Biowaiver Monographs for Immediate Release Solid Oral Dosage

Forms: Levooxacin
MARCELLE O. KOEPPE,
1
RODRIGO CRISTOFOLETTI,
1
EDUARDO F. FERNANDES,
1
SILVIA STORPIRTIS,
2
HANS E. JUNGINGER,
3
SABINE KOPP,
4
KAMAL K. MIDHA,
5
VINOD P. SHAH,
6
SALOMON STAVCHANSKY,
7
JENNIFER B. DRESSMAN,
8
DIRK M. BARENDS
9
1
Brazilian Health Surveillance Agency (Anvisa), Division of Bioequivalence, Brazil
2
Faculty of Pharmaceutical Sciences, University of S ao Paulo, Brazil
3
Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand
4
World Health Organization, Geneva, Switzerland
5
University of Saskatchewan, Saskatoon, Saskatchewan, Canada
6
International Pharmaceutical Federation FIP, The Hague, the Netherlands
7
Pharmaceutics Division , College of Pharmacy, University of Texas at Austin, Austin, Texas 78712
8
Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany
9
RIVMNational Institute for Public Health and the Environment, Bilthoven, the Netherlands
Received 13 September 2010; revised 2 November 2010; accepted 2 November 2010
Published online 21 January 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22413
ABSTRACT: Literature data relevant to the decision to allowa waiver of in vivo bioequivalence
(BE) testing for the approval of immediate release (IR) solid oral dosage forms containing
levooxacin as the only active pharmaceutical ingredient (API) are reviewed. According to the
current Biopharmaceutics Classication System, levooxacin can be assigned to Class I. No
problems with BE of IR levooxacin formulations containing different excipients and produced
by different manufacturing methods have been reported and hence the risk of bioinequivalence
caused by these factors appears to be low. In addition, levooxacin has a wide therapeutic
index. On the basis of this evidence, a biowaiver is recommended for IR solid oral dosage
forms containing levooxacin as the single API provided that (a) the test product contains only
excipients present in IR levooxacin drug products that have been approved in International
Conference on Harmonization (ICH) or associated countries and which have the same dosage
form; (b) both the test and comparator dosage form are very rapidly dissolving or rapidly
dissolving with similarity of the dissolution proles demonstrated at pH 1.2, 4.5, and 6.8; and
(c) if the test product contains polysorbates, it should be both qualitatively and quantitatively
identical to its comparator in terms of polysorbate content. 2011 Wiley-Liss, Inc. and the
American Pharmacists Association J Pharm Sci 100:16281636, 2011
Keywords: levooxacin; absorption; Biopharmaceutics Classication System (BCS); perme-
ability; regulatory science; solubility
Correspondence to: D.M. Barends (Telephone: 31-30-274-4209;
Fax: 31-30-2744462; E-mail: dirk.barends@rivm.nl)
A project of the International Pharmaceutical Federation FIP,
Special Interest Group BCS & Biowaiver, www.p.org/bcs. This
article reects the scientic opinion of the authors and not nec-
essarily the policies of regulating agencies, the International
Pharmaceutical Federation (FIP) and the World Health Orga-
nization (WHO), nor the Brazilian Health Surveillance Agency
(Anvisa).
Journal of Pharmaceutical Sciences, Vol. 100, 16281636 (2011)
2011 Wiley-Liss, Inc. and the American Pharmacists Association
INTRODUCTION
A biowaiver monograph based on literature data is
presented on levooxacin, with respect to its biophar-
maceutical properties and the risk of waiving in vivo
bioequivalence (BE) testing in the approval of new
immediate release (IR) solid oral dosage forms
containing levooxacin, including both reformu-
lated products and new multisource drug products.
This evaluation refers to drug products containing
1628 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011
BIOWAIVER MONOGRAPH FOR LEVOFLOXACIN 1629
levooxacin as the only active pharmaceutical ingre-
dient (API) and not to combination products. The pur-
pose and scope of this series of monographs have been
previously discussed.
1
Summarized in few words, the
aim is to evaluate all pertinent data available from
literature sources for a given API to assess the risks
associated with a biowaiver. For these purposes, risk
is dened as the probability of an incorrect biowaiver
decision as well as the consequences of the decision
in terms of public health and individual patient risks.
On the basis of these considerations, a recommenda-
tion can be made as to whether a biowaiver approval
is advisable or not. This systematic approach to rec-
ommend or advise against a biowaiver decision is re-
ferred to in the recently published World Health Or-
ganization (WHO) guideline.
2
These monographs do
not intend to simply apply the WHO,
2
United States
Food and Drug Administration (FDA),
3
and/or Euro-
pean Medicine Agency (EMA) Guidance,
4
but aimalso
as a critical evaluation of these and other countries
regulatory documents. Biowaiver monographs have
already been published for several APIs, also avail-
able online at www.p.org/bcs.
5
Experimental
Literature data were obtained from Web of Science,
PubMed, and Micromedex databases up to Decem-
ber 2009. The keywords used for searching were
levooxacin, intestine absorption, linear absorption,
absolute bioavailability (BA), BE, log P, solubility,
permeability, and lipophilicity. Information was also
obtained fromregulatory documents published by the
WHO,
2
the FDA,
3
and the EMA.
4
GENERAL CHARACTERISTICS
Levooxacinum/Levooxacin (INN),
6
(-)-(S)-9-uoro-
2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-
oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic
acid.
6,7
The molecule exists as a zwitterion at the pH
conditions in the small intestine. The commercially
available drug substance is the hemihydrate with
the empirical formula C
18
H
20
FN
3
O
4

1
2
H
2
O and
containing 97.6% levooxacin by mass.
8
Its structure
is shown in Figure 1.
Stereochemistry
Levooxacin is the S-(-) isomer of the racemic drug
substance ooxacin; it is signicantly more active
against bacterial pathogens than R-(+)-ooxacin.
6,7
Therapeutic Indication
Levooxacin has a broad spectrum of in vitro
activity against Gram-positive and Gram-negative
bacteria.
8,9
In Brazil, its labeled indications include
treatment of adults ( 18 years old) with mild, mod-
Figure 1. Structure of levooxacin hemihydrate (Molec-
ular weight = 370.38).
erate, and severe infections caused by susceptible
strains such as upper and lower respiratory tract
infection, infection of skin and/or subcutaneous tis-
sue, urinary tract infection, acute pyelonephritis,
osteomyelitis, related septicemia/bacteremia, intra-
abdominal infections, prostatitis, and nosocomial
pneumonia.
10
In the United States (US) in addition
to the above-mentioned indications, levooxacin has
been approved to treat infection caused by inhaled
anthrax (prophylaxis or postexposure).
11
Also, accord-
ing to the 16th edition of WHOs Essential Medicines
List, levooxacin may be used as an alternative to
ooxacin in the treatment of multidrug resistant
tuberculosis.
