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© World Health OrganizationWHO Technical Report Series, No. 937, 2006
Annex 8Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms
Introduction
1. Background
2. WHO revisions to the criteria for Biopharmaceutics Classifi cation System classifi cation
3. WHO extensions to the scope of application of the biowaiver
4. WHO additional criteria for application of the biowaiver procedure
5. Explanation of the tables
6. Biowaiver testing procedure according to WHO
IntroductionThis proposal is closely linked to the Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchange-ability (WHO Technical Report Series, No. 937, Annex 7). It aims to give national authorities suffi cient background information on the various orally administered active pharmaceutical ingredients (APIs) on the WHO Model List of Essential Medicines (EML), also taking into account local usage of the API, to enable them to make an informed decision as to whether generic formulations should be subjected to in vivo bioequivalence (BE) studies or whether a biowaiver can be granted. In light of scientifi c work and dis-cussion in the last decade, some of the criteria used to evaluate the API in terms of potential for a biowaiver have been revised to allow a broadened scope of application. The result is that many APIs on the EML can now be considered for the biowaiver procedure, subject to the usage and risks in the national setting.
1. Background1.1 Initiatives to allow biowaivers based on the Biopharmaceutics
Classifi cation System
In 1995 the American Department of Health and Human Services, US Food and Drug Administration (HHS-FDA) instigated the Biopharmaceutics
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Classifi cation System (BCS), with the aim of granting so-called biowaiv-ers for scale-up and post-approval changes (SUPAC) (www.fda.gov/cder/guidance/cmc5.pdf). A biowaiver means that in vivo bioavailability and/or bioequivalence studies may be waived (i.e. not considered necessary for product approval). Instead of conducting expensive and time-consuming in vivo studies, a dissolution test could be adopted as the surrogate basis for the decision as to whether two pharmaceutical products are equivalent. At that time the biowaiver was only considered for SUPAC to pharmaceutical products.
More recently, the application of the biowaiver concept has been extended to approval of certain orally administered generic products (www.fda.gov/cder/guidance/3618fnl.htm).
Within the context of the documents cited above, only APIs with high solu-bility and high permeability and which are formulated in solid, immediate-release (IR) oral formulations can be approved on the basis of the biowaiver procedure. A major advantage of the biowaiver procedure is the simplifi ca-tion of the product approval process and the reduction of the time required, thus reducing the cost of bringing new products to market.
1.2 What is the Biopharmaceutics Classifi cation System?
The Biopharmaceutics Classifi cation System (BCS) was proposed in 1995 by Amidon et al.1 It is a scientifi c framework which divides APIs into four groups, according to their solubility and permeability properties.
1.3 Classifi cation of active pharmaceutical ingredients according to the Biopharmaceutics Classifi cation System
According to the HHS-FDA defi nitions in the documents cited above, the four possible categories for an API according to the BCS are:
• BCS class I: “high” solubility – “high” permeability• BCS class II: “low” solubility – “high” permeability• BCS class III: “high” solubility – “low” permeability• BCS class IV: “low” solubility – “low” permeability.
Depending on the classifi cation, the oral availability of the API may be expected to range from being heavily dependent on the formulation and manufacturing method (e.g. Class II APIs: poorly soluble yet highly perme-able) to being mostly dependent on the API permeability properties (e.g. Class III APIs: highly soluble yet poorly permeable).
1 Amidon GL, Lennemas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classifi cation: the correlation of in vitro drug product dissolution and in vivo bioavailability. Phar-maceutics Research, 1995, 12:413–420.
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1.4 How is high or low solubility currently defi ned by the Department of Health and Human Services, US Food and Drug Administration?
The aqueous solubility of a drug substance is considered as high according to the HHS-FDA BCS criteria when:
• the ratio of the highest orally administered dose (in mg) to the solubility (mg/ml) is 250 ml or lower.— This criterion is met over the pH range 1–7.5 at 37 °C.
According to HHS-FDA guidances, the determination of the equilibrium solubility should be carried out with the shake-fl ask method (other methods such as acid or base titration are permitted when their ability to predict the equilibrium solubility is justifi ed). The experiments should be carried out at a temperature of 37 ± 1°C. Further, a suffi cient number of pH conditions should be chosen to cover the pH range of 1–7.5 and each determination should be carried out at least in triplicate. The buffer solutions given in the United States Pharmacopeia (USP) are appropriate for the tests, but other buffers are also allowed for these experiments. The pH value of each buffer solution should be checked before and after each experiment. Degradation of the API due to pH or buffer composition should be reported together with other stability data.
The reason for the 250-ml cut-off criterion for the dose:solubility ratio is that in pharmacokinetic bioequivalence studies, the API formulation is to be ingested with a large glass of water (8 ounces corresponds to about 250 ml). If the highest orally administered dose can be completely dissolved in this amount of water, independent of the physiological pH value (hence the determination over the pH range 1–7.5), solubility problems are not expected to hinder the uptake of the API in the small intestine.
The other important parameter for the BCS is the intestinal permeability of the API.
1.5 How is high or low permeability currently defi ned by the Department of Health and Human Services, US Food and Drug Administration?
According to HHS-FDA a drug is considered highly permeable, when 90 % or more of the orally administered dose is absorbed in the small intestine.
Permeability can be assessed by pharmacokinetic studies (for example, mass balance studies), or intestinal permeability methods, e.g. intestinal perfusion in humans, animal models, Caco 2 cell lines or other suitable, validated cell lines. In vivo or in situ animal models or in vitro models (cell lines) are only considered appropriate by HHS-FDA for passively trans-ported drugs. It should be noted that all of these measurements assess the fraction absorbed (as opposed to the bioavailability, which can be reduced substantially by fi rst-pass metabolism).
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HHS-FDA suggests use of two different methods for determining the per-meability classifi cation if results with one method are inconclusive.
1.6 Which pharmaceutical formulations can currently be considered for a biowaiver according to the Department of Health and Human Services, US Food and Drug Administration?
To be considered bioequivalent according to the HHS-FDA biowaiver pro-cedure, a pharmaceutical product:
• should contain a Class I API;• should be rapidly dissolving, meaning it should release at least 85% of
its content in 30 minutes in three different media (pH 1.2, pH 4.5 and pH 6.8, composition see “Multisource document”)1 in a paddle (50 rpm) or basket (100 rpm) apparatus at 37 °C and a volume of 900 ml;
• should not contain excipients which could infl uence the absorption of the API;
• should not contain an API with a narrow therapeutic index; and• should not be designed to be absorbed from the oral cavity.
The reasoning for the above-mentioned dissolution restrictions is that when a highly soluble, highly permeable API dissolves rapidly, it behaves like a solution in the gastrointestinal tract. If this is the case, the pharmaceutical composition of the product is insignifi cant, provided that excipients which infl uence the uptake across the gut wall are excluded from the formulation. The API is not prone to precipitation after its dissolution due to its good solu-bility under all pH conditions likely to be found in the upper gastrointestinal tract. The high permeability ensures the complete uptake (> 90%) of the API during its passage through the small intestine. The rapid dissolution of the product guarantees that the API is available long enough for the uptake in the small intestine (the passage time in the small intestine is approximately four hours) and negates any slight differences between the formulations.
Pharmaceutical products containing an API with a narrow therapeutic index should always be tested with in vivo methods, because the risk to the patient resulting from a possible incorrect bioequivalence decision using the bio-waiver procedure is considered too high with these kinds of APIs.
As the BCS is only applicable to APIs which are absorbed from the small intestine; drugs absorbed from other sites (e.g. from the oral cavity) are not eligible for a biowaiver.
It is clear that the HHS-FDA requirements for the classifi cation of APIs and eligibility criteria for the biowaiver are very strict. During the last decade,
1 Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).
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several publications and continuing scientifi c discussions have suggested that the original HHS-FDA criteria for application of the biowaiver pro-cedure could be relaxed without substantially increasing the risk to public health or to the individual patient. On the basis of these publications and dialogue, WHO has proposed revised BCS criteria and additional consid-erations for the eligibility of a pharmaceutical product for the biowaiver procedure in the “Multisource document”.1
2. WHO revisions to the criteria for BCS classifi cationWHO revisions to the BCS criteria are as follows:
• WHO high-solubility defi nition When an API shows a dose:solubility ratio of 250 ml or lower at 37 °C
over a pH range of 1.2–6.8, it can be classifi ed as “highly soluble”. The decrease in pH from 7.5 in the FDA guidances to 6.8 refl ects the need to dissolve the drug before it reaches the mid-jejunum to ensure absorption from the gastrointestinal tract.
• Furthermore, the dose that is to be used for the calculation is the highestdose indicated in the Model List of Essential Medicines (EML). In some countries, products may be available at doses exceeding the highest dose on the EML. In such cases, the classifi cation given in the tables at the end of this Annex may no longer be appropriate and the dose:solubil-ity ratio and the permeability will have to be reassessed at the product dose.
• WHO permeability defi nition When an API is absorbed to an extent of 85% or more, it is considered
to be “highly permeable”. The permeability criterion was relaxed from 90% in the FDA guidance to 85% in the WHO “Multisource document”. Some examples of APIs now included in BCS Class I that were previ-ously considered to be in Class III are paracetamol, acetylsalicylic acid, allopurinol, lamivudine and promethazine.
Application of these revised criteria has changed the classifi cation of some APIs in the list. Thus, the classifi cations in the tables attached to this docu-ment supersede those in previous publications. As new APIs appear on the EML, it will be necessary to classify them according to the revised BCS; so it is therefore anticipated that the tables will be revised regularly. In addition, some APIs have not yet been suffi ciently characterized to assign them a BCS classifi cation. As the tables evolve, it is anticipated that more concrete information will be generated for these APIs as well.
1 Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).
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The potential impact of the revised guidelines on registration requirements to es-tablish interchangeability is that many of the medicines on the EML could become eligible for approval based on in vitro bioequivalence testing in accordance with the dissolution tests prescribed in Section 9 of the “Multisource document”.1
3. WHO extensions to the scope of applicationof the biowaiverIn the “Multisource document”,1 the WHO has broadened the scope of ap-plication of the biowaiver in three directions:
(1) The criteria for classifi cation as a Class I API have been relaxed with respect to both the dose:solubility ratio and permeability requirements.
(2) The new requirements allow pharmaceutical products containing Class III APIs to be considered for a biowaiver, under application of more stringent dissolution criteria.
(3) The document further allows pharmaceutical products containing BCS Class II APIs that are weak acids which have a dose:solubility ratio of 250 ml or less at pH 6.8 to be eligible for the biowaiver procedure, pro-vided that they dissolve rapidly at pH 6.8 and similarly to the compara-tor product at pH 1.2 and 4.5.
Diagrams depicting the products eligible for the biowaiver procedure under the HHS-FDA guidance and those eligible according to the WHO “Multi-source document” are presented in Fig. 1.
Figure 1.Eligibility for the biowaiver procedure based on solubility and permeabilitycharacteristics of the active pharmaceutical ingredient
a. according to HHS-FDA
1 Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).
CLASS IHighly permeableHighly soluble
Eligible
CLASS IIHighly permeablePoorly soluble
Not eligible
CLASS IIIPoorly permeableHighly soluble
Not eligible
CLASS IVPoorly permeablePoorly soluble
Not eligible
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b. according to WHO
4. WHO additional criteria for application of the biowaiver procedureFor all APIs on the EML, it is imperative to consider not only the physical, chemical and absorption properties of the API when evaluating them for bio-waiver, but (as outlined in the “Multisource document”)1 to perform a benefi t–risk analysis in view of the products’ usage at the national level. As an example, in some countries amoxicillin is used primarily for the treatment of ambulatory patients with mild-to-moderate infections of the upper respiratory tract, urinary tract and other sites. In other countries, amoxicillin might also be used to treat severe or even life-threatening infections, in which case the risk to the patient of arriving at the wrong bioequivalence decision would be far greater.
Thus, the eligibility criteria according to WHO are:
(1) The BCS classifi cation (according to the revised criteria) of the API.(2) Risk assessment: only if the risk of an incorrect biowaiver decision
and an evaluation of the consequences (of an incorrect, biowaiver-based equivalence decision) in terms of public health and risks to individual patients is outweighed by the potential benefi ts accrued from the bio-waiver approach may the biowaiver procedure be applied.
(3) Dissolution requirements for the pharmaceutical product:
— very rapidly dissolving (release of > 85% of the labelled amount of drug in 15 minutes) in standard media at pH 1.2, 4.5 and 6.8, at a rotational speed of 75 rpm in the paddle apparatus or 100 rpm in
CLASS IHighly permeableHighly soluble
Eligible
CLASS IIHighly permeablePoorly soluble
Eligible only if the D:Sis 250 ml or lower at pH 6.8
CLASS IIIPoorly permeableHighly soluble
Eligible if very rapidly dissolving
CLASS IVPoorly permeablePoorly soluble
Not eligible
D:S 250 ml
85% abs
1 Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).
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the basket apparatus (applies to pharmaceutical products containing Class III APIs);
— rapidly dissolving (release of > 85% of the labelled amount of drug in 30 minutes) in standard media at pH 1.2, 4.5 and 6.8, at a rota-tional speed of 75 rpm in the paddle apparatus or 100 rpm in the bas-ket apparatus (applies to pharmaceutical products containing Class I APIs and/or Class II APIs which are weak acids and meet the 250 mldose:solubility requirement at pH 6.8).
