SFPO and ESOP Recommendations for The

Home , Chlormethine, Fotemustine, Nelarabine

Annales Pharmaceutiques Françaises (2013) 71, 376—389

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ORIGINAL ARTICLE

SFPO and ESOP recommendations for the

practical stability of anticancer drugs:

An update

Mise à jour des recommendations de la SFPO et de l’ESOP pour la

stabilité pratique des anticancéreux

a,∗ b c d

J. Vigneron , A. Astier , R. Trittler , J.D. Hecq ,

e f g h

M. Daouphars , I. Larsson , B. Pourroy , F. Pinguet

Pharmacy, university hospital, rue du Morvan, 54511 Vandœuvre, France

UMR 7054, school of medicine, Henri-Mondor hospital, 94010 Créteil, France

University hospital, Freiburg, Germany

University hospital Mont Godinne, 5530 Yvoir, Belgium

Centre Henri-Becquerel, 76038 Rouen, France

Amgros, Copenhagen, Denmark

Pharmacy, university hospital, 13005 Marseille, France

Val d’Aurelle cancer center, 34298 Montpellier, France

Received 20 May 2013; accepted 12 June 2013

Available online 28 August 2013

KEYWORDS Summary The recommandations for the practical stability of anticancer drugs published in

Stability; 2010 by the French Society of Hospital Pharmacists (SFPO) and the European Society of Oncology

Anticancer drugs; Pharmacists (ESOP) have been updated. Ten new molecules have been included (asparagi-

Monoclonal nase, azacitidine, bevacizumab, clofarabine, eribuline mesylate, folinate sodium, levofolinate

antibodies; calcium, nelarabine, rituximab, temsirolimus).

∗

Corresponding author.

E-mail address: [email protected] (J. Vigneron).

SFPO and ESOP recommendations for the practical stability of anticancer drugs 377

MOTS CLÉS

Résumé Les recommandations concernant la stabilité pratique des préparations

Stabilité ;

d’anticancéreux émanant de la Société franc¸aise de pharmacie oncologique (SFPO) et

Anticancéreux ;

de la Société européenne de pharmacie oncologique (ESOP) parue en 2010 ont été actual-

Anticorps

isées. Dix nouvelles molécules ont été ajoutées (asparaginase, azacitidine, bevacizumab,

monoclonaux ;

clofarabine, eribuline mesylate, folinate sodium, levofolinate calcium, nelarabine, rituximab,

Dose banding ; temsirolimus)

Stabilis®

Introduction change in chemistry [i.e., peptide mapping] and biological

activity [e.g. cytotoxicity on cells, bioassays). Other inter-

These recommendations for storage conditions of anticancer esting studies which uses only one or two methods were not

drugs are the result of the deliberations of the SFPO (French selected [3,4].

Society for Oncology Pharmacy) stability group. The ﬁrst For some drugs, interesting results were not selected due

edition of the data were published in 2008 by the Cen- to various reasons. The stability of bendamustine was stud-

tre national hospitalier d’information sur le médicament, ied by Krämer et al. [5] with a 9 hours stability at room

CNHIM — National Information Centre on Hospital Drugs. temperature and a 5 days in the refrigerator. The results

The stability group comprised Arnaud P, Astier A, Bellanger of this study published in 1994 were based on the classi-

A, Bonan B, Breilh D, Burnel S, Daouphars M, Ferrio AL, cal T90% of the initial concentration. However, today, the

Havard L, Helvig A, Husson MC, Pinguet F, Poisson N, Sar- recommendations of the manufacturer [6] are based on the

rut B, Vigneron J. These recommendations were adopted as T95% with a 3.5 hours stability at room temperature and

the European standard by ESOP in 2010 and published in the 2 days in the refrigerator. These data were in accordance

European Journal of Oncology Pharmacy [1]. with the T95% of Krämer et al. We decided to use the rec-

A new group with members of SFPO and European hospital ommendation « Follow SPC) ». Moreover, this decision is in

pharmacists has updated this work in 2012. This new group accordance with the European guideline for stability studies

comprised Alain Astier, Mikaël Daouphars, Frédéric Pinguet, of anticancer drugs [7].