12
Therapeutic Index and Toxicity
Levooxacin exhibits a low potential for acute tox-
icity. The median lethal dose (LD
50
) values were
around 1800 mg/kg for mice, 1500 mg/kg for rats, and
more than 250 mg/kg in female monkeys.
13
Gener-
ally, its serum and tissue levels do not require rou-
tine monitoring.
911
Depending on the indication, the
dosage regimen can vary from 250 mg daily for 3
days to 500 mg daily for 28 days. Daily doses can
be as high as 750 mg.
813
The most common adverse
reactions ( 3%) in humans are nausea, headache,
diarrhea, insomnia, constipation, and dizziness.
19
Dysglycemia
2023
and liver disorders
24,25
in associa-
tion with levooxacin have been reported in the liter-
ature. Disturbances of blood glucose levels are labeled
in the product monograph.
9
As with other quinolones,
disturbances of blood glucose, including symptomatic
hyper and hypoglycemia, have been reported, usu-
ally in diabetic patients receiving concomitant treat-
ment with an oral hypoglycemic agent (e.g., glyburide/
glibenclamide) or with insulin. In these patients, care-
ful monitoring of blood glucose is recommended.
811
Postmarketing reports of severe hepatotoxicity (in-
cluding acute hepatitis and fatal events) have been
received for patients treated with levooxacin. The
majority of fatal hepatotoxicity reports occurred in
patients with 65 years old or older and most were not
associated with hypersensitivity.
19,2529
Rare cases of sensory or sensorimotor axonal
polyneuropathy affecting small and/or large axons
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011
1630 KOEPPE ET AL.
resulting in paresthesias, hypoesthesias, dysesthe-
sias, weakness, and infrequent cases of arrhyth-
mia have been reported.
811
Clinical pharmacologic
studies performed with supratherapeutic doses also
showed an increase in QT intervals.
10,19
The risk of
developing levooxacin-associated tendinitis and ten-
don rupture is further increased in older patients
(usually dened as over 60 years old), in those tak-
ing corticosteroid drugs, and in patients with kidney,
heart, or lung transplants. In this case the therapy
should be discontinued.
19,26
CHEMICAL PROPERTIES
Solubility
The solubility of levooxacin in water is around
25 mg/mL (temperature not reported, presumably
ambient).
1933
Levooxacin shows pH-dependent sol-
ubility. Over the pH range of 25, the solubility is es-
sentially constant, approximately 200 mg/mL; above
pH5.5, the solubility increases to a maximumvalue of
approximately 300 mg/mL at about pH 6.5, whereas
above pH 6.5, the solubility decreases and reaches its
minimum value of approximately 30 mg/mL at about
pH 7.5. All these data were taken at 20

C.
34
Polymorphs
Three polymorphic forms (anhydrous ", $, () and two
pseudopolymorphic forms (hemihydrate and mono-
hydrate) of levooxacin occurs, depending on the
temperature used in the manufacturing process.
35,36
Polymorph-dependent BA has not been reported.
Partition Coefcient (log P)
Log P and log D (pH 7) values of 1.49 0.79 and
1.35, respectively, were calculated for levooxacin
by using the software Solaris v4.67 (ACD/Labs,
Toronto, Canada).
37
The temperature was not re-
ported, presumably ambient. Other authors reported
a log P of 0.40 without reporting the experimental
conditions.
34
PKa
Levooxacin is a zwitterionat physiological pH,
38
pos-
sessing a carboxylic group with pKa = 5.5, a piper-
azinyl group with pKa = 8.0 and another proton-
accepting function with pKa = 6.8 0.3.
37
Available Dosage Form Strengths
The WHO Essential Medicines List includes lev-
ooxacin as an alternative for ooxacin, based on
availability and programme considerations; however,
no dosage formand dosage formstrengths are given.
39
Other WHO documents report 500 mg
40
and 250 mg,
500 mg and 750 mg tablets, respectively.
41
Commer-
cially available are tablets of 250, 500, and 750 mg
(Table 1).
PHARMACOKINETIC PROPERTIES
Absorption and BA
The pharmacokinetics of levooxacin is well described
by a linear two-compartment open model with rst-
order elimination. Plasma concentrations in healthy
volunteers reach a mean peak drug plasma concentra-
tion (C
max
) of approximately 2.8 and 5.2 mg/L within
12 h after oral administration of levooxacin 250
and 500 mg tablets, respectively.
8
The BA of oral lev-
ooxacin is very rapid and approaches 100%and is lit-
tle affected by administration with food.
8,10,19,34,4245
Frick et al.
34
calculated the in vivo dissolution of lev-
ooxacin tablets by numerical deconvolution fromthe
plasma concentrations measured in a BA study com-
paring intravenous infusion versus oral administra-
tion, and estimated that more than 80% of the oral
dose had been absorbed after 1 h, which was inter-
preted as indicating that gastric emptying controls
the absorption rate. Single oral doses of levooxacin
from50 to 1000 mg produce a mean C
max
and area un-
der the plasma concentrationtime curve (AUC) from
approximately 0.6 to 9.4 mg/L and 4.7 to 108 mgh/
L, respectively, both increasing linearly in a dose-
proportional fashion.
8,19
The pharmacokinetics of lev-
ooxacin is similar during multiple- and single-dose
regimens.
8,19,41,46
Although chelation of levooxacin
by divalent cations can occur, it is less marked than
with other uoroquinolones.
47,48
The BA of oral lev-
ooxacin (100 mg) was reduced signicantly during
concomitant administration of aluminum hydroxide
1 g (by 44%), magnesium oxide 500 mg (by 22%), and
ferrous sulfate 160 mg (by 19%).
49
Permeability
The log P values reported differ widely. However, as
human BA data are available, partition coefcient
data can be disregarded for the permeability classi-
cation of levooxacin. Because levooxacin is a zwit-
terionic compound, passive diffusion may not fully
explain the high intestinal absorption.
46
In Caco-2
cells the apical inux clearance value at pH 6 was
much greater than the basolateral inux clearance
value, suggesting uptake across the apical membrane
in Caco-2 cells to be mediated by a specic trans-
port system.
50
A good correlation was found between
the expression levels of organic anion transporting
polypeptide 1A2 (OATP 1A2) and levooxacin inux
clearance in Caco-2 cells.
46
The in vitro permeability
of levooxacin was evaluated using a suitable Caco-
2 assay according to the criteria in the Biopharma-
ceutics Classication System (BCS) Guidance.
