Download A Warning on Gemcitabine Generics Used For

Source Journal of Pharmaceutical Sciences
Letter To Editor
Open Access
Safety and Efficacy of Generic Drug Substitution in Oncology: A Warning
on Gemcitabine Generics Used For Endovesical Instillation
Pourroy Bertrand1*, Correard Florian1, Savry Amandine1, Gauthier-Villano Laurence1 and Pisano Pascale2
1
Oncopharma Unit, Pharmacy department, La Timone University Teaching Hospital, Marseille
Pharmacology Laboratory, Faculty of Pharmacy, Aix Marseille University, Marseille
2
*Corresponding author: Bertrand Pourroy, Oncopharma Unit, Pharmacy department, La Timone University Teaching
Hospital, Marseille, Tel: +33 (0) 491 38 81 83; Fax: +33 (0) 491 38 81 90; E-mail: [email protected]
Substitution of generic drugs for brand-name
effects and intoxication [4].
products has been highly controversial in the past.
Nevertheless,
as
frequently observed
in
Historically, the debate has focused on the issue of
oncology, gemcitabine may be used in an off label
bioequivalence, and clinical practice has identified
manner. Thus, gemcitabine is administrated by
several drug classes, drug formulation or clinical
endovesical instillation, in order to treat Bacille-
situations for which generic substitution should be
Calmette-Guérin refractory transitional cell carcinoma
approached with caution (digoxine, anticonvulsivants
of the bladder [5]. Briefly, 2 g of gemcitabine, in the
drugs, modified release formulations, geriatrics) [1].
smaller possible volume, have to be instilled directly in
Generic drugs in oncology have an enormous
the bladder twice a week for 2 months. Thus,
potential to generate significant cost savings and
gemcitabine is used without dilution and cystitis due to
consequently increase access to cancer treatments,
the acidic pH of gemcitabine concentrates was early
mainly in low- and middle-income countries [2].
identified as a potential adverse event of this therapeutic
Moreover, even if generics are widely used in clinical
[6] but conduce to a first gemcitabine misuse (e.g. pH of
oncology practice, few problems have been identified -
a
except for oral drugs [3] concerning these drugs. In fact,
bicarbonate leading to gemcitabine crystallization) [7].
most of cytotoxic drugs are administrated intravenously
This off label use of gemcitabine was historically done
and, consequently, bioequivalence between generics and
with Gemzar®. Currently, a detailed analysis of
their branded originator drugs is ensured.
gemcitabine generics composition has to be realized.
gemcitabine
solution
adjusted
with
sodium
Few years ago, Eli Lilly laboratories lost patent
This analysis conduces to identify other putative
for its anti-cancer drug Gemzar® (gemcitabine) and
misuse-risks. In fact, as expose in table 1, some generics
generic
many
present the same excipient composition than Gemzar®
different ways were followed by generic producers,
(mannitol, sodium acetate) whereas other ones, the
conducing to commercialization of 2 types of
ready-to-use concentrates, clearly appeared different.
gemcitabine generic (e.g. powder to reconstitute and
For one hand, aqueous solutions are more acidic than
ready-to-use concentrates) and 4 different formulations
reconstituted Gemzar®, whereas, on the other hands,
(Table 1). Bioequivalence of gemcitabine generics was
alcoholic solutions present a sub-neutral pH. Nor the
ensured but a new problem appeared. Thus, incorrect
safety of this high level of alcohol (around 20 g) neither
dilution of alcoholic ready-to-use concentrates of
the safety of macrogol 300 or propylene glycol for the
gemcitabine
than
bladder is ensured. In fact, few is described concerning
recommended alcohol concentrations in the final
direct contact safety of highly concentrate alcohol,
intravenous infusion solution, leading to local adverse
propylene glycol or macrogol 300 on bladder tissue [8-
competition
have
started.
been
Interestingly,
result
Volume 1│Issue 1│2015
in
higher
Page 1 of 3
© 2015 Bertrand Pourroy; licensee Source Journals. This is an open access article is properly cited and
distributed under the terms and conditions of creative commons attribution license which permits
unrestricted use, distribution and reproduction in any medium.
11]. Thus, even if all gemcitabine generics may be used
Altogether, these data highlight the major role
by intravenous route, endovesical route requires a
of pharmacist for generic choice, and identify a new
carefully literature analysis in order to choose safety
issue to study - anticancer drugs generics and
drugs (e.g without alcohol, without macrogol and with
administration
the highest possible pH). To conclude, the precautionary
practitioners.
route
-
for
oncology
pharmacy
principle and the datas of the literature conduce to
choose only gemcitabine generics that present a similar
composition to Gemzar® for endovesical instillation.
Form
Brand name
Gemcitabine
and
concentration
producer
Gemzar®
Eli Lilly
Gemcitabine
Teva®
Powder for
Gemcitabine
reconstitution
Kabi®
Gemcitabine
Actavis®
Gemcitabine
Accord®
Gemcitabine
Teva®
Gemcitabine
Ready to use
EG®
alcoholic solution
Gemcitabine
Actavis®
Gemcitabine
Mylan®
(mg/mL)
Composition (for 2g gemcitabine)
Excipients b, d
Ethanol
quantity
38 mg/mL a
0g
38 mg/mL a
0g
Mannitol
38 mg/mL a
0g
Sodium
Acetate
38 mg/mL a
0g
38 mg/mL a
0g
40 mg/mL
19.75 g
38 mg/mL
Ethanol
22.14 g
Disodium
40 mg/mL
Phosphate
40 mg/mL
19.75 g
19.75 g
pH
2.7 to
3.3 c
2.7 to
3.3 c
2.7 to
3.3 c
2.7 to
3.3 c
2.7 to
3.3 c
7.0 to
8.0 c
7.0 to
9.5 c
7.2 to
7.8 c
7.2 to
7.8 c
Macrogol
Ready to use
Gemcitabine
alcoholic solution
Intas®
300
100 mg/mL
Propylene
8.8 g
glycol
7.0 to
8.0 c
Ethanol
Gemcitabine
Ready to use
Sandoz®
aqueous solution
Gemcitabine
Hospira®
40 mg/mL
38 mg/mL
0g
Water for
injection
0g
2.0 to
2.8 d
2.0 to
3.0 d
Table 1: main commercialized specialties containing gemcitabine.
a
concentration after reconstitution;
b
HCl and/or NaOH are added for pH adjustement;
c
datas provided by
laboratories; d datas from Summary of Product Caracteristics.
Volume 1│Issue 1│2015
Page 2 of 3
© 2015 Bertrand Pourroy; licensee Source Journals. This is an open access article is properly cited and
distributed under the terms and conditions of creative commons attribution license which permits
unrestricted use, distribution and reproduction in any medium.
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