Bertrand Pourroy, Jean Vigneron for SFPO and Jean Daniel For vincristine, the extended stability in polyoleﬁne bags

Hecq from Belgium, Iben Larsson from Denmark and Rainer was also demonstrated in polypropylene syringes [8] but

Trittler from Germany. the information has not been selected because of the rec-

In this updated article, new drugs have been included ommendations of the World Health Organisation [9] who

(asparaginase, azacitidine, bevacizumab, clofarabine, recommend to prepare the vinca-alcaloids only in infusion

eribuline mesylate, folinate sodium, levofolinate calcium, bags to avoid inadvertent intrathecal injections.

nelarabine, rituximab, temsirolimus). Some drugs received Below, we present the new informations and their inter-

new informations (cisplatine, docetaxel, ﬂudarabine, oxali- ests in the daily practice. We have separated the long-term

platine, vincristine). Three drugs no longer available on the and the short-term stability studies. ‘‘Long-term’’ has been

market have been removed from the table: chlormethine, arbitrarily deﬁned as a stability of at least 2 weeks.

mitoguazone and pirarubicine. The updated recommendations are presented in Table 1.

Long-term stability studies

Selection criteria for the articles

These studies can be divided into ﬁve categories.

New informations were selected by using the Stabilis

database. For each monograph, the new publications until

2008 have been revised according to a checklist to select The stability of monoclonal antibodies

inclusion criteria for the physical and chemical stability. The

articles were selected if they brought new informations for The three studies presented here are the ﬁrst fully validated

the daily practice (for example, extended stability for the stability studies according to the ICH guideline Q5C. Several

preparation in advance). We decided to include the infor- complementary methods have been used to evaluate the sta-

mations presented in posters if the stability study was in bility of rituximab. Various protein characterization methods

accordance to our criteria and submitted to publication. were used to determine changes in physicochemical proper-

The stability data of simple solutions (one drug in one con- ties of rituximab, including size-exclusion chromatography,

tainer) have been selected. The stability of mixtures or of dynamic light scattering, turbidimetry, cation-exchange

non-injectable drugs were not in the ﬁeld of this work. chromatography, second-derivative ultraviolet and infrared

Stability studies of monoclonal antibodies carried out spectroscopy, and peptide mapping. Cell culture was used

in accordance with the recommendations of ICH Guide- to assess biological stability.

lines Q5C [2] were selected. These stability studies use The authors have demonstrated a 6 months stability for

at least three complementary methods (study of aggre- the infusions at 1 mg/mL in 0.9% sodium chloride in poly-

gation [e.g. size exclusion chromatography, turbidimetry], oleﬁne container (Freeﬂex ) [71]. This long-term stability

378 J. Vigneron et al. References 3 [10—12] 1 [13,14] [15] [16] [17] [18—20] [21,22] C C ◦ ◦ at days hours

4 C

room for C ◦

◦ or 84

at 2.5 C

light ◦ C light light light light C C C

25 C—15 ◦ or ◦ ◦ ◦ C C

◦ C—8 C, ◦ ◦ ◦ ◦ C room or 20

◦ days

2 2—8 13 4

from − 4 2—8 2—8 2—8 4 room from from from from at

2—8 2—8 83 at at at at

conditions at at at at at at at

SPC SPC SPC SPC SPC

at at

day temperature

days days days days days hours hours hours days days hours which polyethylene

days days

temperature Protected 19 48 36 30 48 Protected 84 temperature Protected temperature protected 5 Recommendations Follow Follow 7 23 Follow 90 Follow 35 30 Follow and 28 storage in room of Protected

mg/mL

1 2.5

solution: mg/mL mg/mL mg/mL mg/mL mg/mL

administration administration administration administration administration administration

0.5 0.5 0.5 0.70—2.15 3.2 0.2

in in in in in in mg/mL

UI/mL mg/mL

to mg/mL

Non-diluted vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: Concentration 80 25 2 Reconstituted: Reconstituted: Diluted Diluted Diluted Diluted Diluted Diluted 6 drugs.