(4) Considerations relating to excipientsThe national authority should be aware that some excipients can infl uence motility and/or permeability in the gastrointestinal tract. Therefore, the ex-cipients used in the multisource product formulation should be scrutinized.
In this regard, the national authority can draw on the experience relat-ing to formulations which have been approved on the basis of human bioequivalence studies in their own or in other jurisdictions.
If the multisource product under consideration contains excipients that have been used before in similar amounts in other formulations of the same API, it can be reasonably concluded that these excipients will have no unexpected consequences for the bioavailability of the product. If, however, the formulation contains different excipients, or amounts of the same excipients that are very different from usual, the national au-thority may choose to declare the biowaiver procedure inapplicable.
A list of usual and acceptable excipients can be found at the following web site: www.fda.gov/cder/iig/iigfaqWEB.htm; formulations of some products can be found on the web sites of some national drug regulatory authorities.
5. Explanation of the tablesThe decision of a national authority to allow a biowaiver based on the BCSshould take into consideration the solubility and permeability char-acteristics as well as the therapeutic use and therapeutic index of the API,its pharmacokinetic properties, the similarity of the dissolution profi les of the multisource and the comparator products in standard buffers with a pH of 1.2, pH 4.5 and pH 6.8 at 37 °C. Data related to the excipients compo-sition in the multisource product are also required. A systematic approach to the biowaiver decision has been established by the International Pharma-ceutical Federation (FIP) and published in the Journal of Pharmaceutical Sciences (http://www3.interscience.wiley.com/cgi-bin/jhome/68503813). The relevant documents can also be downloaded from the FIP web site at: http://www.fi p.org/. These monographs provide detailed information which should be taken into account whenever available in the biowaiver consideration.
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5.1 Which active pharmaceutical ingredients are included in the tables?
The substances listed in the 14th WHO Model List of Essential Medicines(EML) of March 2005 have been evaluated and classifi ed according to the revised criteria given above.
5.2 Where do the data come from?
The solubility and permeability values were found in the publicly available literature, such as Martindale’s, the Merck Index and scientifi c journals.
Please note that the doses used for the calculation of the dose:solubility ratio are those stated in the EML.
The indications given in the tables are reproduced directly from the EML. If the EML specifi es the dosage form (e.g. sublingual tablet) this is indicated under “comments”.
5.3 “Worst case” approach to the Biopharmaceutics Classifi cation System
The drugs listed in the EML were classifi ed according to the criteria explained above. Where no clear classifi cation could be made, the “worst case” was as-sumed. For example if a substance is highly soluble, but absolute bioavailability data were not available, the test conditions for BCS Class III substances have been proposed. The same procedure was adopted for fi xed combinations, for example amoxicillin and clavulanic acid, the testing procedure was always fi xed according to the “worst” BCS classifi cation, in this example clavulanic acid (BCS Class III/1), because amoxicillin is a BCS Class I drug. This com-bination would therefore be tested according to BCS Class III requirements.
The results of the revised classifi cation can be found in Tables 1–3.
5.4 Why are there three Tables?
Table 1 lists all APIs on the EML that are administered orally, with the excep-tion of the APIs listed as complementary. Table 2 summarizes the APIs listed as complementary in the EML and Table 3 lists the APIs for which no classifi cation had previously been assigned, or that had been introduced with the 14th EML (March 2005), together with a more detailed explanation of their classifi cation.
5.5 Risk assessment
To minimize the risks of an incorrect biowaiver decision in terms of public health and risks to individual patients, the therapeutic indications of the API, known pharmacokinetic variations, food effects, etc. should be evalu-ated based on local clinical experience, taking into account the indications
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for which the API is prescribed in that country as well as specifi c pharmaco-kinetic population variations (for example CYP polymorphisms). Known potential risks are listed under “potential risks” in the tables. The absence of an entry under “potential risks” should not, however, be misconstrued as meaning that there are no risks associated with the use of the medicine.
6. Biowaiver testing procedure according to WHODepending on the BCS classifi cation of the API, based on solubility and permeability characteristics listed in the accompanying tables, the testing procedure is defi ned in section 9.2.1 of the “Multisource document”1:
6.1 For pharmaceutical products containing Biopharmaceutics Classifi cation System Class I (highly soluble, highly permeable) APIs
For rapidly dissolving (as defi ned above) pharmaceutical products contain-ing BCS Class I APIs, more than 85% dissolution of the labelled amount is required within 30 minutes in standard media at pH 1.2, 4.5 and 6.8 using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm. The dis-solution profi les of the comparator and the multisource products should be compared by an f
2 > 50 or an equivalent statistical criterion.
If within 15 minutes more than 85% of the API are released from the compar-ator and the multisource formulation under the above-mentioned conditions the products will be considered very rapidly dissolving. In this case the prod-ucts are deemed to be equivalent and a profi le comparison is not required.
6.2 For pharmaceutical products containing Biopharmaceutics Classifi cation System Class III (highly soluble, low permeability) APIs
A biowaiver can be considered only if both the multisource and the com-parator product are very rapidly dissolving. Eighty-fi ve per cent or more dissolution of the labelled amount of the API should be achieved within 15 minutes in standard media at pH 1.2, 4.5 and 6.8 using the paddle ap-paratus at 75 rpm or the basket apparatus at 100 rpm.
Generally, the risks of an inappropriate biowaiver decision should be more critically reviewed (e.g. site-specifi c absorption, induction/competition at the absorption site, excipient composition and therapeutic risks) for prod-ucts containing BCS Class III APIs than for BCS Class I drugs.
1 Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).
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6.3 For pharmaceutical products containing APIs with high solubility at pH 6.8 but not at pH 1.2 or 4.5 and with high permeability (by defi nition, BCS Class II compounds with weak acidic properties)
These are eligible for a biowaiver provided that the multisource product:
• is rapidly dissolving, i.e. 85% or more dissolution of the labelled amount of the API should be achieved within 30 minutes in standard media at pH 6.8 using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm; and
• the multisource product exhibits similar dissolution profi les, as deter-mined with the f
2 value or equivalent statistical evaluation, to those of
the comparator product in buffers at all three pH values (pH 1.2, 4.5 and 6.8).
For multisource products containing BCS Class II APIs with dose:solubility ratios of 250 ml or less, at pH 6.8, the excipients should also be critically evaluated in terms of type and amounts of surfactants in the formulation.
Further details of eligibility for the biowaiver and appropriate test proce-dures can be found in sections 5 and 9 of the “Multisource document”.1
1 Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).
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Tab
le 1
Su
bst
ance
s o
n t
he
WH
O M
od
el L
ist
of
Ess
enti
al M
edic
ines
(E
ML
)
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
Lis
ta
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
abac
avir
200
mg
hig
hlo
w3
9.2.
1.2
an
tiret
rovi
ral
acet
azol
amid
e25
0 m
glo
wlo
w (
?)4/
2N
ot e
ligib
le
for
bio
wai
ver
an
tigla
ucom
am
edic
ine
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
acet
ylsa
licyl
icac
id50
0 m
ghi
gh
hig
h1
9.2.
1.1
N
SA
ID, a
ntim
i-g
rain
e m
edic
ine
acet
ylsa
licyl
icac
id10
0 m
ghi
gh
hig
h1
9.2.
1.1
an
tithr
omb
otic
m
edic
ine
acic
lovi
r20
0 m
ghi
gh
low
39.
2.1.
2
antih
erp
esm
edic
ines
alb
end
azol
e40
0 m
glo
wlo
w (
?)4/
2N
ot e
ligib
le
for
bio
wai
ver
an
thel
min
thic
chew
able
tab
let;
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
allo
pur
inol
100
mg
hig
hhi
gh
19.
2.1.
1
gou
t
alum
iniu
mhy
dro
xid
e50
0 m
g
N
RN
A
anta
cid
used
for
loca
l ef
fect
NS
AID
, Non
-ste
roid
al a
nti-i
nfl a
mm
ator
y d
rug
; BA
, bio
avai
lab
ility
.
TSR2006_Annexs6-9.indd 402TSR2006_Annexs6-9.indd 402 4.5.2006 15:48:574.5.2006 15:48:57
403
amilo
ride
hyd
roch
lorid
e5
mg
hig
hhi
gh
19.
2.1.
1
diu
retic
amitr
ipty
line
hyd
roch
lorid
e25
mg
(1)
hig
hhi
gh
19.
2.1.
1
psy
chot
hera
peu
-tic
med
icin
e
amlo
dip
ine
5 m
ghi
gh
hig
h1
9.2.
1.1
an
tihyp
erte
nsiv
e m
edic
ine
amod
iaq
uine
(bas
e)20
0 m
ghi
gh
bor
der
line
BA
>
75%
3/1
9.2.
1.2
CY
P2C
8p
olym
orp
hism
,in
crea
sed
ris
k fo
r ag
ranu
lo-
cyto
sis
and
liv
er to
xici
ty
antim
alar
ial
exte
nt o
f fi rs
t-p
ass
met
abol
ism
un
cert
ain
amox
icill
in (
a)
+ c
lavu
lani
c ac
id (
c)
(a)
500
mg
+(c
) 12
5 m
g
(a)
hig
h +
(c)
hig
h
(a)
hig
h +
(c)
bor
der
line
abso
rptio
n>
73%
(rad
ioac
-tiv
e ex
cret
ion)
(a)
1 + (c
) 3/
19.
2.1.
2an
tibac
teria
l
com
bin
atio
nsh
ould
be
test
ed
acco
rdin
g to
cl
avul
anic
aci
d
req
uire
men
ts
amox
icill
inan
hyd
rous
500
mg
hig
hhi
gh
19.
2.1.
1an
tibac
teria
l
arte
met
her (
a) +
lum
efan
trine
(l)
(a)
20 m
g +
(l) 1
20 m
g(a
and
l)
unkn
own
low
(a
and
l)
(a)
4/3
+ (l) 4
/3N
ot e
ligib
le
for
bio
wai
ver
antim
alar
ial
asco
rbic
aci
d50
mg
hig
hhi
gh
19.
2.1.
1vi
tam
in
aten
olol
100
mg
hig
hlo
w
39.
2.1.
2
antia
ngin
al,
antih
yper
tens
ive,
an
tiarr
hyth
mic
med
icin
e an
d
used
in h
eart
fa
ilure
BA
, bio
avai
lab
ility
.
TSR2006_Annexs6-9.indd 403TSR2006_Annexs6-9.indd 403 4.5.2006 15:48:584.5.2006 15:48:58
404
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
Lis
ta
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
azith
rom
ycin
500
mg
low
low
(?)
4/2
Not
elig
ible
fo
r b
iow
aive
r
antib
acte
rial
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
ben
znid
azol
e10
0 m
ghi
gh
low
39.
2.1.
2A
mer
ican
tryp
anos
omia
sis
bip
erid
enhy
dro
chlo
ride
2 m
ghi
gh
insu
ffi ci
ent
liter
atur
e3/
19.
2.1.
2an
tipar
kins
onm
edic
ine
carb
amaz
epin
e20
0 m
glo
w(n
eutr
al)
hig
h2
Not
elig
ible
fo
r b
iow
aive
r
antie
pile
ptic
,p
sych
othe
rap
eu-
tic m
edic
ine
scor
ed ta
ble
t
cefi x
ime
400
mg
low
low
(?)
4/2
Not
elig
ible
fo
r b
iow
aive
ran
tibac
teria
l
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
chlo
ram
phen
icol
250
mg
hig
hlo
w3
9.2.
1.2
narr
ow th
era-
peu
tic in
dex
antib
acte
rial
chlo
roq
uine
p
hosp
hate
or
sulfa
te15
0 m
ghi
gh
hig
h1
9.2.
1.1
DM
AR
D,
antim
alar
ial
BA
, bio
avai
lab
ility
; DM
RD
, dis
ease
mod
ifyin
g a
ntirh
eum
atic
dru
g.
TSR2006_Annexs6-9.indd 404TSR2006_Annexs6-9.indd 404 4.5.2006 15:48:584.5.2006 15:48:58
405
chlo
rphe
na-
min
e hy
dro
gen
m
alea
te4
mg
hig
hB
A 2
5-59
%,
fi rst
pas
s 3/
19.
2.1.
2C
YP
2D6
pol
y-m
orp
hism
antia
llerg
ic
exte
nt o
f fi rs
t-p
ass
met
abol
ism
un
cert
ain
chlo
rpro
maz
ine
hyd
roch
lorid
e10
0 m
ghi
gh
low
39.
2.1.
2 p
sych
othe
rap
eu-
tic m
edic
ine
cip
rofl o
xaci
n hy
dro
chlo
ride
250
mg
hig
h
BA
70–
82%
, p
ossi
ble
fi rs
t p
ass,
hig
h in
C
aco-
2 ce
lls3/
19.
2.1.
2 an
tibac
teria
l
exte
nt o
f fi rs
t-
pas
s m
etab
olis
m
unce
rtai
n
clof
azim
ine
100
mg
insu
ffi ci
ent
liter
atur
elo
w4/
3
Not
elig
ible
fo
r b
iow
aive
rat
pre
sent
an
tilep
rosy
m
edic
ine
clom
ifene
citr
ate
50 m
ghi
gh
insu
ffi ci
ent
liter
atur
e3/
19.
2.1.