3,51,52
Metoprolol, labetalol, and atenolol served as high
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011 DOI 10.1002/jps
BIOWAIVER MONOGRAPH FOR LEVOFLOXACIN 1631
Table 1. Excipients
a
Present in Levooxacin IR Solid Oral Drug Products with a Marketing Authorization (MA)
b
in a Number of
Countries
c
and the Minimal and Maximal Amount of that Excipient Present Pro Dosage Unit in Solid Oral Drug Products with a MA in
the US
Excipient
Drug products containing that excipient with a MA
granted by the named country
Range present in solid oral
dosage forms with a MA in
the US (mg)
Cellulose BR (1,2) CA (311) CZ (1215) DE (16) DK (1719) ES (2029) FI (30,31)
FR (32,33) HU (3436) IE (3740) IL (41) NL (4248) SE (4951) UK (52)
US (53,54)
4.61385
d
Copovidone CA (911) DK (17,19) ES (21) FI (30) HU (35) IE (37) 357854
Croscarmellose sodium BR (55) CA (5,56,57) CZ (58) DK (59) ES (6062) HU (6365) IE (66,67)
NL (68,69)
2180
Crospovidone BR (1,2) CA (3,4,611) CZ (1215) DE (16) DK (1719) ES (2029) FI (30,31)
FR (32,33) HU (3436) IE (3740) IL (41) NL (4248) SE (4951) UK (52)
US (53,54)
4.4792
d
Glycerol dibehenate BR (55) CA (57) CZ (58) DK (59) ES (6062) HU (64,65) IE (66) NL (68) 2.514
Hydroxypropylcellulose BR (55) CA (3,8,56,57) CZ (14) DK (18) ES (22) HU (63) IE (38,67) NL (4347,69)
SE (49,51)
4132
Hypromellose BR (1,2,55) CA (48,10,56,57) CZ (12,13,15) DE (16) ES (20,2329) FI (31)
FR (32,33) HU (34,36) IE (39,40) IL (41) NL (42,48) SE (50) UK (52) US (53,54)
0.8537
Lactose BR (55) CA (57) CZ (58) DK (59) ES (6062) HU (64,65) IE (66) NL (68) 231020
d
Macrogols BR (1,2,55) CA (411,56,57) DE (16) ES (20,23,26,27) FR (32,33) US (53,54) 0.12961
d
Magnesium stearate BR (2 ) CA (411,56) CZ (1214) DK (18) ES (20,2224,26,27) FI (31) HU (63)
IE (38,67) NL (4348,69) SE (49,51) US (53,54)
0.15401
d
Methylcellulose CA (56) 2.8184
Polydextrose CA (7,10) 3.88.1
Polysorbates CA (4,6) US (53,54) 0.4418
d
Poly(vinylalcohol) CA (9,11) 0.720
Povidone BR (55) CA (5,57) CZ (58) DK (59) ES (6062) HU (64,65) IE (66) NL (68) 0.1780
Silica BR (55) CA (3,911,56,57) CZ (12,13,58) DK (17,19,59) ES (20,21,23,24,26,27,6062)
FI (30,31) HU (35,6365) IE (37,66,67) NL (68,69)
0.50100
Sodium starch
glycolate
BR (55) CA (57) CZ (58) DK (59) ES (6062) HU (6365) IE (66,67) NL (68,69) 2876
d
Sodium stearyl
fumarate
BR (1) CA (3) CZ (15) DE (16) DK (17,19) ES (21,25,28,29) FI (30) FR (32,33)
HU (34-36) IE (37,39,40) IL (41) NL (42) SE (50) UK (52)
1.226
Starch CA (5) 0.441135
d
Stearic acid CA (56) CZ (12,13) ES (20,23,24,26,27) FI (31) 0.972
d
Talc BR (1,55) CA (9,11,57) CZ (12,13,58) DE (16) DK (59) ES (20,23,24,26,27,6062)
FI (31) FR (32,33) HU (6365) IE (66,67) NL (48,68,69)
0.10220
d
Triacetin CA (7,10) 0.7215
1. TAVANIC
R
levooxacino. 2. Levaquin comprimido revestido 500 mg [Janssen-Cilag]. 3. CO LEVOFLOXACIN (levooxacin tablets 250/500/750 mg). 4.
LEVAQUIN (levooxacin tablets 250/500/750 mg). 5. Mylan-Levooxacin (levooxacin tablets 250/500 mg). 6. NOVO-LEVOFLOXACIN (levooxacin tablets
250 mg). 7. NOVO-LEVOFLOXACIN (levooxacin tablets 500 mg). 8. NOVO-LEVOFLOXACIN (levooxacin tablets 750 mg). 9. pms-LEVOFLOXACIN
(levooxacin tablets 250 mg). 10. pms-LEVOFLOXACIN (levooxacin tablets 500 mg). 11. pms-LEVOFLOXACIN (levooxacin tablets 750 mg). 12. Aobax
250/500 mg, potahovan e tablety. 13. Levooxacin Liconsa 250/500 mg potahovan e tablety. 14. Levooxacin Mylan 250/500 mg. 15. TAVANIC 250/500 mg. 16.
Tavanic 250/-500 mg Filmtabletten. 17. Levooxacin Nucleus, lmovertrukne tabletter (250/500 mg). 18. Voan, lmovertrukne tabletter (levooxacin
tablets 250/500 mg). 19. Felvosin, lmovertrukne tabletter (levooxacin 250/500 mg). 20. ASEY 500 mg comprimidos recubiertos con pelcula EFG. 21.
Levooxacino Actavis 250/500 mg comprimidos recubiertos con pelcula EFG. 22. Levooxacino MYLAN 250/500 mg comprimidos recubiertos con pelcula
EFG. 23. LEVOFLOXACINO NORMON 500 mg Comprimidos recubiertos con pelcula EFG. 24. Levooxacino Pensa 500 mg comprimidos recubiertos con
pelcula EFG. 25. Levooxacino ratiopharm 500 mg comprimidos recubiertos con pelcula EFG. 26. Levooxacino STADA 500 mg comprimidos recubiertos con
pelcula EFG. 27. LEVOFLOXACINO SUPPORT PHARMA 250/500 mg comprimidos recubiertos con pelcula EFG. 28. PRIXAR 250/500 mg comprimidos
recubiertos con pelcula. 29. TAVANIC 250/500 mg comprimidos recubiertos con pelcula. 30. Levooxacin Actavis 250/500 mg tabletti, kalvop a allysteinen. 31.
Levooxacin Liconsa 250/500 mg tabletit, kalvop a allysteiset. 32. TAVANIC 500 mg cp pellic s ec [Pharma Lab]. 33. TAVANIC 500 mg cp pellic s ec
[Sano-Aventis France]. 34. LevoWin 250/500 mg lmtabletta. 35. Levoxa 250/500 mg lmtabletta. 36. Tavanic 250/500/750 mg lmtabletta. 37. Levooxacin
Actavis 250/500 mg lm-coated tablets. 38. Tavager 250/500 mg lm-coated tablets. 39. Tavanic 250/500 mg lm-coated tablets [sano-aventis Ireland Ltd]. 40.