5% 5% 5%

anticancer C)

◦ of 0.9% 0.9% 0.9% 0.9% 0.9% 0.9% 0.9%

NaCl WFI Vehicle NaCl NaCl NaCl NaCl NaCl Dextrose NaCl Dextrose Dextrose stability

anticancéreux.

des

practical

- -

the

glass

pratique for 2-piece syringes Glass Container Polypropylene Polypropylene syringes Polypropylene Glass Polypropylene Glass Polyethylene polypropylene polypropylene syringes polyethylene polyethylene Glass PVC Polypropylene or

stabilité

pour

light recommendations

ESOP

from

ESOP

polycarbonate

SFPO

and

with

busulfan

PVC protected SFPO

freeze use 1

Should Table Recommandations Product Alemtuzumab Azacitidine Bendamustine Bleomycin Busulfan Never Incompatible (dimethylacetamide) Carmustine Never Caelyx Amifostine Asparaginase Bevacizumab Bortezomib Carboplatin

SFPO and ESOP recommendations for the practical stability of anticancer drugs 379 References [23—25] [26] [27] [28] [29,30] [31] [32] [33] C at at ◦ at

light 18 or

C C

room ◦ ◦ light

light

days days

2 4 for

the C

at 4 3

◦ light or or light light light and

light light light the 4 in C

from and ◦

C C C C C and and and without in ◦ ◦

at ◦ ◦ ◦ C

◦ C C C 4 from ◦ ◦ ◦

from from from room room 2—8 23 25 4

from from from 25 25

C 4 4 4 room at

◦

conditions at at at at at at at at

4 hours

at at at at

temperature temperature

protected 48 at

hours days days days days days days C

hours hours ◦ days days days days

30 29 2 4 28 7 protected 28 Recommendations 14 7 4 7 24 4 temperature Protected temperature temperature protected room room and Protected protected protection temperature Protected storage and

mg/mL

mg/mL mg/mL

(PVC)

mg/mL mg/mL mg/mL

and

mg/mL

administration administration administration administration administration administration administration administration administration mg/mL mg/mL

0.1—0.5 1 0.5—0.9 0.016 1 0.018 1.25 1.5 0.640 mg/mL mg/mL 28

in in in in in in in in in

mg/mL

vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: 0.4 Diluted Reconstituted: Diluted Diluted 0.2—0.6 Diluted Diluted 25 0.1—0.4 or or or

5%5% Diluted Diluted 5% 5% 5% 5% 5%

0.9% Diluted 0.9%0.9% Diluted 0.9% 0.9% 0.9% 0.9%

NaCl NaCl Vehicle Concentration Dextrose NaCl Dextrose Dextrose Dextrose NaCl NaCl NaCl NaCl -

glass

vinyl

VerrePVC NaCl0.9% Amber polyethylene Polyethylene Dextrose Ethyl PVC, polyethylene Polyoleﬁne Dextrose PVC EVA PVC PVC acetate polyethylene PVC Polyethylene Dextrose light

the

from if

protected

form

) tubing)

+ may

protected

not (bag

Continued

is administered (

1 products light

yclophosphamide ProductCladribine Container Clofarabine C Cytarabine Dacarbazine Toxic from Must solution Cisplatin Table

380 J. Vigneron et al. References [34] [35,36] [37] [38] [38,39] [40] [41] [41,42] [43] [41,42] [44]

at at

◦ and C

light light light C ◦

at ◦ C C

and 23 43 ◦ and C ◦

◦ 20 C for 4 ◦ C the the the

− 20

◦ and

2—8 5 20

protected and and and light C, light light in in in

light

◦ − or or

◦

C C, C, C C C C C C ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ C C—8 C C 20 or ◦ ◦ ◦ ◦ 4 23

the

from − 4 2 25 25 20 25 25 4 4 from from 25 25 25 C

◦ at at in

conditions 4 without at at at at at at at at at at at at at

SPC

temperature light

at or

days days C C

hours days ◦ days days ◦ days days days days days days days C

hours hours hours ◦

8 24 28 43 24 20 43 protected 124 150 56 Protected from Recommendations Follow 28 14 43 8 4 4 Protected 28 days storage 25 room 25 with

mg/mL

mg/mL mg/mL

10 1 8

mg/mL > mg/mL mg/mL

mg/mL mg/mL mg/mL

and administration administration administration administration administration administration administration administration administration administration administration administration administration mg/mL mg/mL mg/mL