2ov
ulat
ion
ind
ucer
clom
ipra
min
ehy
dro
chlo
ride
25 m
ghi
gh
66%
exc
rete
d
in th
e ur
ine,
th
e re
mai
nder
b
eing
elim
i-na
ted
in th
e fa
eces
3/1
9.2.
1.2
psy
chot
hera
peu
-tic
med
icin
ela
ck o
f ab
solu
te
bio
avai
lab
ility
dat
a
clox
acill
in (
as
sod
ium
sal
t)10
00 m
ghi
gh
low
39.
2.1.
2an
tibac
teria
l
cod
eine
pho
spha
te30
mg
hig
hlo
w3
9.2.
1.2
risk
of a
bus
e
opio
id a
nalg
esic
,d
iarr
hoea
in
adul
ts
dap
sone
100
mg
low
(w
eak
bas
e)
hig
h2
Not
elig
ible
fo
r b
iow
aive
rG
6PD
defi
-ci
ency
antil
epro
sy
med
icin
e
dia
zep
am5
mg
hig
hhi
gh
19.
2.1.
1p
sych
othe
rap
eu-
tic m
edic
ine
scor
ed ta
ble
t
BA
, Bio
avai
lab
ility
; G6P
D, g
luco
se-6
-pho
spha
te d
ehyd
rog
enas
e.
TSR2006_Annexs6-9.indd 405TSR2006_Annexs6-9.indd 405 4.5.2006 15:48:584.5.2006 15:48:58
406
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
Lis
ta
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
did
anos
ine
200
mg
hig
hlo
w3
9.2.
1.2
antir
etro
vira
lb
uffe
red
che
wab
le,
dis
per
sib
le ta
ble
t
did
anos
ine
400
mg
hig
hlo
w3
see
com
men
tan
tiret
rovi
ral
unb
uffe
red
ent
eric
co
ated
cap
sule
n
ot e
ligib
le fo
r b
iow
aive
r in
this
d
osag
e fo
rmi
dig
oxin
250
μghi
gh
hig
h1
9.2.
1.1
antia
rrhy
thm
ican
d u
sed
in
hear
t fai
lure
dilo
xani
de
furo
ate
500
mg
low
(2)
low
(?)
4/2
Not
elig
ible
fo
r b
iow
aive
ran
tipro
tozo
al
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
dox
ycyc
line
hyd
roch
lorid
e10
0 m
ghi
gh
hig
h1
9.2.
1.1
antib
acte
rial
efav
irenz
200
mg
low
(1)
low
(?)
4/2
Not
elig
ible
fo
r b
iow
aive
ran
tiret
rovi
ral
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
enal
april
2.5
mg
hig
hlo
w3
9.2.
1.2
antih
yper
tens
ive
med
icin
e
BA
, Bio
avai
lab
ility
.
TSR2006_Annexs6-9.indd 406TSR2006_Annexs6-9.indd 406 4.5.2006 15:48:594.5.2006 15:48:59
407
erg
ocal
cife
rol
1.25
mg
(50
000
IU)
hig
hlo
w3
9.2.
1.2
vita
min
eryt
hrom
ycin
st
eara
te +
et
hyls
ucci
nate
250
mg
low
low
4N
ot e
ligib
le
for
bio
wai
ver
antib
acte
rial
etha
mb
utol
hyd
roch
lorid
e40
0 m
ghi
gh
low
39.
2.1.
2ris
k of
dos
e-re
-la
ted
oto
toxi
city
antit
uber
culo
sis
med
icin
e
ethi
nyle
stra
dio
l50
μg
hig
h
bor
der
line,
B
A 4
0–50
%,
fi rst
pas
s 3/
19.
2.1.
2es
trog
en
exte
nt o
f fi rs
t-p
ass
met
abol
ism
un
cert
ain
ethi
nyle
stra
dio
l(e
) +
levo
norg
-es
trel (
l)30
μg
+ 1
50 μ
ghi
gh
(e)
bor
der
line,
B
A 4
0–50
%,
fi rst
pas
s +
(l)
hig
h3/
1+
19.
2.1.
2ho
rmon
al
cont
race
ptiv
e
exte
nt o
f fi rs
t-p
ass
met
abol
ism
un-
cert
ain;
com
bin
a-tio
n sh
ould
be
test
ed a
ccor
din
g
to e
thin
yles
trad
iol
req
uire
men
ts
ethi
nyle
stra
dio
l(e
) +
nor
ethi
s-te
rone
(n)
35 μ
g +
1 m
ghi
gh
(e)
bor
der
line,
B
A 4
0–50
%,
fi rst
pas
s+
(n)
hig
h3/
1+
19.
2.1.
2ho
rmon
al
cont
race
ptiv
e
exte
nt o
f fi rs
t-p
ass
met
abol
ism
un-
cert
ain;
com
bin
atio
nsh
ould
be
test
ed
acco
rdin
g to
et
hiny
lest
rad
iol
req
uire
men
ts
ferr
ous
salt
equi
vala
lent
to
60 m
g ir
onhi
gh
(see
fo
otno
te)
low
39.
2.1.
2an
tiana
emia
med
icin
eco
mm
only
use
d
salts
: see
foot
note
BA
, Bio
avai
lab
ility
; GI,
gas
troin
test
inal
.
TSR2006_Annexs6-9.indd 407TSR2006_Annexs6-9.indd 407 4.5.2006 15:48:594.5.2006 15:48:59
408
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
Lis
ta
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
ferr
ous
salt
(fs)
+fo
lic a
cid
(fa
)
equi
vale
nt to
60
mg
iron
+
400
μg fo
lic
acid
(fs)
hig
h+
(fa
) hi
gh
(fs)
low
+ (
fa)
low
(ur
inar
y re
cove
ry
28.5
%)
(2)
3 +
3/
19.
2.1.
2
antia
naem
iam
edic
ine
(dur
ing
p
reg
nanc
y)
lack
of a
bso
lute
b
ioav
aila
bili
ty d
ata;
co
mm
only
use
d
salts
: see
foot
note
;co
mb
inat
ion
shou
ld b
e te
sted
ac
cord
ing
to
ferr
ous
salt
req
uire
men
ts
fl uco
nazo
le50
mg
hig
hhi
gh
19.
2.1.
1an
tifun
gal
folic
aci
d5
mg
hig
hlo
w (
?)3/
19.
2.1.
2an
tiana
emia
med
icin
ela
ck o
f ab
solu
te
bio
avai
lab
ility
dat
a
furo
sem
ide
40 m
glo
wlo
w (
?)4/
2N
ot e
ligib
le
for
bio
wai
ver
hig
hly
varia
ble
B
A
med
icin
e us
ed
in h
eart
failu
re,
diu
retic
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
glib
encl
amid
e5
mg
low
low
(?)
4/2
Not
elig
ible
fo
r b
iow
aive
ran
tidia
bet
icag
ent
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
NS
AID
, Non
-ste
roid
al a
nti-i
nfl a
mm
ator
y d
rug
s; G
I, g
astro
inte
stin
al.
TSR2006_Annexs6-9.indd 408TSR2006_Annexs6-9.indd 408 4.5.2006 15:48:594.5.2006 15:48:59
409
gly
cery
l tr
initr
ate
500
μghi
gh
sub
ling
ual
app
licat
ion,
per
mea
bil-
ity in
the
oral
ca
vity
mor
e im
por
tant
th
an G
I p
erm
eab
ility
3/1
NA
h
loca
l ab
sorp
tion
antia
ngin
alm
edic
ine
sub
ling
ual
app
licat
ion
gris
eofu
lvin
250
mg
low
(neu
tral
) hi
gh
2N
ot e
ligib
le
for
bio
wai
ver
antif
ung
al
halo
per
idol
2 m
g
bor
der
line
< 0
.01
mg
/ml2
low
4/3
Not
elig
ible
fo
r b
iow
aive
rp
sych
othe
rap
eu-
tic m
edic
ine
hyd
rala
zine
hyd
roch
lorid
e50
mg
hig
hlo
w3
9.2.
1.2
antih
yper
tens
ive
med
icin
e
hyd
roch
loro
-th
iazi
de
25 m
ghi
gh
low
39.
2.1.
2
antih
yper
tens
ive
med
icin
e, d
iure
tican
d u
sed
in
hear
t fai
lure
scor
ed ta
ble
t
ibup
rofe
n40
0 m
g
low
, wea
k ac
id(p
Ka4
.4,
5.2)
hig
h2
9.2.
1.3
NS
AID
, ant
imi-
gra
ine
med
icin
e
ind
inav
ir su
lfate
400
mg
low
low
(?)
4/2
Not
elig
ible
fo
r b
iow
aive
rC
YP
450
3A
4,
food
effe
ct (
–)an
tiret
rovi
ral
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
D:S
, Dos
e:so
lub
ility
rat
io; B
A, b
ioav
aila
bili
ty.
TSR2006_Annexs6-9.indd 409TSR2006_Annexs6-9.indd 409 4.5.2006 15:48:594.5.2006 15:48:59
410
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
Lis
ta
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
iop
anoi
c ac
id50
0 m
g
low
,w
eak
acid
(p
Ka
4.8)
(2
)hi
gh
2N
ot e
ligib
le
for
bio
wai
ver
rad
ioco
ntra
stm
edia
Insu
ffi ci
ently
so
lub
le in
wat
er
(15
μg/m
l) to
be
elig
ible
for
bio
wai
ver
ison
iazi
d30
0 m
g
hig
hb
ord
erlin
e3/
19.
2.1.
2an
titub
ercu
losi
s m
edic
ine
ison
iazi
d (
i) +
etha
mb
utol
(e)
(i) 1
50 m
g +
(e)
400
mg
(i) h
igh
+(e
) hi
gh
(i) b
ord
erlin
e +
(e)
low
(i) 3
/1
+ (
e) 3
See
foot
note
g
ocul
ar to
xici
tyan
titub
ercu
losi
s m
edic
ine
isos
orb
ide
din
itrat
e5
mg
hig
h
sub
ling
ual
app
licat
ion,
per
mea
bil-
ity in
the
oral
ca
vity
mor
e im
por
tant
th
an G
I p
erm
eab
ility
3/
1N
Ah
antia
ngin
alm
edic
ine
sub
ling
ual
iver
mec
tin6
mg
pra
ctic
ally
inso
lub
lein
wat
er3
D:S
>
6000
ml
low
(?)
4/2
Not
elig
ible
fo
r b
iow
aive
ran
tifi la
rial
scor
ed ta
ble
t; un
know
n w
heth
er
poo
r B
A is
due
to
poo
r so
lub
ility
or
poo
r so
lub
ility
and
p
oor
per
mea
bili
ty
lam
ivud
ine
150
mg
hig
hhi
gh
19.
2.1.
1an
tiret
rovi
ral
BA
, bio
avai
lab
ility
; GI,
gas
troin
test
inal
; D:S
, Dos
e: s
olub
ility
rat
io.
TSR2006_Annexs6-9.indd 410TSR2006_Annexs6-9.indd 410 4.5.2006 15:49:004.5.2006 15:49:00
411
leva
mis
ole
hyd
roch
lorid
e15
0 m
ghi
gh
bor
der
line
3/1
9.2.
1.2
anth
elm
inth
ic
levo
dop
a (l)
+ca
rbid
opa
(c)
(l) 2
50 m
g +
(c)
25 m
g(l)
hig
h +
(c)
hig
h
(l) h
igh
+(c
) in
suffi
cien
t d
ata
(BA
hum
ans 5
8%,
BA
dog
s 88%
)(l)
1 +
(c)
3/1
9.2.
1.2
narr
ow th
era-
peu
tic in
dex
an
tipar
kins
onm
edic
ine
exte
nt o
f hum
an
fi rst
-pas
s m
e-ta
bol
ism
unc
er-
tain
; com
bin
atio
n sh
ould
be
test
ed
acco
rdin
g to
car
bi-
dop
a re
qui
rem
ents
levo
norg
estre
l30
μg
hi
gh
hig
h1
9.2.
1.1
horm
onal
co
ntra
cep
tive
levo
norg
estre
l75
0 μg
× 2
(p
ack
of tw
o)hi
gh
hig
h1
9.2.
1.1
horm
onal
co
ntra
cep
tive
levo
thyr
oxin
e so
diu
m s
alt
100
μghi
gh
low
39.
2.1.
2na
rrow
ther
a-p
eutic
ind
ex
thyr
oid
hor
mon
e
lithi
umca
rbon
ate
300
mg
hig
hhi
gh
19.
2.1.
1na
rrow
ther
a-p
eutic
ind
ex
psy
chot
hera
peu
-tic
med
icin
e
lop
inav
ir (l)
+
riton
avir
(r)
(l) 1
33.3
mg
+(r
) 33
.3 m
g(l)
low
+(r
) lo
w
(l) lo
w (
insu
ffi -
cien
t dat
a) (
?)
+ (
r) lo
w (
?)
(l) 4
/2
+ (
r)
4/2
Not
elig
ible
fo
r b
iow
aive
ran
tiret
rovi
ral
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
NS
AID
, Non
-ste
roid
al a
nti-i
nfl a
mm
ator
y d
rug
s.
