will start in October 2017

Keywords: CYP 3A4 inhibitors; Docetaxel; Imputability estimation; Medullar aplasia; Taxane toxicity

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.   


Patient

Age

Cancer

Protocol

Cure

Last cure Date

Evolution

H.N

44

breast

TH

C2

43075

Death

M.F

41

breast

AT

C1

30/05/2017

Death

S.N

26

breast

AT

C3

42802

Death

B.F

41

breast

AT

C4

42893

Death

C.K

70

Cavum

PTX

C2

42894

Death

F.M

35

Cavum

PTX

C2

16/08/2017

M.A

TH: Taxotère® - Herceptine®;AT: Adriamycine® -Taxotère® ;PTX :Cisplatine® -Taxotère®- Xeloda®


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

 

Patient

Protocol

Intrinsec Imputability

Extrinsec Imputability

H.N

Docetaxel

C2S3 è I5

B4

TAXOTERE®

Sanofi laboratoiry

Batch N°6F278A

Trastuzumab

C2S2 è I3

B4

M.B.F

Docetaxel

C2S2 è I3

B4

TAXOTERE®

Sanofi laboratoiry

Batch N°6F278A

Doxorubicine

C2S2 è I3

B4

S.N

Docetaxel

C2S1 è I2

B4

DOCETAX®

Cipla laboratoiry

Batch N°GE60636

Doxorubicine

C2S1 è I2

B4

B.F

Docetaxel

C2S2 è I3

B4

TAXOTERE®

 Sanofi laboratoiry

Batch N°6F295A

Doxorubicine

C2S2 è I3

B4

C.K

Docetaxel

C2S3 è I5

B4

DOCETAX®

Cipla laboratoiry

Batch N°GE60636

Capecitabine

C2S2 è I3

B4

Cisplatine

C2S2 è I3

B4

F.M

Docetaxel

C2S2 è I3

B4

DOCETAX®

Cipla laboratoiry

Batch N°GE60636

Capecitabine

C2S2 è I3

B4

Cisplatine

C2S2 è I3

B4

  Intrinsec imputability Illustration , Extrinsec imputability Illustration: B4 :Labeled side effect


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

Citation: Toumi H, Belmekki H, Mansouri Z, Bekhti INH, Amara N, et al. (2017) Fatal Medullar Aplasia: Is DOCETAXEL Responsible? About Six Cases. J Pharmacovigil Pharm Ther: JPPT-123. DOI: 10.29011/JPPT-123. 100123

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