0.01 0.1 2 4 8 4 0.3—0.9 0.3—0.9 0.24 1—2 0.1 1—2 0.1

in in in in in in in in in in in in in

g/mL ␮

Diluted Diluted vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: Concentration Diluted Diluted Diluted Diluted Diluted Reconstituted: Diluted Diluted 440 Diluted Diluted Diluted Diluted

or or or

or or

5% 5% 5% 5% 5% 5%

solvent

Lactate Lactate Lactate

0.9% 0.9% 0.9% 0.9% 0.9% 0.9% 0.9%

NaCl dextrose dextrose Vehicle Dextrose Dextrose WFI Ringer Ringer Ringer Special NaCl NaCl Dextrose NaCl Dextrose None NaCl NaCl NaCl

polyethylene

Polypropylene Glass Polyoleﬁne PVC Polypropylene Polypropylene Container PVC Polypropylene Polyethylene Polypropylene - PVC PVC Polyethylene PVC for

) mg/mL mg/mL mg/mL

after (

(solution

photosensitive 0.5 0.5 0.5

) photosensitive > > >

mg/mL photosensitive

not vials) vial)

not

days days

not is

7 7

is (two (one containers containers

days mesylate

Continued 7 (

least least PVC PVC 1

at at

concentrations concentrations concentrations least mg/mL)

daunorubicin Doxorubicin epirubicin Avoid Avoid at Product Dactinomycin Daunorubicin At Docetaxel Doxorubicin At Epirubicin At Eribuline 20 reconstitution for for Docetaxel Dexrazoxane Daunoxome Table

SFPO and ESOP recommendations for the practical stability of anticancer drugs 381 References [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] C ◦ C ◦ 4 C low

C in ◦

◦ C

the the days

4 ◦ at

C light

hours

7 ◦

at for 25

in in

or 20

25 C C protected C and or and light light or C light light light

the protected

◦ ◦

◦

PVC

◦ or and

C C C C or or and in ◦ ◦ ◦

◦ C C, C C C 25 25

◦ ◦ ◦ ◦ on ◦ C C C 4

< < room ◦ ◦ ◦

from from 4 23 25 − 4 room 4 ≤ 4 23 from from from

4 4 4 at at at

temperature, at

conditions

without at at at at at at at at at at

at at at C—32

◦ light light or

light C

room 23 days hours hours days days days ◦ hours days days days days days days

weeks days days days

24 14 4 2 96 24 8 90 28 at at the 30 35 31 temperature from protected with Recommendations 35 light light temperature 30 from 25 Protected Protected 21 Protected concentrations) protected storage (adsorption

and mg/mL 4 mg/mL mg/mL

mg/mL

10 20 38 mg/mL mg/mL

mg/mL

and to

mg/mL mg/mL mg/mL mg/mL mg/mL

mg/mL

administration administration administration administration administration administration administration administration administration administration administration administration

15.4 0.2 0.4 0.04 1.5 0.1—0.5 1—1.5 3.2 0.2—2 1—10 0.1 30

in in in in in in in in in in in in mg/mL 31

g/mL ␮

mg/mL

0.1—10 Diluted Diluted vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: Reconstituted: Reconstituted: 20 Reconstituted: Diluted Diluted Diluted Diluted 43.3 or or or or or

or or or

5% 5% 5% 5% Diluted 5% Diluted 5% 5% 5% 5% 5%

0.9%0.9% Diluted 0.9% Diluted Diluted 0.9% 0.9%0.9% Diluted 0.9% 0.9% 0.9% 0.9% 0.9% 0.9% 0.9%

NaCl dextrose dextrose Dextrose Vehicle Concentration WFI NaCl NaCl Dextrose Dextrose Dextrose Dextrose NaCl Dextrose Dextrose NaCl NaCl NaCl NaCl NaCl

PVC NaCl PVC PVC

or or or

Polypropylene syringes PVC PVC Glass Glass Polyoleﬁne NaCl Polypropylene NaCl PVC Glass Glass PVC Polypropylene Glass Polypropylene NaCl light

from

)

protected

phosphate

calcium sodium Polyethylene Dextrose Continued

(

Product Container Fluorouracil Folinate Fotemustine Administer Gemcitabine Ifosfamide Folinate Idarubicin Etoposide Fludarabine Etoposide Table