Tavanic 500mg Film-coated tablets [PCO Manufacturing Ltd]. 41. TAVANIC
R
500 and 250 mg tablets. 42. Tavanic 250/500 mg, lmomhulde tabletten 250/500
mg. 43. Levooxacine Mylan 250/500 mg, lmomhulde tabletten 250/500 mg. 44. Levooxacine 250/500 mg Mylan, lmomhulde tabletten 250/500 mg. 45.
Levooxacine Mylan 250/500 mg, lmomhulde tabletten 250/500 mg. 46. Levooxacine Mylan 250/500 mg, lmomhulde tabletten 250/500 mg. 47.
Levooxacine 250/500 mg Mylan, lmomhulde tabletten 250/500 mg. 48. Levooxacine advisors 250/500 mg lmomhulde tabletten. 49. Levooxacin Mylan
250/500 mg lmdragerad tablett. 50. Tavanic 250/500 mg lmdragerad tablett. 51. Voan 250/500 mg tablett. 52. Tavanic 250/500 mg lm-coated tablet. 53.
LEVAQUIN (levooxacin) tablet, lm coated (250/500/750 mg)[McNeil Pharmaceuticals]. 54. LEVAQUIN (levooxacin) tablet, lm coated (250/500/750
mg)[Ortho-McNeil-Janssen Pharmaceuticals Inc.]. 55. Levooxacino 250 mg e 500 mg. 56. APO-LEVOFLOXACIN (levooxacin tablets 250/500/750 mg). 57.
SANDOZ LEVOFLOXACIN (levooxacin tablets 250/500/750 mg). 58. Levooxacin ZAK 250/500 mg potahovan e tablety. 59. Levooxacin Lek,
lmovertrukne tabletter (levooxacin tablets 250/500 mg). 60. Levooxacino Acost 500 mg comprimidos recubiertos con pelcula EFG. 61. Levooxacino Bexal
500 mg comprimidos recubiertos con pelcula EFG. 62. Levooxacino Sandoz 500 mg comprimidos recubiertos con pelcula EFG. 63. Leokin 250/500 mg
lmtabletta. 64. Levooxacin 1 A Pharma 500 mg lmtabletta. 65. Levooxacin Sandoz 250/500 mg lmtabletta. 66. Levooxacin 250/500 mg lm-coated
tablets. 67. Levooxacin Teva 250/500 mg Film-Coated Tablets. 68. Levooxacine Sandoz 250/500 mg, lmomhulde tabletten. 69. Levooxacine 250/500 mg
PCH, lmomhulde tabletten.
a
Colorants, avors, and ingredients present in the coating and/or the printing ink are not included.
b
The approval of a drug product by the local regulatory authority. Also the terms Drug approval and registration, are used.
c
Abbreviations of the countries: see, text.
d
The upper range value reported is unusually high for solid oral dosage forms and the authors doubt its correctness.
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011
1632 KOEPPE ET AL.
permeability and low permeability reference stan-
dards and an apparent permeability coefcient (P
app
)
of levooxacin of 28.36 1.93 10
6
cm/s was re-
ported. In the same study, metoprolol, labetalol, and
atenolol showed P
app
values of 29.88 3.17 10
6
cm/
s, 18.05 1.90 10
6
cm/s, and 1.86 0.47 10
6
cm/
s, respectively; hence, levooxacin was classied as
highly permeable. The authors also concluded that
levooxacin is an efux protein substrate, although
its efux ratio was only 4:1.
52
According to the Bio-
pharmaceutical Drug Disposition Classication Sys-
tem (BDDCS), extensive metabolism of an API indi-
cates a high permeability.
53,54
Levooxacin is mainly
eliminated by renal excretion of the unaltered drug,
hence not extensively metabolised,
8,19,5557
suggest-
ing levooxacin not to be highly permeable.
53,54
How-
ever, BDDCS was developed as a surrogate systemfor
situations in which no BA data are available, which
is not so for levooxacin. Moreover, discrepancies be-
tween BCS and BDDCS have been observed.
53,54,5860
Distribution, Metabolism, and Elimination
Levooxacin is widely distributed throughout the
body, with a mean volume of distribution of 1.1 L/
kg and penetrates well into most body tissues and
uids. It is approximately 24%38% bound to serum
plasma proteins (primarily albumin).
8,19
The drug un-
dergoes limited metabolism in humans and is pri-
marily excreted as unchanged drug in the urine.
The only metabolites identied in humans are the
desmethyl and N-oxide inactive metabolites, which
account for less than 5% of a dose.
19
Following oral
administration in healthy volunteers or patients with
complicated urinary infections or pyelonephritis, ap-
proximately 80%87% of an administered dose was
recovered as unchanged drug in urine,
8,19,5557
whereas less than 4% of the dose was recovered
in feces.
19
The excretion occurs through glomeru-
lar ltration and tubular secretion. Renal clearance
and total body clearance are highly correlated
with creatinine clearance (Cl
cr
), and dosage ad-
justments are required in patients with signicant
renal dysfunction.
8,19
The mean terminal plasma
elimination half-life of levooxacin ranges from ap-
proximately 6 to 8 h following single or multiple doses
of levooxacin given orally or intravenously.
8,19
DOSAGE FORM PERFORMANCE
BE Studies
Two reports in the literature have demonstrated
BE of two different generic formulation of oral lev-
ooxacin (500 mg) marketed in Mexico and Tavanic
R
(500 mg).
61,62
In the rst report, 26 healthy volun-
teers (14 men and 12 women) were enrolled and the
90% condence intervals (CIs) for log-transformed
C
max
, AUC
024
, and AUC
0-
were 94.48%106.22%,
90.01%116.44%, and 85.11%114.00%, respectively.
The composition of the formulation was not
reported.
61
In the second report, BE was assessed in
27 male healthy subjects. The CIs for log-transformed
C
max
, AUC
024
, and AUC
0-
were 95.57%111.97%,
102.73%106.36%, and 102.04%106.75%, respec-
tively. The composition of formulation was not
reported.
62
All the results meet the current BE
criteria.
Excipients
Excipients present in IR levooxacin tablets with
a marketing authorization (MA)

in BR
63
, Canada
(CA)
64
, Czech Republic (CZ)
65
, Germany (DE)
66
, Den-
mark (DK)
67
, Spain (ES)
68
, Finland (FI)
69
, France
(FR)
70
, Hungary (HU)
71
, Ireland (IE)
72
, Israel (IL)
73
,
the Netherlands (NL)
74
, Sweden (SE)
75
, United King-
dom (UK),
76
and US
77
are summarized in Table 1. In
view of their MAs and national regulations, it can be
inferred that the drug products listed in Table 1 suc-
cessfully passed an in vivo BE study or clinical trial.