TSR2006_Annexs6-9.indd 411TSR2006_Annexs6-9.indd 411 4.5.2006 15:49:004.5.2006 15:49:00
412
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
Lis
ta
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
meb
end
azol
e50
0 m
glo
wlo
w (
?)4/
2N
Aan
thel
min
thic
chew
able
tab
let;
anth
elm
inth
ics
usua
lly a
pp
lied
or
ally
for
actio
n in
G
I tra
ct: s
olub
ility
m
ore
imp
orta
nt
than
per
mea
bil-
ity, b
ut u
nkno
wn
whe
ther
poo
r B
A is
d
ue to
poo
r so
lub
il-ity
or p
oor
solu
bili
ty
and
poo
r p
erm
e-ab
ility
mefl
oq
uine
hy
dro
chlo
ride
250
mg
low
2lo
w (
?)4/
2N
ot e
ligib
le
for
bio
wai
ver
antim
alar
ial
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
DL-
met
hion
ine
250
mg
hig
hhi
gh
19.
2.1.
1an
tidot
e
met
form
in
hyd
roch
lorid
e50
0 m
ghi
gh
low
39.
2.1.
2an
tidia
bet
icag
ent
met
hyld
opa
250
mg
hig
hlo
w3
9.2.
1.2
antih
yper
tens
ive
med
icin
e
met
oclo
pram
ide
hydr
ochl
orid
e10
mg
hig
hlo
w3
9.2.
1.2
antie
met
ic
TSR2006_Annexs6-9.indd 412TSR2006_Annexs6-9.indd 412 4.5.2006 15:49:004.5.2006 15:49:00
413
met
roni
daz
ole
500
mg
hig
hhi
gh
19.
2.1.
1an
tipro
tozo
al,
antib
acte
rial
mor
phi
nesu
lfate
10 m
ghi
gh
insu
ffi ci
ent
dat
a (B
A
~ 3
0% b
ut
exte
nsiv
e fi r
st
pas
s)3/
19.
2.1.
2ris
k of
ab
use
opio
id a
nalg
esic
exte
nt o
f fi rs
t p
ass
met
abol
ism
un
cert
ain
nelfi
navi
r m
esila
te25
0 m
glo
wlo
w (
?)4
Not
elig
ible
fo
r b
iow
aive
rC
YP
450
3A
4,
food
effe
ct (
+)
antir
etro
vira
l
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
neos
tigm
ine
bro
mid
e15
mg
hig
hlo
w3
9.2.
1.2
mus
cle
rela
xant
nevi
rap
ine
200
mg
low
(w
eak
bas
e)hi
gh
2N
ot e
ligib
le
for
bio
wai
ver
antir
etro
vira
l
nicl
osam
ide
500
mg
low
low
(?)
4/2
NA
anth
elm
inth
ic
chew
able
tab
let;
anth
elm
inth
ics
usua
lly a
pp
lied
or
ally
for
actio
n in
G
I tra
ct: s
olub
ility
m
ore
imp
orta
nt
than
per
mea
bili
ty
nico
tinam
ide
50 m
ghi
gh
hig
h1
9.2.
1.1
vita
min
nife
dip
ine
10 m
g
low
, wea
k ac
id, s
olu-
bilit
y at
pH
7 0.
0056
mg/
ml2
hig
h2
Not
elig
ible
fo
r b
iow
aive
ran
tioxy
toci
c
BA
, bio
avai
lab
ility
; GI,
gas
troin
test
inal
.
TSR2006_Annexs6-9.indd 413TSR2006_Annexs6-9.indd 413 4.5.2006 15:49:014.5.2006 15:49:01
414
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
Lis
ta
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
nifu
rtim
ox25
0 m
ghi
gh
low
39.
2.1.
2A
mer
ican
tryp
anos
omia
sis
nitro
fura
ntoi
n10
0 m
g
low
, wea
k ac
id, s
olub
il-ity
at p
H 7
.0
0.37
4 m
g/m
l (p
Ka 7
.2
(25
°C))
(2)
hig
h2
Not
elig
ible
fo
r b
iow
aive
ran
tibac
teria
l
Not
sol
uble
en
oug
h at
pH
6.8
to
be
elig
ible
for
bio
wai
ver
nore
this
tero
ne5
mg
hig
hhi
gh
19.
2.1.
1p
rog
esto
gen
nyst
atin
500
000
IU–
–N
RN
Aan
tifun
gal
loca
l effe
ct
par
acet
amol
500
mg
hig
hhi
gh
19.
2.1.
1N
SA
ID, a
ntim
i-g
rain
e m
edic
ine
pen
icill
amin
e25
0 m
ghi
gh
low
39.
2.1.
2an
tidot
e
phe
nob
arb
ital
100
mg
hig
hhi
gh
19.
2.1.
1na
rrow
ther
a-p
eutic
ind
exan
tiep
ilep
tic
phe
noxy
met
hyl
pen
icill
in (
as
pot
assi
um s
alt)
250
mg
hig
hhi
gh
19.
2.1.
1an
tibac
teria
l
phe
nyto
inso
diu
m s
alt
100
mg
low
, wea
k ac
id, s
ol.
at p
H 6
.8
1.7
mg
/ml
(4)
pK
a8.3
(25
°C))
(2)
hig
h2
9.2.
1.3
narr
ow th
era-
peu
tic in
dex
, no
n-lin
ear
pha
rmac
o-ki
netic
san
tiep
ilep
tic
TSR2006_Annexs6-9.indd 414TSR2006_Annexs6-9.indd 414 4.5.2006 15:49:014.5.2006 15:49:01
415
pot
assi
umio
did
e60
mg
hig
hhi
gh
19.
2.1.
1
thyr
oid
horm
ones
and
ant
ithyr
oid
m
edic
ines
pra
ziq
uant
el60
0 m
glo
w(n
eutr
al)
hig
h2
Not
elig
ible
fo
r b
iow
aive
r
anth
elm
inth
ic,
antis
chis
toso
mal
,an
titre
mat
ode
pre
dni
solo
ne25
mg
hig
hhi
gh
19.
2.1.
1an
tialle
rgic
prim
aqui
ned
ipho
spha
te15
mg
hig
hhi
gh
19.
2.1.
1an
timal
aria
l
pro
gua
nil
hyd
roch
lorid
e10
0 m
ghi
gh
hig
h1
9.2.
1.1
antim
alar
ial
pro
met
hazi
ne
hyd
roch
lorid
e25
mg
hig
hhi
gh
19.
2.1.
1C
YP
2D6
pol
ymor
phi
sman
tiem
etic
pro
pra
nolo
l hy
dro
chlo
ride
40 m
ghi
gh
hig
h1
9.2.
1.1
antim
igra
ine
med
icin
e
pro
pyl
thio
urac
il50
mg
hig
hhi
gh
19.
2.1.
1an
tithy
roid
m
edic
ine
pyr
ante
lem
bon
ate
250
mg
low
low
(?)
4/2
NA
anth
elm
inth
ic
chew
able
tab
let;
anth
elm
inth
ics
usua
lly a
pp
lied
or
ally
for
actio
n in
G
I tra
ct: s
olub
ility
m
ore
imp
orta
nt
than
per
mea
bili
ty
pyr
azin
amid
e40
0 m
ghi
gh
bor
der
line
3/1
9.2.
1.2
Live
r to
xici
tyan
titub
ercu
losi
s m
edic
ine
pyr
idox
ine
hyd
roch
lorid
e25
mg
hig
hhi
gh
19.
2.1.
1vi
tam
in
NS
AID
, Non
-ste
roid
al a
nti-i
nfl a
mm
ator
y d
rug
s.
TSR2006_Annexs6-9.indd 415TSR2006_Annexs6-9.indd 415 4.5.2006 15:49:014.5.2006 15:49:01
416
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
Lis
ta
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
pyr
imet
ham
ine
25 m
g
bord
erlin
e;<
0.1
m
g/m
l3lo
w4/
3N
ot e
ligib
le
for
bio
wai
ver
anti-
pne
umo-
cyst
osis
and
an
titox
opla
smo-
sis
med
icin
e
qui
nine
bis
ul-
fate
or
sulfa
te30
0 m
g
hig
hhi
gh
19.
2.1.
1an
timal
aria
l
rani
tidin
ehy
dro
chlo
ride
150
mg
hig
hlo
w3
9.2.
1.2
antiu
lcer
med
icin
e
retin
ol
pal
mita
te11
0 m
g(2
00 0
00 IU
)lo
w (
3)lo
w (
?)4/
2N
ot e
ligib
le
for
bio
wai
ver
vita
min
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
ribofl
avi
n5
mg
hig
hhi
gh
19.
2.1.
1vi
tam
in
rifam
pic
in30
0 m
g
low
(am
-p
hip
hilic
)(p
Ka1
.7,
7.9)
(1)
hi
gh
2N
ot e
ligib
le
for
bio
wai
ver
antil
epro
sy a
nd
antit
uber
culo
sis
med
icin
e
rifam
pic
in (
r) +
ison
iazi
d (
i)(r
) 30
0 m
g +
(i) 1
50 m
g(r
) lo
w +
(i) h
igh
(r)
hig
h +
(i) b
ord
erlin
e(r
) 2
+(i)
3/1
See
foot
note
g
antit
uber
culo
sis
med
icin
e
rifam
pic
in (
r) +
ison
iazi
d (
i) +
p
yraz
inam
ide
(p)
(r)
150
mg
+(i)
150
mg
+ (
p)
500
mg
(r)
low
+(i)
hig
h +
(p)
hig
h
(r)
hig
h +
(i) b
ord
erlin
e + (p
) b
ord
erlin
e
(r)
2 +
(i) 3
/1
+ (
p)
3/1
See
foot
note
g
antit
uber
culo
sis
med
icin
e
BA
, bio
avai
lab
ility
.
TSR2006_Annexs6-9.indd 416TSR2006_Annexs6-9.indd 416 4.5.2006 15:49:014.5.2006 15:49:01
417
rifam
pic
in (
r) +
ison
iazi
d (
i) +
p
yraz
inam
ide
(p)
+ e
tham
bu-
tol (
e)
(r)
150
mg
+(i)
75
mg
+(p
) 40
0 m
g +
(e)
275
mg
(r)
low
+(i)
hig
h +
(p)
hig
h +
(e)
hig
h
(r)
hig
h +
(i) b
orde
rline
+(p
) bor
der-
line
+(e
) lo
w
(r)
2 +
(i) 3
/1
+ (
p)
3/1
+
(e)
3Se
e fo
otno
teg
antit
uber
culo
sis
med
icin
e
riton
avir
100
mg
low
low
(?)
4/2
Not
elig
ible
fo
r b
iow
aive
rC
YP
450
3A
4an
tiret
rovi
ral
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
salb
utam
olsu
lfate
4 m
ghi
gh
hig
h1
9.2.
1.1
antia
sthm
atic
and
med
icin
e fo
r C
OP
D
saq
uina
vir
200
mg
low
low
(?)
4/2
Not
elig
ible
fo
r b
iow
aive
rC
YP
450
3A
4,
food
effe
ct (
+)
antir
etro
vira
l
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
senn
a7.
5 m
g(s
enno
sid
e)–
–N
RN
Ala
xativ
elo
cal e
ffect
spiro
nola
cton
e25
mg
bor
der
line
low
4/3
Not
elig
ible
fo
r b
iow
aive
rd
iure
tic
stav
udin
e40
mg
hig
hhi
gh
19.
2.1.
1an
tiret
rovi
ral
sulfa
met
hoxa
-zo
le (
s) +
tr
imet
hop
rim (
t)(s
) 40
0 m
g +
(t)
80 m
g
(s)
low
(am
phi
phi
l)+
(t)
low
(w
eak
bas
e)(s
) hi
gh
+(t
) hi
gh
(s)
2 +
(t
) 2
Not
elig
ible
fo
r b
iow
aive
rG
6PD
defi
cie
ncy
antib
acte
rial
G6P
D, G
luco
se-6
-pho
spha
te d
ehyd
rog
enas
e; B
A, b
ioav
aila
bili
ty; C
OP
D: C
hron
ic O
bst
ruct
ive
Pul
mon
ary
Dis
ease
.
TSR2006_Annexs6-9.indd 417TSR2006_Annexs6-9.indd 417 4.5.2006 15:49:024.5.2006 15:49:02
418
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
Lis
ta
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
sulfa
sala
zine
500
mg
low
low
4N
R
gas
troin
test
inal
, an
ti-in
fl am
mat
ory
med
icin
e
used
for
loca
l ac-
tion
in th
e g
astro
-in
test
inal
trac
t
thia
min
ehy
dro
chlo
ride
50 m
ghi
gh
low
39.
2.1.
2vi
tam
in
tric
lab
end
azol
e25
0 m
gin
suffi
cien
t lit
erat
ure
low
4/3
Not
elig
ible
fo
r b
iow
aive
ran
tisch
isto
som
al,
antit
rem
atod
e
trim
etho
prim
200
mg
low
(w
eak
bas
e)hi
gh
2N
ot e
ligib
le
for
bio
wai
ver
antib
acte
rial
valp
roic
aci
d
sod
ium
sal
t50
0 m
ghi
gh
hig
h1
see
com
men
t
antie
pile
ptic
,p
sych
othe
rap
eu-
tic m
edic
ine
ente
ric-c
oate
dta
blet
not
elig
ible
fo
r b
iow
aive
r in
this
d
osag
e fo
rmi
vera
pam
ilhy
dro
chlo
ride
80 m
glo
w (
wea
k b
ase)
hig
h2
Not
elig
ible
fo
r b
iow
aive
r
antia
ngin
al a
nd
antia
rrhy
thm
icm
edic
ine
war
farin
so
diu
m s
alt
5 m
g
hig
h(s
olub
le 1
in le
ss
than
1 o
f w
ater
) (1
) hi
gh
19.