382 J. Vigneron et al. References [55] [56] [57] [58] [59] [60] [61] [62] [63]

C ◦ C at ◦

C light ◦ 23 hour

or 23 light

◦ 4 1

at for

the

at and of

room 2—8 light and and C light light light light light light

in C C

◦ and ◦ ◦

C C C or and or and

◦ ◦ ◦ C C

20 ◦ ◦ C C 4 4 ◦ ◦

from room − 2—8 4 2—8 4 from from from from from from 26

4 room 4 at at

temperature

presence conditions

at at at at at at at

SPC SPC SPC

at at at

C room days days days hours hours days days days ◦

days hours days days

4 24 3 95 48 7 temperature Protected 30 28 25 Protected 30 temperature Recommendations Follow Follow 42 Follow 28 Protected protected 7 temperature Protected at storage Protected Protected mg/mL mg/mL

mg/mL

2.8

mg/mL

to mg/mL mg/mL mg/mL

administration administration administration administration administration administration administration administration

0.6—40 0.4 1.6 0.2 0.06 2.5 0.225—24 0.04—0.4

in in in in in in in in

mg/mL mg/mL

Diluted Diluted vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: 2 Concentration Diluted Diluted Diluted Diluted 5 Diluted Diluted or or

or or

5% 5% 5% 5% 5%

0.9% 0.9% 3% 0.9% 0.9% 0.9% 0.9%

NaCl None dextrose Dextrose NaCl Vehicle Dextrose Dextrose Dextrose NaCl NaCl Ready-to-use solution NaCl NaCl NaCl

vinyl

bottle

Polypropylene syringes acetate PVC Container PVC PVC Polyethylene PVC, polyethylene PVC PVC Ethylene Glass used

melphalan

) temperature

not

the

calcium must

with 5%

Continued (

degradation

Product Levofolinate Melphalan Dextrose Methotrexate Mitomycin Myocet The increases Interleukin Irinotecan Mitoxantrone Nelarabine Table

SFPO and ESOP recommendations for the practical stability of anticancer drugs 383 References [64] [65] [66,67] [68,69] [70] [71] [72] [73,74] days

room days

light from 12

for

or C

31 ◦

◦ room light light light light light the

C and protected protected C

◦ C and ◦ at with protected and in ◦

C C C C—8 C

◦ ◦ ◦ ◦ ◦ C—8 C 4 23

◦ ◦

or 4 room 2 4 from from from from from

25 2 room 20 2—8 4 at at

protection

conditions at at at at

SPC

at at at at at at

light light light C C

◦ ◦ days

5 4 days days days days hours

days days days days days days days

4 90 30 13 9 at 2 48 Protected Protected Recommendations 3 180 Follow 3 from 28 3 temperature temperature from temperature Protected from Protected temperature 4 at Protected light storage without

mg/mL mg/mL

mg/mL

mg/mL mg/mL mg/mL mg/mL

mg/mL

administration administration administration administration administration administration administration administration administration mg/mL mg/mL

0.25 0.7 0.3—1.2 0.3 1.2 25 5 5

in in in in in in in in in

mg/mL

Diluted Diluted Diluted Diluted vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: 0.002—0.02 vehicle: Concentration Diluted Reconstituted: Diluted 1 Diluted

or or or or

5% Diluted 5% Diluted 5% 5% 5% 5% 5%

0.9% 0.9% 0.9% 0.9% 0.9% 0.9% 0.9% 0.9% 0.9% 0.1

NaCl Dextrose dextrose dextrose dextrose dextrose Vehicle NaCl NaCl NaCl NaCl

bags Dextrose bags Dextrose

bags

Polypropylene syringes Polyolefin PVC, polyolefin Polypropylene NaCl Polyolefin Polyethylene NaCl PVC PVC Polyolefine Polyethylene NaCl Glass filter due

DEHP in-line

m precipitation ␮

) temperature of

(microparticles increasing

0.22 or

a ◦ at risk containing

used

at Continued

PVC (

be stable form),

increased less stored

ProductOxaliplatin Paclitaxel Exclude Container Streptozocin Thiotepa Is has to concentration might Rituximab Pemetrexed If Pentostatin Temsirolimus Polypropylene NaCl Table