Because one formulation will most probably be regis-
tered in several countries, these drug products corre-
spond to a far lower number of formulations. Also, it
cannot be taken for granted that each and every reg-
istered drug product has successfully met the current
in vivo BE criteria.
78
Nevertheless, it seems safe to
conclude that the risk of bioinequivalence caused by
an excipient effect is low for excipients present in a
large number of registered drug products, when the
excipient is present in amounts not exceeding its nor-
mal use in IR tablets. Table 1 shows the range of that
excipients present in solid oral dosage forms with a
MA in the US.
79
The approval of a drug product by
the local regulatory authority. Also, the terms Drug
Approval and Registration are used.
Dissolution
A dissolution method for levooxacin tablets is not
included in present editions of the USP, European
Pharmacopoeia, British Pharmacopoeia, or the In-
ternational Pharmacopoeia,
8083
but the dissolution
methods database of the FDA contains a test for lev-
ooxacin tablets: USP Apparatus I (basket), 100 rpm,
medium900 mL of 0.1 N HCl at 37

C.
84
In the phar-
macokinetic study of Frick et al.,
34
the drug prod-
uct showing more than 80% of the dose absorbed af-
ter 1 h was also tested by in vitro dissolution; more
than 80% of the dose was dissolved in 30 min under
the following conditions: basket, 100 rpm, 900 mL of
0.1 N HCl.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011 DOI 10.1002/jps
BIOWAIVER MONOGRAPH FOR LEVOFLOXACIN 1633
DISCUSSION
Solubility
According to the current regulatory guidances, an API
is highly soluble if its dose/solubility ratios (D/S) is
250 mLor less at the pHrange of 1.06.8
2,4
or 1.07.5
3
at 37

C, in which dose is to be understood as highest

dose strength
2,3
or highest single dose administered.
4
Levooxacins D/S at pH 1.07.5 are over the range
from 2.5 to 25 mL, based on 750 mg of levooxacin
as the highest dosage strength and also the highest
single dose administered, and thus far less than the
D/S cut-off for the high solubility biowaiver criteria.
However, these data refer to 20

C, not at 37

C.
24
But,
if levooxacin, like most APIs, has an endothermic
heat of solution, it can be assumed that it will exhibit
a higher solubility at 37

C. Therefore, it seems safe to

conclude that levooxacin is highly soluble according
to BCS criteria.
24
Permeability
Because its BA is nearly complete following oral ad-
ministration, levooxacin is highly permeable accord-
ing to all BCS criteria.
24,8,19,4245,5557
Data from
Caco-2 studies support this classication.
34,52
BCS Classication
According to all current BCS class denitions,
24
lev-
ooxacin can be assigned to BCS I. Frick et al.
34
and
the WHO
40,85,86
reached the same classication.
Risks with Respect to Excipient and/or Manufacturing
Variations
No study directly investigating the inuence of ex-
cipients on the absorption of levooxacin has been
reported. Moreover, there is no report of bioinequiva-
lence seen in the literature.
Surrogate Techniques for in vivo BE Testing
In the highly unlikely case that a test product is
bioinequivalent, and that this is caused by a large
difference in in vivo desintegration and/or in vivo dis-
solution between test product and comparator, it is
most likely that comparative in vitro dissolution of
the test product versus its comparator in the three
biowaiver-relevant media
24
will be able to detect the
difference.
There is presently no surrogate technique for in
vivo BE testing able to detect BE caused by a dif-
ference in in vivo permeability between test product
and comparator, but this risk will be low if the test
product contains only excipients also present in IR
levooxacin drug products approved in ICH or asso-
ciated countries in the same dosage form, as listed on
Table 1.
However, one of the excipients listed in Table 1,
polysorbates,
87
may have an effect on the in vivo per-
meability. Also, levooxacin has been reported to be a
substrate of uptake transporters like OATP1A2
46
and
efux transporters,
52
and in view of these more criti-
cal permeability characteristics, more stringent crite-
ria are recommended when polysorbates are present
in the test product. In that case, the test prod-
uct should be both qualitatively and quantitatively
identical to its comparator in terms of polysorbate
content.
4
Patients Risks Associated with Bioinequivalence
According to the Code of Federal Regulations, an API
has a narrow therapeutic index when there is less
than a twofold difference in LD
50
and median effec-
tive dose (ED
50
) values, and/or safe and effective use
of the drug products requires careful dosage titra-
tion and patient monitoring.
88
Because the LD
50
in
rats is 1500 mg/kg
13
and the ED
50
range in rats is
0.1816.3 mg/kg,
89
resulting in an almost 10-fold dif-
ference, and there is generally no need to monitor
blood levels, levooxacin can be considered as a wide
therapeutic index drug, according to the US FDA.
88
Furthermore, Health Canada published a guidance
including drugs which commonly exhibit adverse ef-
fects that limit the therapeutic use to doses close to
those required for the therapeutic effect (e.g., nar-
row therapeutic range drugs) or drugs for which the
therapeutic use may result in dose or concentration-
dependent adverse effects, which are persistent, irre-
versible or slowly-reversible, or life threatening (e.g.,
highly toxic drugs), and this list does not include
levooxacin.
90
Further, levooxacin is not on the list
of Narrow Therapeutic Range Drugs of the Japanese
Health Authorities.
91
Despite the low potential of lev-
ooxacin for acute toxicity
19
and its acceptance as a
wide therapeutic index drug, it is nonetheless advis-
able to monitor blood glucose levels in diabetic pa-
tients and monitor hepatic functions in patients 60
years old or older taking levooxacin.
19
CONCLUSION
A biowaiver for IR solid oral dosage forms containing
levooxacin is scientically justied, provided that (a)
the test product contains only excipients present in IR
levooxacin drug products approved in ICH or asso-
ciated countries in the same dosage form; (b) both
the test and comparator dosage form are very rapidly
dissolving or rapidly dissolving with similarity of the
dissolution proles demonstrated at pH 1.2, 4.5, and
6.8; and (c) if the test product contains polysorbates, it
should be both qualitatively and quantitatively iden-
tical to its comparator in terms of polysorbate content.
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011
1634 KOEPPE ET AL.
ACKNOWLEDGMENTS
Arthur da Silva, Camila Costa, Camila Redigu-
ieri, Cristina Serra, Diana Nunes, Jacqueline de
Souza, Kelen Soares, Varley Sousa, Taina Nunes,
and Valentina Porta are acknowledged for helping
the construction of this monograph that is a product
fromthe work of Brazilian Biowaiver Working Group.
Kik Groot, RIVM, is acknowledged for producing
Table 1.