2.1.
1na
rrow
ther
a-p
eutic
ind
ex
med
icin
esaf
fect
ing
coa
gu-
latio
n
zid
ovud
ine
300
mg
hig
hhi
gh
19.
2.1.
1an
tiret
rovi
ral
zinc
sul
fate
10 m
g (
per
uni
t d
osag
e fo
rm)
hig
hlo
w3
9.2.
1.2
dia
rrho
ea in
ch
ildre
n
TSR2006_Annexs6-9.indd 418TSR2006_Annexs6-9.indd 418 4.5.2006 15:49:024.5.2006 15:49:02
419
a14
th W
HO
Mod
el L
ist o
f Ess
entia
l Med
icin
es, M
arch
200
5; a
vaila
ble
at:
http
://w
hqlib
doc
.who
.int/h
q/2
005/
a870
17_e
ng.p
df.
b
Sol
ubili
ty b
ased
on
the
low
est s
olub
ility
in th
e p
H r
ang
e fro
m 1
to 6
.8 a
t 37
°C. “
Low
” in
dic
ates
a d
osea
:sol
ubili
ty r
atio
> 2
50 m
l for
at l
east
one
pH
val
ue in
this
ran
ge.
c P
erm
eab
ility
bas
ed o
n fr
actio
n of
the
dos
e ab
sorb
ed a
fter o
ral d
osin
g in
hum
ans,
exc
ept w
here
oth
erw
ise
ind
icat
ed. “
Low
” in
dic
ates
that
less
than
85%
of t
he o
ral d
ose
was
ab
sorb
ed
at th
e hi
ghe
st o
ral s
treng
th li
sted
in th
e E
ML.
d
The
acce
pta
nce
crite
ria th
at h
ave
bee
n ad
apte
d b
y W
HO
are
exp
lain
ed in
Sec
tion
2 (“
WH
O re
visi
ons
to th
e cr
iteria
for
BC
S c
lass
ifi ca
tion”
).e
WH
O “
Mul
tisou
rce
doc
umen
t”: M
ultis
ourc
e (g
ener
ic) p
harm
aceu
tical
pro
duc
ts: g
uid
elin
es o
n re
gis
trat
ion
req
uire
men
ts to
est
ablis
h in
terc
hang
eab
ility
(WH
O T
echn
ical
Rep
ort S
erie
s,
No.
937
, Ann
ex 7
).f
Kno
wn
pot
entia
l ris
ks a
re in
dic
ated
whe
re a
pp
rop
riate
. W
here
no
info
rmat
ion
is g
iven
, th
is o
ften
ind
icat
es la
ck o
f av
aila
bili
ty o
f d
ata
and
sho
uld
not
be
cons
true
d a
s m
eani
ng t
hat
ther
e ar
e no
ris
ks a
ssoc
iate
d w
ith u
se o
f the
com
pou
nd. A
sses
smen
t of r
isks
sho
uld
be
mad
e b
y th
e in
div
idua
l nat
iona
l aut
horit
y b
ased
on
loca
l con
diti
ons
of u
se.
g
The
pos
sib
ility
of b
iow
aivi
ng fi
xed
-dos
e co
mb
inat
ions
of a
ntitu
ber
culo
sis
dru
gs
is s
till u
nder
con
sid
erat
ion
bec
ause
of t
heir
spec
ifi c
stab
ility
, tox
icity
and
inte
ract
ion
issu
es.
h M
edic
ine
is a
pp
lied
sub
ling
ually
, maj
or s
ite o
f ab
sorp
tion
is fr
om th
e or
al c
avity
.i
Dos
age
form
not
des
igne
d fo
r im
med
iate
rele
ase.
NR
, not
rele
vant
: loc
ally
act
ing
, no
sig
nifi c
ant s
yste
mic
ab
sorp
tion.
NA
, not
ap
plic
able
, inc
lud
es: l
ocal
ly a
ctin
g, s
yste
mic
ab
sorp
tion
from
the
oral
cav
ity o
r d
osag
e fo
rm n
ot d
esig
ned
for
imm
edia
te re
leas
e.
Com
pou
nds
intro
duc
ed to
the
EM
L si
nce
Mar
ch 2
005
or fo
r w
hich
no
clas
sifi c
atio
n ha
d b
een
pre
viou
sly
rep
orte
d.
1.C
lark
e’s
anal
ysis
of d
rug
s an
d p
oiso
ns. 3
rd e
d. L
ond
on, P
harm
aceu
tical
Pre
ss, R
oyal
Pha
rmac
eutic
al S
ocie
ty o
f Gre
at B
ritai
n, 2
004.
2. B
ritta
in K
, Flo
rey
HG
. Ana
lytic
al p
rofi l
es o
f dru
g s
ubst
ance
s an
d e
xcip
ient
s. O
xfor
d U
nive
rsity
Pre
ss.
3. S
wee
tman
S. M
artin
dal
e: th
e co
mp
lete
dru
g re
fere
nce,
34t
h ed
. Lon
don
, Pha
rmac
eutic
al P
ress
, 200
4.4.
Stip
ple
r E
. [D
isse
rtat
ion]
. Bio
rele
vant
Dis
solu
tion
Test
Met
hod
s to
Ass
ess
Bio
equi
vale
nce
of D
rug
Pro
duc
ts. G
erm
any,
Joh
ann-
Wol
fgan
g v
on G
oeth
e U
nive
rsity
Fra
nkfu
rt, 2
004.
5.M
erck
ind
ex. N
ew J
erse
y, U
SA
, Mer
ck P
ublis
hers
, 200
4.
Fer
rou
s sa
lts:
Com
mon
ly u
sed
iron
sal
ts:3
– fe
rrou
s as
corb
ate
(anh
ydro
us)
– fe
rrou
s as
par
tate
(te
trah
ydra
te)
– fe
rrou
s ch
lorid
e (t
etra
hyd
rate
)–
ferr
ous
fum
arat
e (a
nhyd
rous
)–
ferr
ous
glu
cona
te (
dih
ydra
te)
– fe
rrou
s g
lyci
ne s
ulfa
te–
ferr
ous
orot
ate
– fe
rrou
s su
ccin
ate
(anh
ydro
us)
– fe
rrou
s su
lfate
(d
ried
)–
ferr
ous
sulfa
te (
hep
tahy
dra
te)
Sol
ubili
ty o
f fer
rous
sal
ts:
– lo
wes
t sol
ubili
ty o
f all
com
mon
ly u
sed
iron
sal
ts: f
erro
us s
ucci
nate
anh
ydro
us,
sp
arin
gly
sol
uble
in w
ater
5 (d
ose:
solu
bili
ty r
atio
6m
l)
TSR2006_Annexs6-9.indd 419TSR2006_Annexs6-9.indd 419 4.5.2006 15:49:024.5.2006 15:49:02
420
Tab
le 2
Act
ive
ph
arm
aceu
tica
l in
gre
die
nts
on
th
e co
mp
lem
enta
ry li
st o
f th
e W
HO
Mo
del
Lis
t o
f E
ssen
tial
Med
icin
es (
EM
L)
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
List
a,g
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
arte
suna
te50
mg
low
bor
der
line
(BA
abs
82–8
8%)
but
d
epen
den
ton
sev
erity
of
dis
ease
(1,
2)
4/2
Not
elig
ible
fo
r b
iow
aive
r
exte
nt o
f ab
sorp
tion
dep
end
s on
se
verit
y of
d
isea
sean
timal
aria
l
azat
hiop
rine
sod
ium
sal
t50
mg
low
low
(?)
4/2
Not
elig
ible
fo
r b
iow
aive
r
imm
unos
up-
pre
ssiv
e, T
DM
re
com
men
ded
imm
unos
upp
res-
sive
, DM
AR
D
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
calc
ium
folin
ate
15 m
ghi
gh
hig
h1
9.2.
1.1
an
ticyt
otox
icm
edic
ine
chlo
ram
buc
il2
mg
hig
h
insu
ffi ci
ent
liter
atur
e (B
A
afte
r re
pea
ted
d
osag
e >
70
% b
ut u
ri-na
ry a
naly
ti-ca
l pro
fi le
i.v.
sim
ilar
to p
.o.)
(3
, 4)
3/1
9.2.
1.2
mye
losu
pp
res-
sion
(le
ukop
e-ni
a) =
dos
e-
limiti
ng to
xici
tycy
toto
xic
med
icin
eg
cycl
osp
orin
e25
mg
low
low
4/3
Not
elig
ible
fo
r b
iow
aive
r
imm
unos
up-
pre
ssiv
e, T
DM
re
com
men
ded
imm
unos
upp
res-
sive
TDM
: The
rap
eutic
Dru
g M
onito
ring
; DM
AR
D, d
isea
se m
odify
ing
ant
irheu
mat
ic d
rug
; BA
, bio
avai
lab
ility
; i.v
., in
trav
enou
s; p
.o. p
er o
rale
.
TSR2006_Annexs6-9.indd 420TSR2006_Annexs6-9.indd 420 4.5.2006 15:49:034.5.2006 15:49:03
421
clin
dam
ycin
150
mg
hig
hhi
gh
19.
2.1.
1
antib
acte
rial
cycl
opho
spha
-m
ide
25 m
ghi
gh
hig
h1
9.2.
1.1
mye
losu
pp
res-
sion
(le
ukop
e-ni
a) =
dos
e-
limiti
ng to
xici
ty,
acce
lera
ted
met
abol
ism
lead
ing
to re
-d
uced
ora
l BA
af
ter
rep
eate
d
treat
men
t cy
cles
cyto
toxi
cm
edic
ineg
cycl
oser
ine
250
mg
hig
h
insu
ffi ci
ent
liter
atur
e (u
rinar
y re
cove
ry 6
5%
(5),
70–
90%
of
the
dos
e is
ab
sorb
ed (
6))
3/1
9.2.
1.3
seru
m le
vels
>
30
μg/m
l as
soci
ated
with
C
NS
toxi
city
antit
uber
culo
sis
med
icin
e
die
thyl
carb
am-
azin
e d
ihyd
ro-
gen
citr
ate
100
mg
hig
hhi
gh
19.
2.1.
2
mye
losu
pp
res-
sion
(le
ukop
e-ni
a) =
dos
e-lim
iting
toxi
city
, ac
cele
rate
dm
etab
olis
mle
adin
g to
re-
duc
ed o
ral B
A
afte
r re
pea
ted
tre
atm
ent
cycl
es
antifi
laria
l
BA
, Bio
avai
lab
ility
; CN
S, c
entr
al n
ervo
us s
yste
m; G
I gas
troin
test
inal
.
TSR2006_Annexs6-9.indd 421TSR2006_Annexs6-9.indd 421 4.5.2006 15:49:034.5.2006 15:49:03
422
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
List
a,g
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
dox
ycyc
line
hyd
roch
lorid
e10
0 m
ghi
gh
hig
h1
9.2.
1.1
antim
alar
ial
ethi
onam
ide
250
mg
hig
h
insu
ffi ci
ent
liter
atur
e (“
read
ily
abso
rbed
from
th
e G
I tra
ct”)
(7
)3/
19.
2.1.
2an
titub
ercu
losi
s m
edic
ine
etho
suxi
mid
e25
0 m
ghi
gh
insu
ffi ci
ent
liter
atur
e3/
19.
2.1.
2
antie
pile
ptic
etop
osid
e10
0 m
glo
wlo
w (
?)4/
2N
ot e
ligib
le
for
bio
wai
ver
mye
losu
pp
res-
sion
(le
ukop
e-ni
a) =
dos
e-
limiti
ng to
xici
ty,
acce
lera
ted
met
abol
ism
lead
ing
to re
-d
uced
ora
l BA
af
ter
rep
eate
d
treat
men
t cy
cles
cyto
toxi
cm
edic
ineg
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
fl ucy
tosi
ne25
0 m
g3
hig
h
bor
der
-lin
e (B
Aab
s
76–8
9%)
(8, 9
)3/
19.
2.1.
2an
tifun
gal
BA
, Bio
avai
lab
ility
; DM
AR
D, d
isea
se m
odify
ing
ant
irheu
mat
ic d
rug
.
TSR2006_Annexs6-9.indd 422TSR2006_Annexs6-9.indd 422 4.5.2006 15:49:034.5.2006 15:49:03
423
leva
mis
ole
hyd
roch
lorid
e50
mg
hig
hno
hum
an
dat
a av
aila
ble
3/1
9.2.
1.2
cy
toto
xic
med
icin
eg
levo
fl oxa
cin
500
mg
hig
hhi
gh
19.
2.1.
1 an
titub
ercu
losi
s m
edic
ine
mefl
oq
uine
hyd
roch
lorid
e25
0 m
glo
w
insu
ffi ci
ent
liter
atur
e (“
wel
l ab
-so
rbed
”) (
7)4/
2N
ot e
ligib
le
for
bio
wai
ver
pha
rmac
o-ki
netic
s of
m
efl o
qui
ne
may
be
alte
red
b
y m
alar
ia
infe
ctio
n (7
)an
timal
aria
l
mer
cap
to-
pur
ine
50 m
glo
wlo
w (
?)4/
2N
ot e
ligib
le
for
bio
wai
ver
cyto
toxi
cm
edic
ineg
unkn
own
whe
ther
p
oor
BA
is d
ue to
p
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
nd
poo
r p
erm
eab
ility
met
hotre
xate
so
diu
m s
alt
2.5
mg
hig
hlo
w3
9.2.