384 J. Vigneron et al. References [75] [76] [77,78] [77,79] [8] [77] [78,80,81] C C C ◦ ◦ ◦ at at

25 25 25 the

light day

at at at at

in for

not light light light light light light light light light light the C

and and and and ◦

C C and in ◦ ◦

C C C C C C C

◦ ◦ ◦ ◦ ◦ ◦ ◦ C C C C 4

◦ ◦ ◦ ◦ from 4 25 4 2—8 4 4 4 4 from from from from from from from from from

8 room 4 4 23 4 at

conditions at at at at at at at at

at at at at at at

temperature temperature

days C

days days days days days days ◦ days days

days days days days days days

7 7 21 21 84 21 2 28 21 7 180 7 7 Protected 25 Recommendations 21 21 protected temperature room Protected Protected Protected light Protected Protected storage room Protected Protected Protected

mg/mL mg/mL

1 1 mg/mL

mg/mL

and to mg/mL mg/mL mg/mL mg/mL mg/mL

mg/mL mg/mL mg/mL

administration administration administration administration administration administration administration administration administration administration administration administration administration

0.5—3 0.025, 0.01 0.01 0.8 0.02 0.1 0.02 0.01 0.05 0.02 0.385 0.5

in in in in in in in in in in in in in

mg/mL mg/mL mg/mL

Diluted Diluted Diluted Diluted Diluted Diluted vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: vehicle: 0.05 Concentration Diluted Diluted Diluted Reconstituted: Diluted Diluted Reconstituted: Diluted Diluted 0.05 0.15

or or or or or or

5% 5% 5% 5% 5% 5% 5%

0.9% 0.9% 0.9% 0.9% 0.9% 0.9% 0.9% 0.9% 0.9% 0.9% 0.9% 0.9%

dextrose dextrose dextrose dextrose dextrose dextrose NaCl Vehicle NaCl NaCl NaCl NaCl NaCl WFI NaCl NaCl NaCl NaCl WFI NaCl Dextrose NaCl

Glass Glass Container PVC Elastomere Polypropylene PVC polypropylene Polypropylene PVC Polypropylene PVC, polyethylene PVC PVC PVC Polyoleﬁn ) Continued (

Product Vinblastine Vindesine Vincristine Vinorelbine Topotecan Trastuzumab Polypropylene Table

SFPO and ESOP recommendations for the practical stability of anticancer drugs 385

study allows the standardization of the dose by different Azacitidine has been approved for the treatment of

manner. The large-scale production of doses at 600, 700, myelodysplasic syndromes and acute myeloid leukemia, this

800 and 900 mg has been carried out at the pharmacy of the drug is administered as a suspension at 25 mg/mL by subcu-

University hospital of Créteil in France. taneous injections daily during one week.

Other approaches using these results have been devel- Azacitidine is a very unstable drug with a stability of

◦

oped in other hospitals like the preparation in advance 45 minutes at room temperature and 8 hours at 2—8 C. This

for a speciﬁed patient. The organization is in accordance stability has been further enhanced by the manufacturer

with the Dose Banding Concept with a maximum deviance with a 22 hours stability if the powder is reconstituted with

of 5% between the dose administered and the dose cal- cold water for injection [84]. The 22 hours stability does not

culated according to the body surface area (BSA). In the allow the preparation in advance especially for the week-

university hospital of Nancy, France doses of rituximab are end.

standardized between 570 and 870 mg by band of 60 mg. For This drug was used 25 years ago and administered

doses between 570 and 630 mg, a rounded dose of 600 mg as intravenous infusions at diluted concentrations of

is prepared; for doses between 630 and 690 mg, we prepare 0.2 mg/mL. Tw o stability studies have demonstrated that

660 mg, etc [82]. the solutions are very unstable but no stability study of the

If the treatment is cancelled or postponed, the infusion suspension had been published [85,86].

is re-used for another patient and another label is put on the In the stability study selected [10], the suspension at

◦

infusion bag according to a specialized procedure. This pos- 25 mg/mL was stable for 8 days at −20 C allowing the

sibility has been written in the standard of ISOPP in chapter production in advance especially for the weekend and

20 where there are recommendations for the re-use of drugs important cost savings (one vial cost 340 euros). In this study,

[83]. the vials were reconstituted with ice-cold water for injec-

As rituximab is always almost used for outpatient, it tion to optimize the T0 concentration. The reconstitution

is very important to have an immediate availability of with water for injection at room temperature should be

the preparation after the prescription. This preparation in avoided because of an immediate 4% drop in the concen-

advance allow other advantages, it decrease the stress of tration after reconstitution.