REFERENCES
1. Vogelpoel H, Welink J, Amidon GL, Junginger HE, Midha KK,
M oller H, Olling M, Shah VP, Barends DM. 2004. Biowaiver
monographs for immediate release solid oral dosage forms
based on biopharmaceutics classication system (BCS) liter-
ature data: Verapamil hydrochloride, propranolol hydrochlo-
ride, and atenolol. J Pharm Sci 93:19451956.
2. WHO. 2006. Proposal to waive in vivo bioequivalence require-
ments for WHO model list of essential medicines immediate-
release, solid oral dosage forms. Technical Report Series,
No 937, 40th Report, Annex 8 of WHO Expert Commit-
tee on Specications for Pharmaceutical Preparations. Ac-
cessed November 20, 2009, at: http://whqlibdoc.who. int/trs/
WHO TRS 937 eng.pdf.
3. USDepartment of Health and Human Services, Food and Drug
Administration, Center for Evaluation and Research (CDER).
2000. Guidances for industry: Waiver of in vivo bioavailabil-
ity and bioequivalence studies for immediate-release solid
oral dosage forms based on a Biopharmaceutics Classication
System. Accessed November 20, 2009, at: http://www.fda.gov/
CDER/GUIDANCE/3618fnl. pdf.
4. European Medicines Agency (EMA), Committee for Pro-
prietary Medicinal Products (CPMP). 2001. Note for
Guidance on the Investigation of Bioavailability and
Bioequivalence. Accessed November August 05, 2010,
at: http://www.ema.europa.eu/docs/en GB/document library/
Scientic guideline/2010/01/WC500070039.pdf.
5. International Pharmaceutical Federation (FIP). 2009. Special
Interest Group on BCS & Biowaiver. Accessed November 20,
2009, at: http://www.p.org/bcs.
6. World Health Organization (WHO). 1990. Guidance on
INN. Accessed November 20, 2009, at: http://www.who.int/
medicines/services/inn/innquidance/en.
7. Martindale. 2006. The Complete Drug Reference, Elec-
tronic Version. Accessed November 20, 2009, at: http://
www.medicinescomplete.com/mc/martindale/2006.
8. Fish DN, Chow AT. 1997. The clinical pharmacokinetics of
levooxacin. Clin Pharmacokinet 32(2):101119.
9. Levaquin (levooxacin) [product monograph]. 2006. Toronto:
Janssen-Ortho Inc.
10. Bul ario eletr onico ANVISA. Accessed November 10, 2009,
at: http://www.anvisa.gov.br/bularioeletronico.
11. Micromedex
R
Healthcare Series. Accessed November 20,
2009, at: https://www.thomsonhc.com/hcs/librarian/CS/
EA2F61/PFActionId/pf.HomePage/ssl/true.
12. World Health Organization (WHO). 2009. WHO Model
Lists of Essential Medicines, 16th ed. Accessed Au-
gust 05, 2010, at: http://www.who.int/medicines/publications/
essentialmedicines/Updated sixteenth adult list en.pdf.
13. Kato M, Furuhama K, Yoshida M, Akahane K, Takayama
S. 1992. Acute oral toxicity of the new quinolone antibacte-
rial agent levooxacin in mice, rats, and monkeys. Arzneimit-
telforschung 43(3A):365366.
14. Davis R, Bryson HM. 1994. Levooxacin: A review of its an-
tibacterial activity, pharmacokinetics and therapeutic efcacy.
Drugs 4:677700.
15. Martin SJ, Meyer JM, Chuck SK, Jung R, Messick CR, Pend-
land SL. 1998. Levooxacin and sparoxacin: New quinolone
antibiotics. Ann Pharmacother 32:320336.
16. Martin SJ, Jung R, Garvin CG. 2001. A risk-benet assess-
ment of levooxacin in respiratory, skin and skin structure,
and urinary tract infections. Drugs 24:199222.
17. Croom KF, Goa KL. 2003. Levooxacin: A review of its use
in the treatment of bacterial infections in the United States.
Drugs 63:27692802.
18. Anderson VR, Perry CM. 2008. Levooxacin: Areviewof its use
as a high-dose, short-course treatment for bacterial infection.
Drugs 68:535565.
19. Food and Drug Administration (FDA). 2009. Levaquin la-
bel. Accessed November 20, 2009, at: http://www.accessdata.
fda.gov/drugsatfda docs/label/2008/021721s020 020635s57
020634s52 lbl.pdf.
20. Park-Wyllie LY, Juurlink DN, Kopp A, Shah BR, Stukel TA,
Stumpo C, Dresser L, Low DE, Mamdani MM. LY 2006 Out-
patient gatioxacin therapy and dysglycemia in older adults.
N Engl J Med 354(13):13521361.
21. Friedrich LV, Dougherty R. 2004. Fatal hypoglycemia associ-
ated with levooxacin. Pharmacotherapy 24(12):18071812.
22. Garon N, Cloutier I. 2001. Une hypoglyc emie associ ee ` a la
l evooxacine (Levaquin). Qu ebec Pharmacie 48(1):7174.
23. Saraya A, Yokokura M, Gonoi T, Seino S. 2004. Effects of uo-
roquinolones on insulin secretion and a-cell ATP-sensitive K+
channels. Eur J Pharmacol 497(1):111117.
24. Papastavros T, Dolovich LR, Holbrook A, Whitehead L, Loeb
M. 2002. Adverse events associated with pyrazinamide and
levooxacin in the treatment of latent multidrug-resistant tu-
berculosis. CMAJ 167(2):131136.
25. Schwalm JD, Lee CH. 2003. Acute hepatitis associated
with oral levooxacin therapy in hemodialysis. CMAJ
168(7):847848.
26. Petri WA. 2001. Goodman & Gilmans. The pharmacological
basis of therapeutics, 10th ed. New York: McGraw-Hill Medi-
calPublishing Division.
27. Kaplowitz N. 2004. Drug-induced liver injury. Clin Infect Dis
38(Suppl 2):S44S48.
28. Canadian Adverse Reaction Newsletter, Volume 17(1), Jan-
uary 2007.
29. World Health Organization (WHO). 2007. The International
Pharmacopoeia: Draft Proposal for the International Pharma-
copoeia (October 2006). WHO Drug Information Vol 21, No. 1,
2007 Recent Publications, Information, and Events. Accessed
at: http://whqlibdoc.who.int/druginfo/21 1 2007.pdf.
30. Beyer R, Pestova E, Millichap JJ, Stosor V, Noskin GA, Pe-
terson LR. 2000. A convenient assay for estimating the possi-
ble involvement of efux of uoroquinolones by Streptococcus
pneumoniae and Staphylococcus aureus: Evidence for dimin-
ished moxioxacin, sparoxacin, and trovaoxacin efux. An-
timicrob Agents Chemother 44:798801.
31. Puustj arvi T, Ter asvirta M, Nurmenniemi P, Lokkila J, Uusi-
talo H. 2006. Penetration of topically applied levooxacin 0.5%
and ooxacin 0.3% into the vitreous of the non-inamed hu-
man eye. Graefes Arch Clin Exp Ophthalmol 244:16331637.