1.2
seve
rity
of
adve
rse
effe
cts
dep
end
s on
d
ose
and
ind
i-ca
tion
cyto
toxi
cm
edic
ineg
,D
MA
RD
mife
pris
tone
– m
isop
rost
ol20
0 m
g
no li
tera
-tu
re d
ata
avai
lab
lelo
w4/
3
Not
elig
ible
fo
r b
iow
aive
r at
pre
sent
oxyt
ocic
ofl o
xaci
n40
0 m
ghi
gh
hig
h1
9.2.
1.1
antit
uber
culo
sis
med
icin
e
oxam
niq
uine
250
mg
low
insu
ffi ci
ent
liter
atur
e (u
ri-na
ry re
cove
ry
as s
ing
le a
cid
70
%)
(7)
4/2
Not
elig
ible
fo
r b
iow
aive
ran
tisch
isto
som
al,
antit
rem
atod
e
BA
, Bio
avai
lab
ility
; DM
AR
D, d
isea
se m
odify
ing
ant
irheu
mat
ic d
rug
.
TSR2006_Annexs6-9.indd 423TSR2006_Annexs6-9.indd 423 4.5.2006 15:49:044.5.2006 15:49:04
424
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
List
a,g
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
p-am
inos
alic
ylic
aci
d50
0 m
glo
w
bor
der
line
(80%
urin
ary
reco
very
(7)
4/2
Not
elig
ible
fo
r b
iow
aive
ran
titub
ercu
losi
s m
edic
ine
pen
icill
amin
e25
0 m
ghi
gh
low
39.
2.1.
2D
MA
RD
pen
tam
ine
300
mg
hig
hno
lite
ratu
re
dat
a3/
19.
2.1.
2
anti-
pne
umoc
ys-
tosi
s an
d a
nti-
toxo
pla
smos
ism
edic
ine
pre
dni
solo
ne25
mg
hig
hhi
gh
19.
2.1.
1ho
rmon
e/
antih
orm
one
pro
carb
azin
e hy
dro
chlo
ride
50 m
ghi
gh
insu
ffi ci
ent
liter
atur
e (u
ri-na
ry re
cove
ry
70%
, 24
h) (
5)3/
19.
2.1.
2
mye
losu
pp
res-
sion
(le
ukop
e-ni
a) =
dos
e-
limiti
ng to
xici
tycy
toto
xic
med
icin
eg
pyr
idos
tigm
ine
bro
mid
e60
mg
hig
hlo
w3
9.2.
1.2
mus
cle
rela
xant
qui
nid
ine
sulfa
te20
0 m
ghi
gh
insu
ffi ci
ent
liter
atur
e (B
A
70%
but
fi rs
t p
ass)
(5)
3/1
9.2.
1.2
antia
rrhy
thm
ic
sulfa
dia
zine
500
mg
bor
der
line
low
4/3
Not
elig
ible
fo
r b
iow
aive
ran
tibac
teria
l
BA
, Bio
avai
lab
ility
; DM
AR
D, d
isea
se m
odify
ing
ant
irheu
mat
ic d
rug
.
TSR2006_Annexs6-9.indd 424TSR2006_Annexs6-9.indd 424 4.5.2006 15:49:044.5.2006 15:49:04
425
sulfa
dox
ine
(s)
+ p
yrim
eth-
amin
e (p
)(s
) 50
0 m
g +
(p
) 25
mg
(s)
hig
h +
(p)
bor
der
-lin
e (<
0.1
m
g/m
l(7)
(s)
insu
ffi ci
ent
dat
a +
(p)
low
(s)
3/1+
(p)
4/3
Not
elig
ible
fo
r b
iow
aive
ran
timal
aria
l
sulfa
sala
zine
500
mg
low
low
4N
RD
MA
RD
Use
d fo
r lo
cal
actio
n in
the
gas
tro-
inte
stin
al tr
act
tam
oxife
nci
trat
e20
mg
hig
hhi
gh
19.
2.1.
1an
tihor
mon
e
a14
th W
HO
Mod
el L
ist o
f Ess
entia
l Med
icin
es, G
enev
a, W
orld
Hea
lth O
rgan
izat
ion,
Mar
ch 2
005;
ava
ilab
le a
t: ht
tp://
whq
libd
oc.w
ho.in
t/hq
/200
5/a8
7017
_eng
.pd
f.b
Sol
ubili
ty b
ased
on
the
low
est s
olub
ility
in th
e p
H r
ang
e fro
m 1
to 6
.8 a
t 37
°C. “
Low
” in
dic
ates
a d
osea
:sol
ubili
ty r
atio
> 2
50m
l for
at l
east
one
pH
val
ue in
this
ran
ge.
c P
erm
eab
ility
bas
ed o
n fr
actio
n of
the
dos
e ab
sorb
ed a
fter o
ral d
osin
g in
hum
ans,
exc
ept w
here
oth
erw
ise
ind
icat
ed. “
Low
” in
dic
ates
that
less
than
85%
of t
he o
ral d
ose
was
ab
sorb
ed
at th
e hi
ghe
st o
ral s
treng
th in
the
EM
L.a
d
The
orig
inal
Bio
pha
rmac
eutic
s C
lass
ifi ca
tion
Sys
tem
(B
CS
)is
ava
ilab
le a
t: ht
tp://
ww
w.fd
a.g
ov/c
der
/gui
dan
ce/3
618f
nl.p
df .
Not
e: th
e ac
cep
tanc
e cr
iteria
hav
e b
een
adap
ted
acc
ord
ing
to W
HO
req
uire
men
ts a
s ex
pla
ined
in S
ectio
n 2
of th
is A
nnex
.e
See
WH
O “
Mul
tisou
rce
doc
umen
t”:
Mul
tisou
rce
(gen
eric
) p
harm
aceu
tical
pro
duc
ts:
gui
del
ines
on
reg
istr
atio
n re
qui
rem
ents
to
esta
blis
h in
terc
hang
eab
ility
(W
HO
Tec
hnic
al R
epor
t S
erie
s, N
o. 9
37, A
nnex
7).
f K
now
n p
oten
tial r
isks
are
ind
icat
ed w
here
ap
pro
pria
te. W
here
no
info
rmat
ion
is g
iven
, thi
s m
ay in
dic
ate
lack
of a
vaila
bili
ty o
f rel
evan
t dat
a an
d s
houl
d n
ot b
e co
nstr
ued
as
mea
ning
th
at th
ere
are
no r
isks
ass
ocia
ted
with
use
of t
he c
omp
ound
. Ass
essm
ent o
f ris
ks s
houl
d b
e m
ade
by
the
natio
nal a
utho
rity
bas
ed o
n lo
cal c
ond
ition
s of
use
.g
Cyt
otox
ic m
edic
ines
: the
ris
ks a
ssoc
iate
d w
ith a
pp
lyin
g th
e b
iow
aive
r p
roce
dur
e sh
ould
be
very
car
eful
ly s
crut
iniz
ed b
y th
e na
tiona
l reg
ulat
ory
auth
ority
.
NR
not
rele
vant
: loc
ally
act
ing
, no
sig
nifi c
ant s
yste
mic
ab
sorp
tion.
Com
pou
nds
intro
duc
ed to
the
EM
L si
nce
Mar
ch 2
005
or fo
r w
hich
no
clas
sifi c
atio
n ha
d b
een
pre
viou
sly
rep
orte
d.
1. N
ewto
n P
et a
l. A
ntim
alar
ial b
ioav
aila
bilit
y an
d di
spos
ition
of a
rtesu
nate
in a
cute
falc
ipar
um m
alar
ia. A
ntim
icro
bial
Age
nts
and
Che
mot
hera
py, 2
000,
44:
972-
977.
2. N
ewto
n PN
et a
l. C
ompa
rison
of o
ral a
rtesu
nate
and
dih
ydro
arte
mis
inin
ant
imal
aria
l bio
avai
labi
litie
s in
acu
te fa
lcip
arum
mal
aria
.Ant
imic
robi
al A
gent
s an
d C
hem
othe
rapy
, 200
2, 4
6:11
25-1
127.
3. M
cLea
n A
et a
l. Ph
arm
acok
inet
ics
and
met
abol
ism
of c
hlor
ambu
cil i
n pa
tient
s w
ith m
alig
nant
dis
ease
. Can
cer T
reat
men
t Rev
iew
s, 1
979,
6, S
uppl
:33-
42.
4. S
ilven
noin
en R
et a
l. Ph
arm
acok
inet
ics
of c
hlor
ambu
cil i
n pa
tient
s w
ith c
hron
ic ly
mph
ocyt
ic le
ukae
mia
: com
paris
on o
f diff
eren
t day
s, c
ycle
s an
d do
ses.
Pha
rmac
olog
y &
Tox
icol
ogy,
200
0,
87:2
23-2
28.
5.C
lark
e’s
Ana
lysi
s of
Dru
gs a
nd P
oiso
ns. 3
rd e
d. L
ondo
n, P
harm
aceu
tical
Pre
ss, 2
004.
6. B
ritta
in H
G, F
lore
y K
. Ana
lytic
al P
rofi l
es o
f Dru
g Su
bsta
nces
and
Exc
ipie
nts.
ed.
Oxf
ord
Uni
vers
ity P
ress
.7.
Sw
eetm
an S
. Mar
tinda
le: T
he c
ompl
ete
drug
refe
renc
e. 3
4 ed
. Lon
don,
Pha
rmac
eutic
al P
ress
, 200
4.8.
Ver
mes
A e
t al.
Popu
latio
n ph
arm
acok
inet
ics
of fl
ucyt
osin
e: c
ompa
rison
and
val
idat
ion
of th
ree
mod
els
usin
g ST
S, N
PEM
, and
NO
NM
EM. T
hera
peut
ic D
rug
Mon
itorin
g, 2
000,
22:
676-
687.
9. V
erm
es A
, Guc
hela
ar H
J, D
anke
rt J.
Flu
cyto
sine
: a re
view
of i
ts p
harm
acol
ogy,
clin
ical
indi
catio
ns, p
harm
acok
inet
ics,
toxi
city
and
dru
g in
tera
ctio
ns. J
ourn
al o
f A
ntim
icro
bial
Che
mot
hera
py,
2000
, 46:
171-
179.
TSR2006_Annexs6-9.indd 425TSR2006_Annexs6-9.indd 425 4.5.2006 15:49:044.5.2006 15:49:04
426
Tab
le 3
Co
mp
ou
nd
s in
tro
du
ced
to
th
e W
HO
Mo
del
Lis
t o
f E
ssen
tial
Med
icin
es s
ince
Mar
ch 2
005
for
wh
ich
no
cer
tain
cla
ssifi
cati
on
had
bee
n
pre
vio
usl
y re
po
rted
(th
ese
com
po
un
ds
also
ap
pea
r in
Tab
le 1
an
d T
able
2)
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
List
(EM
L)a
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
amlo
dip
ine
5 m
g
slig
htly
solu
ble
(1)
,D
:S 5
ml
BA
abs
60–6
5%,
excr
etio
n of
d
rug
met
abo-
lites
in u
rine
90–9
5% (
2)1
9.2.
1.1
antih
yper
tens
ive
med
icin
e
BA
abs <
85%
as
crib
ed to
fi rs
t-p
ass
met
abol
ism
amod
iaq
uine
(bas
e)20
0 m
g45
mg
/ml2 ,
D:S
4.4
ml
BA
> 7
5% (
3)3/
19.
2.1.
2
CY
P2C
8p
olym
orp
hism
,in
crea
sed
ris
k fo
r ag
ranu
locy
-to
sis
and
hep
a-to
toxi
city
(4)
antim
alar
ial
amox
icill
in +
cl
avul
anic
aci
d50
0 m
g +
12
5 m
g
freel
y so
lub
le in
w
ater
(1)
,D
:S 1
.25
ml
abso
rptio
n >
73
% (
5)1
+
3/1
9.2.
1.2
an
tibac
teria
l
test
s b
ased
on
clav
ulan
ic a
cid
cl
assi
fi cat
ion
arte
suna
te50
mg
very
sl
ight
lyso
lub
le (
6),
D:S
500
ml;
(wea
k ac
id,
pK
a ~
6.4
)
BA
abs 8
2% (1
),B
Aab
s 88%
(7),
BA
abs 6
1% (8
)4/
2N
ot e
ligib
le
for
bio
wai
ver
antim
alar
ial
per
mea
bili
ty
dep
end
s on
s
ever
ity o
f dis
ease
D:S
, Dos
e: s
olub
ility
; BA
, Bio
avai
lab
ility
.
TSR2006_Annexs6-9.indd 426TSR2006_Annexs6-9.indd 426 4.5.2006 15:49:054.5.2006 15:49:05
427
azith
rom
ycin
500
mg
pra
ctic
ally
inso
lub
lein
wat
er (
1)<
0.0
1mg
/m
l, D
:S
50 0
00 m
l
BA
abs 1
6% (9
);B
A 3
7%(1
0, 1
1);
4/2
Not
elig
ible
fo
r b
iow
aive
ran
tibac
teria
l
unkn
own
whe
ther
poo
r B
A is
due
top
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
ndp
oor
per
mea
bili
ty
calc
ium
folin
ate
15 m
g
spar
ing
lyso
lub
lein
wat
er
(Ph.