the pharmaceutical team who can prepared in advance out- The thawing of the frozen suspensions were performed at

side the hours of the main activity in the afternoon, it room temperature for 45 minutes and then the syringe were

◦

decrease the stress of the nursing staff who do not wait for stable for 8 hours at 4 C.

the treatment and it allow also important cost savings. A more recent study submitted for publication was pre-

A similar organization has be performed for beva- sented during the last congress of the French society of

cizumab infusions with 3 months stability for the solution Oncology Pharmacists and during the last ECCO congress

diluted in 0.9% sodium chloride in polyoleﬁne bags and for in Stockholm, the presentation is available on the Stabilis

trastuzumab with 6 months stability for the 0.8 mg/mL solu- website [11]. The study demonstrated a 5 days stability

◦ ◦

tion stored at 4 C [76]. at 4 C after reconstitution with ice-cold water for injec-

tion.

A Canadian publication recently extends the stability

Stability studies of classical molecules to allow

of the frozen suspension at 23 days allowing the possibil-

the Dose Banding concept ity of Dose Banding (syringes at 55, 60, 65, 70, 75 mg)

[12].

Long-term stability have been demonstrated for cispla-

tine docetaxel, ﬂudarabine, oxaliplatine and vincristine. For

Stability studies of adjuvant therapy

azacitidine, the long-term stability has been demonstrated

for the frozen suspension.

The stability of levofolinate calcium, folinate sodium has

Vincristine is mainly administered as a 2 mg infusion and

been demonstrated after freezing and microwave thawing

therefore is an easy drug for the standardization. A 84 days

to allow the batch production in Centralized Intravenous

stability has been demonstrated in polyoleﬁne containers

Additive Service (CIVAS).

allowing the batch scale production in advance.

Freezing and microwave thawing is mainly developed for

For the other drugs, extended stability have been demon-

antibiotic therapy and allow the delivery of ready-to-use

strated (28 days for cisplatine [23], 28 days for the new

infusions to the wards. The organization has been developed

formulation of docetaxel (ready to use solution at 20 mg/mL)

in North America but also in Europe [87]. It can also be used

and 56 days for the formulation at 10 mg/mL [39,40], 21 days

for adjuvant therapy.

for ﬂudarabine phosphate [47], and 90 days for oxalipla-

In the study selected, levofolinate calcium and folinate

tine [64]. This allows the standardization of the doses and ◦

sodium infusions were stable for 90 days at −20 C and then

the batch production or the preparation in advance for one ◦

30 days at 2 to 8 C [50,56].

patient and the re-use of the drug if the administration is cancelled or postponed.

Vieillard V, Appudurai O, Voytenko S, Astier A, Paul M. Sta-

Morand K, Paul M, Lahlou A, Blanchet B, Astier A. Stabilité de bilité physico-chimique de la suspension d’azacitidine (25 mg/mL)

◦

solutions diluées de bévacizumab en fonction de la température. conservée à 4 C. Poster presented SFPO Congress Mandelieu,

Poster presented at the SFPO Congress Mandelieu, France 2009 (Sub- France 2011 (submitted to publication), available on Sta-

mitted to publication), available on Stabilis.(www.stabilis.org). bilis.(www.stabilis.org).

386 J. Vigneron et al.

Stability studies of rarely used molecules to the ICH Q5C recommendations . Size exclusion chro-

matography (SEC), dynamic light scattering (DLS) describing

(clofarabine, eribuline mesylate and nelarabine) to allow submicronic populations and corresponding mean diameter,

the production in advance or to keep the infusion if the turbidity at 350 nm, thermal aggregation curves and deter-

administration is canceled or postponed. mination of L-Aspa concentration by UV at 280 nm (chemical

Clofarabine is a halogenated-adenosine analogue stability) have been used to evaluate the stability. The

approved for the treatment of relapsed or refractory enzymatic activity was also investigated. The authors have

◦

hematologic malignancies (acute lymphoblastic leukemia demonstrated a 7 days stability at 4 C for a normal saline

[ALL] or acute myeloid leukemia [AML]). solution at 80 UI/mL in Freeﬂex bags. This extended sta-

Ready-to-use clofarabine infusions (0.2 and 0.6 mg/mL) bility allow the preparation in advance especially for the

in polyoleﬁne bags in 0.9% NaCl and 5% glucose are physico- weekend, the drug being prescribed every 2 days in various

chemical stable over at least 28 days when refrigerated or protocols.

stored at room temperature [27]. Temsirolimus received approval by the European

Nelarabine, a new purine nucleoside analogue, was Medicines Agency (EMA) in November 2007 for the treat-

approved in 2007 by the EMA for the treatment of T-cell ment of advanced renal cell carcinoma and in September

acute lymphoblastic leukaemia and T-cell lymphoblastic 2011 for the treatment of adult patients with relapsed or

lymphoma. refractory mantle cell lymphoma.