32. Fukuda M, Sasaki K. 1995. In vitro topically applied uo-
roquinolone penetration into the anterior chamber. Nippon
Ganka Gakkai Zasshi 99(5):532536.
33. Robertson SM, Curtis MA, Schlech BA, Rusinko A, Owen GR,
Dembinska O, Liao J, Dahlin DC. 2005. Ocular pharmacoki-
netics of moxioxacin after topical treatment of animals and
humans. Surv Ophthalmol 50(Suppl 1):S32S35.
34. Frick A, Moller H, Wirbitzki E. 1998. Biopharmaceutical
characterization of oral immediate release drug products.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011 DOI 10.1002/jps
BIOWAIVER MONOGRAPH FOR LEVOFLOXACIN 1635
In vitro/in vivo comparison of phenoxymethylpenicillin potas-
sium, glimepiride and levooxacin. Eur J Pharm Biopharm
46(3):305311. Solubility data were read from Fig 1.
35. Niddam-hildesheim V, Gershon N, Amir E, Wizel S.
2006. Patent EP1451194. Preparation of levooxacin hemi-
hydrate. Teva Pharmaceutical Industries Ltd. Accessed
November 23, 2009, at: http://www.freepatentsonline.com/
EP1451194B1.html.
36. Kitaoka H, Wada C, Moroi R, Hakusui H. 1995. Effect of dehy-
dration on the formation of Levooxacine Pseudopolymorphs.
Chem Pharm Bull 43(4):649653.
37. Michot JM, Seral C, Van Bambeke F, Mingeot-Leclercq
MP, Tulkens PM. 2005. Inuence of efux transporters
on the accumulation and efux of four quinolones
(ciprooxacin, levooxacin, garenoxacin, and moxioxacin)
in J774 macrophages. Antimicrob Agents Chemother
49(6):24292437.
38. Yano I, Ito T, Takano M, Inui K. 1997. Evaluation of renal tubu-
lar secretion and reabsorption of levooxacin in rats. Pharm
Res 14(4):508511.
39. World Health Organization (WHO). 2009. WHO Model Lists
of Essential Medicines, 16th ed. Accessed November 20,
2009, at: http://www.who.int/selection medicines/committees/
expert/17/sixteenth adult list en.pdf.
40. World Health Organization (WHO). 2009. Biopharmaceu-
tics Classication System (BCS)-based biowaiver appli-
cations: Anti-tuberculosis medicines. Accessed November
20, 2009, at: http://apps.who.int/prequal/info applicants/BE/
BW TB 2009February.pdf.
41. World Health Organization (WHO). 2009. Recommended
comparator products: anti-tuberculosis medicines. Ac-
cessed November 20, 2009, at: http://apps.who.int/prequal/
info applicants/BE/Comparators-TB2009--28September.pdf.
42. Chulavatnatol S, Chindavijak B, Vibhagool A, Wananukul W,
Sriapha C, Sirisangtragul C. 1999. Pharmacokinetics of lev-
ooxacin in healthy Thai male volunteers. J Med Assoc Thai
82(11):112735.
43. Furlanut M, Brollo L, Lugatti E, Di Qual E, Dolcet F, Talmas-
sons G, Pea F. 2003. Pharmacokinetic aspects of levooxacin
500 mg once daily during sequential intravenous/oral therapy
in patients with lower respiratory tract infections. J Antimi-
crob Chemother 51(1):101106.
44. Chien SC, Rogge MC, Gisclon LG, Curtin C, Wong F, Natara-
jan J, Williams RR, Fowler CL, Cheung WK, Chow AT. 1997.
Pharmacokinetic prole of levooxacin following once-daily
500-milligram oral or intravenous doses. Antimicrob Agents
Chemother 41(10):22562260.
45. Rodvold KA, Neuhauser M. 2001. Pharmacokinetics and
pharmacodynamics of uoroquinolones. Pharmacotherapy
21(10 Pt 2):233S252S.
46. Maeda T, Takahashi K, Ohtsu N, Oguma T, Ohnishi T, At-
sumi R, Tamai I. 2007. Identication of inux transporter
for the quinolone antibacterial agent levooxacin. Mol Pharm
4:8594.
47. Tanaka M, Kurata T, Fujisawa C, Ohshima Y, Aoki H, Okazaki
O, Hakusui H. Mechanistic study of inhibition of levooxacin
absorption by aluminum hydroxide. 1993. Antimicrob Agents
Chemother 37(10):21732178.
48. Shiba K, Saito A, Miyahara T, Tachizawa H, Fujimoto T. 1988.
Effect of aluminum hydroxide, an antacid, on the pharmacoki-
netics of new quinolones in humans. Xenobiot Metab Dispos
3:717722.
49. Shiba K, Sakai O, Shimada J, Okazaki O, Aold H, Hakusui
H. 1992. Effect of antacids, ferrous sulfate, and ranitidine
on absorption of DR-3355 in humans. Antimicrob Agents
Chemother 36:22702274.
50. Takaai M, Suzuki H, Ishida K, Tahara K, Hashimoto Y. 2007.
Pharmacokinetic analysis of transcellular transport of lev-
ooxacin across LLC-PK1 and Caco-2 cell monolayers. Biol
Pharm Bull 30:21672172.
51. Volpe DA, Ciavarella AB, Asafu-Adjaye EB, Ellison CD,
Faustino PJ, Yu LX. 2001. Method suitability of a Caco-2
cell model for drug permeability classication. AAPS Pharm-
Sci 3(S1). Accessed November 20, 2009, at: http://www.
aapspharmaceutica.com/search/abstract view.asp?id=385&ct
=01Abstracts.
52. Volpe DA. 2004. Permeability classication of representative
uoroquinolones by a cell culture method. AAPS J 6(2):16.
53. Wu CH, Benet LZ. 2005. Predicting drug disposition via ap-
plication of BCS: Transport/absorption/elimination interplay
and development of a biopharmaceutics drug disposition clas-
sication system. Pharm Res 22(1):1123.
54. Shugarts S, Benet LZ. 2009. The role of transporters in the
pharmacokinetics of orally administered drugs. Pharm Res
26(9):20392054.
55. Wagenlehner FM, Kinzig-Schippers M, S orgel F, Weidner W,
Naber KG. 2006. Concentrations in plasma, urinary excre-
tion and bactericidal activity of levooxacin (500 mg) versus
ciprooxacin (500 mg) in healthy volunteers receiving a single
oral dose. Int J Antimicrob Agents 28(6):551559.
56. Wagenlehner FM, Wagenlehner C, Redman R, Weidner W,
Naber KG. 2009. Urinary bactericidal activity of Doripenem
versus that of levooxacin in patients with complicated uri-
nary tract infections or pyelonephritis. Antimicrob Agents
Chemother 53(4):156773.