Eur
. 5.
2); v
ery
solu
ble
(US
P 2
8);
D:S
15
ml
and
0.01
5 m
l, re
spec
-tiv
ely
BA
abs 9
2% 2
5 m
g (
12, 1
3);
BA
abs 7
3.4%
(15
mg
) (1
4);
fully
abs
orbe
d;A
UC
and
t 1/2
sim
ilar
afte
r i.v
. & p
.o (
15)
19.
2.1.
1 an
ticyt
otox
icm
edic
ine
levo
dop
a (l)
+
carb
idop
a (c
)(l)
250
mg
+
(c)
25 m
g
(l) h
igh
+(c
) so
lub
le
1 in
500
of
wat
er,
freel
y so
lub
le in
3
M H
Cl
(1)
(l) h
igh
+(c
) B
A 5
8%
(16)
; BA
abs
88%
(d
ogs)
(1
7)(l)
1 +
(c)
3/1
9.2.
1.2
narr
owth
erap
eutic
ind
exan
tipar
kins
onm
edic
ine
test
s b
ased
on
carb
idop
acl
assi
fi cat
ion
cefi x
ime
400
mg
slig
htly
solu
ble
(2)
,D
:S 4
00 m
l22
–54%
(2)
4N
ot e
ligib
le
for
bio
wai
ver
antib
acte
rial
D:S
, Dos
e: s
olub
ility
; BA
: Bio
avai
lab
ility
; Ph.
Eur
., E
urop
ean
Pha
rmac
opoe
ia; U
SP,
Uni
ted
Sta
tes
Pha
rmac
opoe
ia; A
UC
, are
a un
der
the
curv
e; i.
v., i
ntra
veno
us.
TSR2006_Annexs6-9.indd 427TSR2006_Annexs6-9.indd 427 4.5.2006 15:49:054.5.2006 15:49:05
428
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
List
(EM
L)a
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
chlo
ram
buc
il2
mg
“pra
ctic
ally
inso
lub
lein
wat
er”
(1),
but
D
:S ~
20
ml
i.v. v
s. p
.o.
sim
ilar
ana-
lytic
al p
rofi l
e in
urin
e =
hi
gh
deg
ree
of a
bso
rptio
n (1
8), B
Aab
s
> 7
0% a
fter
rep
eate
d o
ral
dos
age
(19,
20)
3/1
9.2.
1.2
mye
losu
pp
res-
sion
(le
ukop
e-ni
a) =
dos
e-lim
iting
toxi
city
;ac
cele
rate
dm
etab
olis
mle
adin
g to
red
uced
or
al B
A a
fter
rep
eate
d tr
eat-
men
t cyc
les
(21,
22)
cyto
toxi
cm
edic
ineg
clin
dam
ycin
150
mg
500
mg/
ml2 ,
D:S
0.3
ml
abou
t 90%
of
the
dos
e ab
sorb
ed (
1)1
9.2.
1.1
dia
rrho
ea/
naus
eaan
tibac
teria
l
cylc
oser
ine
250
mg
solu
ble
100
mg/
ml2 ,
D:S
2.5
ml
65%
urin
ary
excr
etio
n (2
),70
–90%
of a
p
.o. d
ose
ab-
sorb
ed (
23)
3/1
9.2.
1.2
seru
m le
vels
>
30
μg/m
l as
soci
ated
with
C
NS
toxi
city
antit
uber
culo
sis
med
icin
e
i.v.,
intr
aven
ous;
p.o
., p
er o
rale
; BA
: Bio
avai
lab
ility
; D:S
, Dos
e: s
olub
ility
.
TSR2006_Annexs6-9.indd 428TSR2006_Annexs6-9.indd 428 4.5.2006 15:49:054.5.2006 15:49:05
429
enal
april
2.5
mg
spar
ing
lyso
lub
lein
wat
er
(1),
D:S
0.
25 m
l; d
isso
lves
in d
ilute
so
lutio
nsof
alk
ali
hyd
roxi
des
(1
)
abso
rptio
np
.o. 6
9%,
urin
ary
re-
cove
ry 7
7%,
BA
38%
, fi rs
t p
ass
10%
(2
4); p
.o. c
hil-
dre
n, u
rinar
y re
cove
ry ~
ab
sorp
tion
50%
(25
)3
9.2.
1.2
antih
yper
tens
ive
med
icin
e
ethi
onam
ide
250
mg
slig
htly
solu
ble
in
wat
er a
t 25
° C
(2)
D:S
< 2
50 m
l
read
ily a
b-
sorb
ed fr
om
the
gas
troin
-te
stin
al tr
act,
exte
nsiv
ely
met
abol
ized
,p
rob
ably
in
the
liver
, les
s th
an 1
% o
f a
dos
e ap
pea
rs
in th
e ur
ine
as
unch
ang
edd
rug
(1)
3/1
9.2.
1.2
antit
uber
culo
sis
med
icin
e
D:S
, Dos
e: s
olub
ility
; BA
: Bio
avai
lab
ility
; p.o
., p
er o
rale
.
TSR2006_Annexs6-9.indd 429TSR2006_Annexs6-9.indd 429 4.5.2006 15:49:054.5.2006 15:49:05
430
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
List
(EM
L)a
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
etop
osid
e10
0 m
g
pra
ctic
ally
inso
lub
lein
wat
er
(2),
D:S
10
00 m
l
excr
etio
n 30
–50%
unch
ang
edin
the
urin
e,
20%
as
met
abol
ites
= 5
0–70
%
(2),
ab
sorp
-tio
n 48
–57%
(2
3), 6
0%
abso
rptio
n in
ch
ildre
n (2
6)4/
2N
ot e
ligib
le
for
bio
wai
ver
mye
losu
pp
res-
sion
(le
ukop
e-ni
a) =
dos
e-lim
iting
toxi
city
; g
reat
var
iab
ility
in
ab
sorp
tion
(all
refe
renc
es)
cyto
toxi
cm
edic
ineg
unkn
own
whe
ther
poo
r B
A is
due
top
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
ndp
oor
per
mea
bili
ty
ferr
ous
salt
equi
vale
nt to
60
mg
iron
hig
h (s
ee
foot
note
,Ta
ble
1)
low
39.
2.1.
2an
tiana
emia
med
icin
eap
plie
s to
com
-m
only
use
d s
alts
ferr
ous
salt
(fs)
+
folic
aci
d (
fa)
equi
vale
nt to
60
mg
iron
+
400
μg fo
lic
acid
(fs) h
igh
(see
foot
note
) +
very
slig
htly
so
lubl
e in
w
ater
(2),
D:S
2.5
ml;
0,00
16m
g/m
l (25
°C
) w
ater
(23)
,D
:S 2
50 m
l
(fs)
low
+(f
a) lo
w (
uri-
nary
reco
very
28
% (
23))
(fs)
3+ (fa
) 3/1
9.2.
1.2
antia
naem
iam
edic
ine
(dur
ing
p
reg
nanc
y)
com
bin
atio
nsh
ould
be
test
edac
cord
ing
to
req
uire
men
ts fo
rB
CS
Cla
ss II
I co
mp
ound
s;ap
plie
s to
com
-m
only
use
d ir
on
salts
D:S
, Dos
e: s
olub
ility
; BA
: Bio
avai
lab
ility
.
TSR2006_Annexs6-9.indd 430TSR2006_Annexs6-9.indd 430 4.5.2006 15:49:064.5.2006 15:49:06
431
fl ucy
tosi
ne25
0 m
g
solu
ble
15
mg
/ml (
2),
D:S
17
ml;
14.2
mg
/ml
(23)
; D:S
17
.6 m
lB
Aab
s 76–
89%
(2
7, 2
8)3/
19.
2.1.
2an
tifun
gal
levo
fl oxa
cin
500
mg
hig
h(3
0–30
0m
g/m
l)(2
9) D
:S
16.7
ml
hig
h (o
ral
vs i.
v. 1
00%
B
A; C
aco-
2 p
erm
eab
ility
hi
gh)
(29
) 1
9.2.
1.1
for
mai
n si
de-
effe
cts
refe
r to
(3
0)an
titub
ercu
losi
s m
edic
ine
meb
end
azol
e50
0 m
g
pra
ctic
ally
inso
lub
lein
wat
er
(bot
hm
onoh
y-d
rate
and
an
hyd
rous
(2
)), D
:S >
50
000
ml
BA
abs 2
%
(31)
; urin
ary
reco
very
2%
of o
rally
ad
min
iste
red
d
ose
(32)
4/2
NA
anth
elm
inth
ic
Che
wab
le ta
ble
t, an
thel
min
thic
s us
u-al
ly a
dm
inis
tere
d
oral
ly fo
r ac
tion
in
GI t
ract
: sol
ubili
ty
mor
e im
por
tant
th
an p
erm
eab
il-ity
– b
ut u
nkno
wn
whe
ther
poo
r B
A is
d
ue to
poo
r so
lub
il-ity
or p
oor
solu
bili
ty
and
poo
r p
erm
e-ab
ility
med
roxy
-p
rog
este
rone
ac
etat
e5
mg
pra
ctic
ally
inso
lub
lein
wat
er
(2),
1 g
in
>10
000
m
l, <
0.1
m
g/m
l, D
:S
< 5
0 m
l
in r
ats
+
dog
s B
A 2
7%
fi rst
-pas
s m
etab
olis
m,
self-
ind
uced
met
abol
ism
;16
% a
nd v
ery
varia
ble
(2)
3/1
9.2.
1.2
pro
ges
tog
en
exte
nt o
f fi rs
t-p
ass
met
abol
ism
in
hum
ans
unce
rtai
n
D:S
, Dos
e: s
olub
ility
; BA
: Bio
avai
lab
ility
; i.v
., in
trav
enou
s.
TSR2006_Annexs6-9.indd 431TSR2006_Annexs6-9.indd 431 4.5.2006 15:49:064.5.2006 15:49:06
432
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
List
(EM
L)a
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
mer
cap
top
u-rin
e50
mg
low
(in
-so
lub
le in
w
ater
; pK
a
7.7/
11.
0,<
0.1
mg
/m
l)2 , D
:S
> 5
00 m
l(2
)
BA
oral v
on
aza
47%
, fi rs
t p
ass,
50%
in
urin
e (2
)4/
2N
ot e
ligib
le
for
bio
wai
ver
antim
etab
olite
,TD
M s
ugg
est-
ed b
y Le
nnar
d
(1)
cyto
toxi
cm
edic
ineg
unkn
own
whe
ther
poo
r B
A is
due
top
oor
solu
bili
ty o
rp
oor
solu
bili
ty a
ndp
oor
per
mea
bili
ty
mife
pris
tone
– m
isop
rost
ol20
0 m
g
no info
rmat
ion
avai
lab
le
BA
70%
; als
o re
por
ted
40%
af
ter
100
mg
or
al d
ose
(2)
4/3
Not
elig
ible
fo
r b
iow
aive
r at
pre
sent
ox
ytoc
ic
insu
ffi ci
ent
info
rmat
ion
avai
lab
le
nicl
osam
ide
500
mg
5–8m
g/l
(20
°C)
(33)
, D:S
77
000
ml
2–25
% o
f a
dos
e of
2 g
ra
dio
lab
elle
dd
rug
reco
v-er
ed in
the
urin
e, re
st in
fa
eces
(33
)4/
2N
Aan
thel
min
thic
chew
able
tab
let,
anth
elm
inth
ics
usua
lly a
pp
lied
or
ally
for
actio
n in
G
I tra
ct: s
olub
ility
m
ore
imp
orta
ntth
an p
erm
eab
ility
ofl o
xaci
n40
0 m
g
hig
h(3
0–30
0m
g/m
l)(2
9), D
:S
13 m
l
dos
ep
rop
ortio
nal
100%
BA
(29
)1
9.2.
1.1
for
mai
n si
de-
effe
cts
refe
r to
(30
)an
titub
ercu
losi
s m
edic
ine
D:S
, Dos
e: s
olub
ility
; BA
: Bio
avai
lab
ility
; TD
M, t
hera
peu
tic d
rug
mon
itorin
g; G
I, g
astro
inte
stin
al.
TSR2006_Annexs6-9.indd 432TSR2006_Annexs6-9.indd 432 4.5.2006 15:49:064.5.2006 15:49:06
433
oxam
niq
uine
250
mg
low
(1
in
3300
at
27 °
C,
0.3
mg
/ml)
(23)
, D:S
82
5 m
l
“rea
dily
ab
-so
rbed
”, u
ri-na
ry e
xcre
tion
70%
as
sing
le
acid
(1)
4/3
Not
elig
ible
fo
r b
iow
aive
r
no s
igni
fi can
tto
xic
effe
cts
on
liver
, kid
ney
or
hear
t, d
ose
15 m
g/k
g (
1)an
tisch
isto
som
al,
antit
rem
atod
e
p-am
inos
alic
ylic
acid
500
mg
low
(1
g
in 6
00 m
l, 1.