The commercially available solution for infusion is not Temsirolimus is administered as a solution to be given

diluted before administration. The appropriate volume of by intravenous infusion over 30 to 60 minutes. The ﬁnished

nelarabine solution for infusion is transferred into ethyl- product, Torisel , is a two-vial system consisting of a con-

ene vinyl acetate (EVA) or polyvinylchloride (PVC) infusion centrate solution containing 25 mg/mL temsirolimus (in one

in paediatric patients [63]. vial) and a speciﬁcally formulated diluent (in another vial)

In the stability study selected, ready-to-use nelarabine composed of polysorbate 80, polyethylene glycol 400, dehy-

infusion solutions in EVA infusion bags were physico- drated alcohol and nitrogen.

chemically stable for at least four weeks, either refrigerated Light is the most important factor inﬂuencing stability of

or at ambient temperature, and with or without protection the drug; sunlight can have a dramatic effect on the stability

from light. of diluted solutions in polypropylene containers. The second

Eribuline mesylate received approval by the European factor that inﬂuences the rate of temsirolimus degradation

Medicines Agency in March 2011 for the treatment of is the temperature.

advanced breast cancer patients who have received at least Ready-to-use temsirolimus infusion solutions could be

◦

two prior chemotherapeutic regimens for late-stage disease, stored, protected from light, 4 days at 4 C and 3 days at

◦

including both anthracycline- and taxane-based chemother- 20 C. The degradation rate under artiﬁcial light is sufﬁ-

apies. ciently low to authorize the absence of opaque infusion

Each vial contains 0.88 mg of eribuline mesylate as a sets. However, the exposition to sunlight must be absolutely

␮

440 g/mL solution in ethanol-water (5:95, v/v). This drug avoided [72].

is administered undiluted or diluted in 0.9% sodium chloride

solution.

In the selected study, ready-to-use solutions at Conclusion

440 ␮g/mL in polypropylene syringes and dilutions in

0.9% sodium chloride in polyoleﬁne containers at 15.4 and These recommendations have to be taken into consider-

␮

343.3 g/mL were physically compatible and chemically ation only if the preparation is carried out according to the

◦

stable for at least 14 days at 4 C in the refrigerator and Good Manufacturing Practices in classiﬁed rooms. Biological

◦

at 20 C with or without any protection against light Safety Cabinet or isolators have to be used for the produc-

[44]. tion and the preparation process has to be validated to prove

The three drugs are very expensive and these long-term the sterility of the syringes or infusions.

stability studies allow the re-use of the preparation if the The use of these stability data can have a great impact

administration is canceled or postponed. for the patient (waiting time reduced or eliminated), for

the pharmaceutical (workload facilitated), for the nursing

staff (better availability of infusions) and for the economical

Short-term stability studies aspects (saving of vials).

L-Asparaginase (Kidrolase ) is an enzyme from

Escherichia coli used for the treatment of lymphocytic

Disclosure of interest

leukemia. Only one stability study was carried out by using

the enzymatic activity as biological criteria to evaluate The authors declare that they have no conﬂicts of interest

the stability [88]. The authors had studied dilutions in concerning this article.

serum saline and ringer lactate in polyoleﬁne and poly-

ethylene bags. The enzymatic activity proved to be stable

◦

for 7 days after storage at 8 C with only a 8% drop in 3

Nicolson O, d’Hayer B, Vieillard V, Dollet S, Astier A, Paul M.

activity.

Stability of diluted L-asparaginase in normal saline solution. Poster

The presented work is the ﬁrst study evaluating the sta- presented at the ECCO Congress Stockholm 2011 — submitted to

bility by using several physico-chemical methods according publication, available on Stabilis.(www.stabilis.org).

SFPO and ESOP recommendations for the practical stability of anticancer drugs 387

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