57. Wagenlehner FM, Kinzig-Schippers M, Tischmeyer U, Wa-
genlehner C, S orgel F, Dalhoff A, Naber KG. 2006. Pharma-
cokinetics of ciprooxacin XR (1000 mg) versus levooxacin
(500 mg) in plasma and urine of male and female healthy vol-
unteers receiving a single oral dose. Int J Antimicrob Agents
27(1):714.
58. Benet LZ, Amidon GL, Barends DM, Lennern as H, Polli JE,
Shah VP, Stavchansky SA, Yu LX. 2008. The use of BDDCS
in classifying the permeability of marketed drugs. Pharm Res
25(3):4838.
59. Chen ML, Yu L. 2009. The use of drug metabolism for predic-
tionof intestinal permeability (dagger). Mol Pharm6(1):7481.
60. Takagi T, Ramachandran C, Bermejo M, Yamashita S, Yu LX,
Amidon GL. 2006. A provisional biopharmaceutical classica-
tion of the top 200 oral drug products in the United States,
Great Britain, Spain, and Japan. Mol Pharm 3:631643.
61. Galan-Herrera JF, Poo JL, Rosales-Sanchez O, Fuentes-
Fuentes E, Cari no L, Burke-Fraga V, Namur S, Parra MG.
2009. Bioavailability of two oral formulations of a single dose
of levooxacin 500 mg: An open-label, randomized, two-period
crossover comparison in healthy Mexican volunteers. Clin
Ther 31(8):1796803.
62. Carrasco-Portugal MDC, Flores-Murrieta F. 2009. Compar-
ative bioavailability of two oral formulations of levooxacin
in healthy Mexican volunteers. Int J Clin Pharmacol Ther
47(4):283286.
63. Brazilian Agency of Health Surveillance. Accessed June 16,
2010, at: www.anvisa.gov.br.
64. Health Canada. Accessed June 14, 2010, at: www.webprod.hc-
sc.gc.ca.
65. State Institute for Drug Control. Accessed June 15, 2010, at:
www.sukl.cz.
66. Rote List. Arzneimittelinformationen fur Deutschland. Ac-
cessed June 14, 2010, at: www.rote-liste.de.
67. Danish Medicines Agency. Accessed June 14, 2010, at:
www.dkma.dk.
68. Agencia Espa nola de Medicamentos y Productos Sanitarios.
Accessed November 20, 2009, at: www.agemed.es.
69. Finnish Medicines Agency. Accessed June 15, 2010, at:
www.nam..
70. Vidal. Accessed June 15, 2010, at: www.vidal.fr.
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011
1636 KOEPPE ET AL.
71. National Institute of Pharmacy. Accessed June 18, 2010, at:
www.ogyi.hu.
72. Irish Medicines Board. Accessed June 15, 2009, at:
www.imb.ie.
73. Ministry of Health of Israel. Accessed June 15, 2010, at:
www.health.gov.il.
74. Medicines Evaluation Board. Accessed June 14, 2010, at:
www.cbg-meb.nl.
75. Medical Products Agency. Accessed June 15, 2010, at:
www.lakemedelsverket.se.
76. Electronic Medicines Compendium. Accessed June 15, 2010,
at: www.medicines.org.uk.
77. DailyMed. Accessed June 15, 2010, at: www.dailymed.
nlm.nih.gov.
78. Olivera ME, Manzo RH, Junginger HE, Midha KK, Shah VP,
Stavchansky S, Dressman JB, Barends DM. 2010. Biowaiver
monographs for immediate release solid oral dosage forms:
Ciprooxacin hydrochloride. J Pharm Sci Published online 02
07 2010 as DOI: 10.1002/jps.22259.
79. FDA. Inactive Ingredients Database. Accessed, August
3, 2010, at: http://www.fda.gov/Drugs/InformationOnDrugs/
ucm113978.htm.
80. The United States Pharmacopeia The National Formulary
(USP 32/NF 27), edition. Rockville, MD: The United States
Pharmacopeial Convention, Inc.
81. The European Pharmacopoeia (Ph.Eur.). 2010. 6
th
ed., Stras-
bourg, France: European Directorate for the Quality of
Medicines, Council of Europe.
82. The British Pharmacopoeia (B.P.). 1993. ed., London, the
United Kingdom: The British Pharmacopoeia Secretariat.
83. The World Health Organization (WHO). 2008. The Interna-
tional Pharmacopoeia4th ed. Accessed November 20, 2009, at:
http://apps.who.int/phint/en/p/about/.
84. Food and Drug Administration (FDA). 2009. Dissolu-
tion methods database. Accessed November 23, 2009,
at: http://www.accessdata.fda.gov/scripts/cder/dissolution/
dsp SearchResults Dissolutions.cfm.
85. World Health Organization (WHO). 2009. General
notes on Biopharmaceutics Classication System (BCS)-
based biowaiver applications. Accessed November 23,
2009, at: http://apps.who.int/prequal/info applicants/BE/
BW general 2009February.pdf.
86. World Health Organization (WHO). 2009. Substances on
the Complementary list of WHO Essential Medicines List
(EML). Accessed November 23, 2009, at: http://www.who.
int/medicines/services/expertcommittees/pharmprep/QAS04
109Rev1 Waive invivo bioequiv.pdf.
87. Rege BD, Kao JP, Polli JE. 2002. Effects of nonionic surfac-
tants on membrane transporters in Caco-2 cell monolayers.
Eur J Pharm Sci 16(45):237246.
88. Food and Drug Administration (FDA). 2009. Title 21Food
and Drugs, Chapter ISubchapter DDrugs for Human
UsePart 320Bioavailability and Bioequivalence Re-
quirements. Accessed November 23, 2009, at: http://www.
accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?
CFRPart=320&showFR=1.
89. Klesel N, Geweniger KH, Koletzki P, Isert D, Limbert M,
Markus A, Riess G, SchrammH, Iyer P. 1995. Chemotherapeu-
tic activity of levooxacin (HR 355, DR-3355) against systemic
and localized infections in laboratory animals. J Antimicrob
Chemother 35(6):805819.
90. Health Canada. 2009. Critical dose drugs. Accessed Novem-
ber 23, 2009, at: http://www.hc-sc.gc.ca/dhp-mps/alt formats/
pdf/prodpharma/applic-demande/guide-ld/bio/critical dose
critique-eng.pdf.
91. National Institute of Health Sciences (NIHS). 2010. Guide-
line for Bioequivalence Studies for Different Strengths of
Oral Solid Dosage Forms. Accessed November 20, 2009,
at: http://www.nihs.go.jp/drug/be-guide(e)/strength/strength.
html.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011 DOI 10.1002/jps