66 m
g/
ml)
(23)
;D
:S 3
01 m
l,w
eak
acid
, p
Ka
not
foun
d in
lit
erat
ure
bor
der
line,
80
% e
xcre
-tio
n in
urin
e (1
)4/
2
Not
elig
ible
fo
r b
iow
aive
r at
pre
sent
an
titub
ercu
losi
s m
edic
ine
bor
der
line
in
bot
h so
lub
ility
an
d p
erm
eab
ility
–
solu
bili
ty p
rofi l
e ne
eds
to b
e b
ette
r ch
arac
teriz
ed
pen
tam
ine
300
mg
hig
h (1
in
10 1
00
mg
/ml)2 ,
D:S
3 m
lno
info
rmat
ion
avai
lab
le3/
19.
2.1.
2
anti-
pne
umo-
cyst
osis
and
an
titox
opla
smo-
sis
med
icin
e
pot
assi
umio
did
e60
mg
very
so
lub
le in
w
ater
, D:S
<
0.0
6 m
l
BA
96.
4%
(35)
; urin
ary
reco
very
89
%, f
aece
s 11
% (
36)
19.
2.1.
1
thyr
oid
ho
rmon
es a
nd
antit
hyro
id
med
icin
es
pro
carb
azin
e hy
dro
chlo
ride
50 m
g
hig
h (2
00
mg
/ml)
(23)
, D:S
0.
25 m
l
read
ily a
b-
sorb
ed,
70%
dos
e ex
cret
ed in
ur
ine
afte
r 24
h (2
)3/
19.
2.1.
2
tum
our
inhi
bito
r,ha
emat
olog
ic(2
)cy
toto
xic
med
icin
eg
D:S
, Dos
e: s
olub
ility
; BA
: Bio
avai
lab
ility
.
TSR2006_Annexs6-9.indd 433TSR2006_Annexs6-9.indd 433 4.5.2006 15:49:074.5.2006 15:49:07
434
Med
icin
ea
Hig
hes
t o
ral
stre
ng
thac
cord
ing
to
W
HO
Ess
enti
al
Med
icin
es L
ista
So
lub
ility
bP
erm
eab
ility
c
BC
Scl
assd
Dis
solu
tio
nte
st (
for
bio
wai
ver)
eP
ote
nti
al r
isks
f
Ind
icat
ion
(s)
acco
rdin
g t
o
WH
O E
ssen
tial
M
edic
ines
List
(EM
L)a
Co
mm
ents
and
spec
ial d
osa
ge
form
ind
icat
ion
sa
pyr
ante
lem
bon
ate
250
mg
low
(pra
ctic
ally
inso
lubl
e in
w
ater
, 1 g
in
>10
000
m
l2 , <
0.1
m
g/m
l), D
:S
> 2
500
ml
16%
BA
oral
(pal
moa
te),
41%
ora
l BA
(c
itrat
e) (
37)
4/2
NA
anth
elm
inth
ic
chew
able
tab
let,
anth
elm
inth
ics
usua
lly a
pp
lied
or
ally
for
actio
n in
G
I tra
ct:s
olub
ility
m
ore
imp
orta
nt
than
per
mea
bili
ty
qui
nid
ine
sulfa
te20
0 m
g
hig
h(1
0 m
g/m
l) (2
3),
D:S
20
ml
rap
idly
abso
rbed
BA
70
%; p
erm
e-ab
ility
var
ies
wid
ely,
fi rs
t p
ass
(2)
3/1
9.2.
1.2
narr
owth
erap
eutic
ind
exan
tiarr
hyth
mic
rani
tidin
ehy
dro
chlo
ride
150
mg
hig
h (f
reel
y so
lub
le in
w
ater
(2)
> 1
000
mg
/ml),
D:S
0.1
5 m
l50
% B
A, fi
rst
pas
s (2
, 38)
3/
19.
2.1.
2an
tiulc
erm
edic
ine
sulfa
dox
ine
25 m
g
very
slig
htly
so
lubl
e in
w
ater
(2),
D:S
< 2
50 m
l
read
ily
abso
rbed
afte
r or
al
adm
inis
trat
ion
(2)
3/1
9.2.
1.2
antim
alar
ial
D:S
, Dos
e: s
olub
ility
; BA
: Bio
avai
lab
ility
; GI,
gas
troin
test
inal
.
TSR2006_Annexs6-9.indd 434TSR2006_Annexs6-9.indd 434 4.5.2006 15:49:074.5.2006 15:49:07
435
tam
oxife
nci
trat
e20
mg
hig
h (v
ery
slig
htly
solu
ble
in
wat
er (
1),
0.1
mg
/ml
-1 m
g/m
l),
D:S
200
ml
BA
abs ~
100
%
(39)
19.
2.1.
1
end
omet
rial
canc
er, u
terin
e sa
rcom
a (1
)an
tihor
mon
e
zinc
sul
fate
10 m
g (
per
uni
t d
osag
e fo
rm)
hig
h (v
ery
solu
ble
in
wat
er)
(1),
D:S
0.0
1,
sam
e so
lu-
bili
ty fo
r al
l hy
dra
tes
of
the
sulfa
te
11 %
ab
-so
rbed
, with
m
eal v
ersu
s p
erce
ntag
e of
i.v.
dos
e ab
sorb
ed20
–30%
39.
2.1.
2d
iarr
hoea
in
child
ren
D:S
, Dos
e:so
lub
ility
; BA
, bio
avai
lab
ility
; i.v
., in
trav
enou
s.
a14
th W
HO
Mod
el L
ist o
f Ess
entia
l Med
icin
es, G
enev
a, W
orld
Hea
lth O
rgan
izat
ion,
Mar
ch 2
005;
ava
ilab
le a
t: ht
tp://
whq
libd
oc.w
ho.in
t/hq
/200
5/a8
7017
_eng
.pd
f.b
Sol
ubili
ty b
ased
on
the
low
est s
olub
ility
in th
e p
H r
ang
e fro
m 1
to 6
.8 a
t 37
°C. “
Low
” in
dic
ates
a d
osea
:sol
ubili
ty r
atio
> 2
50m
l for
at l
east
one
pH
val
ue in
this
ran
ge.
c P
erm
eab
ility
bas
ed o
n fr
actio
n of
the
dos
e ab
sorb
ed a
fter o
ral d
osin
g in
hum
ans,
exc
ept w
here
oth
erw
ise
ind
icat
ed. “
Low
” in
dic
ates
that
less
than
85%
of t
he o
ral d
ose
was
ab
sorb
ed
at th
e hi
ghe
st o
ral s
treng
th in
the
EM
L.a
d
The
orig
inal
Bio
pha
rmac
eutic
s C
lass
ifi ca
tion
Sys
tem
(B
CS
) is
ava
ilab
le a
t: ht
tp://
ww
w.fd
a.g
ov/c
der
/gui
dan
ce/3
618f
nl.p
df.
Not
e: th
e ac
cep
tanc
e cr
iteria
hav
e b
een
adap
ted
acc
ord
ing
to W
HO
req
uire
men
ts a
s ex
pla
ined
in S
ectio
n 2
of th
is A
nnex
.e
See
WH
O “
Mul
tisou
rce
doc
umen
t”:
Mul
tisou
rce
(gen
eric
) p
harm
aceu
tical
pro
duc
ts:
gui
del
ines
on
reg
istr
atio
n re
qui
rem
ents
to
esta
blis
h in
terc
hang
eab
ility
(W
HO
Tec
hnic
al R
epor
t S
erie
s, N
o. 9
37, A
nnex
7).
f K
now
n p
oten
tial r
isks
are
ind
icat
ed w
here
ap
pro
pria
te. W
here
no
info
rmat
ion
is g
iven
, thi
s m
ay in
dic
ate
lack
of a
vaila
bili
ty o
f rel
evan
t dat
a an
d s
houl
d n
ot b
e co
nstr
ued
as
mea
ning
th
at th
ere
are
no r
isks
ass
ocia
ted
with
use
of t
he c
omp
ound
. Ass
essm
ent o
f ris
ks s
houl
d b
e m
ade
by
the
natio
nal a
utho
rity
bas
ed o
n lo
cal c
ond
ition
s of
use
.g
Cyt
otox
ic m
edic
ines
: the
ris
ks a
ssoc
iate
d w
ith a
pp
lyin
g th
e b
iow
aive
r p
roce
dur
e sh
ould
be
very
car
eful
ly s
crut
iniz
ed b
y th
e na
tiona
l reg
ulat
ory
auth
ority
.
NR
not
rele
vant
: loc
ally
act
ing
, no
sig
nifi c
ant s
yste
mic
ab
sorp
tion.
NA
not
ap
plic
able
, loc
ally
act
ing
.
Fer
rou
s sa
lts:
(se
e fo
otno
te to
Tab
le 1
).
TSR2006_Annexs6-9.indd 435TSR2006_Annexs6-9.indd 435 4.5.2006 15:49:074.5.2006 15:49:07
436
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004.
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d p
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ns. 3
rd e
d. L
ond
on, P
harm
aceu
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ss, R
oyal
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aris
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ith p
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arid
ine
and
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ated
ant
imal
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l dru
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5.
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6.Th
e In
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atio
nal P
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acop
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s, q
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y sp
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aceu
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l. C
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l art
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ate
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arte
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imal
aria
l bio
avai
lab
ilitie
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te fa
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rap
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002,
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l bio
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15. G
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ion
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16. Y
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emet
CR
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umm
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17. O
bac
h R
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arg
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A, V
alle
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. The
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arb
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Phar
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l in
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nt d
isea
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r Tre
atm
ent R
evie
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ell D
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The
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rmac
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d p
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ustin
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h Jo
urna
l of C
linic
al P
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acol
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3.20
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ell D
R e
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Stu
die
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rmac
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etic
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oram
buc
il an
d p
red
nim
ustin
e in
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. Brit
ish
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nal o
f Clin
ical
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rmac
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21. N
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le A
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SJ,
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fi eld
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il in
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ymp
hoid
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igna
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ymp
hom
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004,
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22. S
ilven
noin
en R
et a
l. P
harm
acok
inet
ics
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hlor
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ucil
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chr
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pho
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leuk
aem
ia: c
omp
aris
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23. B
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d U
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K. P
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inet
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RK
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eutic
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g D
isp
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26. C
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CL
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l. B
ioav
aila
bili
ty a
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inet
ic fe
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200
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2:31
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ics
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com
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TS,
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EM
, an
d N
ON
ME
M.
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ts p
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acol
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icat
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ty a
nd d
rug
inte
ract
ions
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rnal
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ntim
icro
bia
l Che
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othe
rap
y, 2
000,
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29. F
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A,
Mol
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H,
Wirb
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E.
Bio
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eutic
al c
hara
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izat
ion
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imm
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te r
elea
se d
rug
pro
duc
ts.
In v
itro/
in v
ivo
com
par
ison
of
phe
noxy
met
hylp
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illin
pot
assi
um,
glim
epiri
de
and
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fl oxa
cin.
Eur
opea
n Jo
urna
l of P
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aceu
tics
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Bio
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eutic
s, 1
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46:
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311.
30. V
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eke
F et
al.
Qui
nolo
nes
in 2
005:
an
upd
ate.
Clin
ical
Mic
rob
iolo
gy
and
Infe
ctio
n, 2
005,
11:
256–
280.
31.S
umm
ary
rep
ort o
n m
eben
daz
ole.
Lon
don
, Eur
opea
n A
gen
cy fo
r th
e E
valu
atio
n of
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icin
al P
rod
ucts
(E
ME
A),
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. Pro
duc
t Inf
orm
atio
n Ve
rmox
®.
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33.W
HO
dat
a sh
eet o
n p
estic
ides
, No.
63.
Gen
eva,
Wor
ld H
ealth
Org
aniz
atio
n, 2
002.
34. S
igm
a-A
ldric
h P
rod
uct I
nfor
mat
ion.
35. A
qua
ron
R e
t al.
Bio
avai
lab
ility
of s
eaw
eed
iod
ine
in h
uman
bei
ngs.
Cel
lula
r an
d M
olec
ular
Bio
log
y (N
oisy
-le-g
rand
), 2
002,
48:
563–
569.
36. J
ahre
is G
et
al.
Bio
avai
lab
ility
of
iod
ine
from
nor
mal
die
ts r
ich
in d
airy
pro
duc
ts –
res
ults
of
bal
ance
stu
die
s in
wom
en.
Exp
erim
enta
l an
d C
linic
al E
ndoc
rinol
ogy
& D
iab
etes
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01,1
09:1
63–1
67.
37. B
jorn
H, H
enne
ssy
DR
, Frii
s C
. The
kin
etic
dis
pos
ition
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yran
tel c
itrat
e an
d p
amoa
te a
nd th
eir e
ffi ca
cy a
gai
nst p
yran
tel-r
esis
tant
Oes
opha
gos
tom
um d
enta
tum
in p
igs.
Inte
rnat
iona
l Jo
urna
l for
Par
asito
log
y, 1
996,
26:
1375
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0.38
. Rob
erts
CJ.
Clin
ical
pha
rmac
okin
etic
s of
ran
itid
ine.
Clin
ical
Pha
rmac
okin
etic
s, 1
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21.
39. M
orel
lo K
C, W
urz
GT,
DeG
reg
orio
MW
. Pha
rmac
okin
etic
s of
sel
ectiv
e es
trog
en re
cep
tor
mod
ulat
ors.
Clin
ical
Pha
rmac
okin
etic
s, 2
003,
42:
361–
372.
TSR2006_Annexs6-9.indd 437TSR2006_Annexs6-9.indd 437 4.5.2006 15:49:084.5.2006 15:49:08
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