annex 8 proposal to waive in vivo bioequivalence

391

© 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

TSR2006_Annexs6-9.indd 391TSR2006_Annexs6-9.indd 391 4.5.2006 15:48:564.5.2006 15:48:56

392

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.


393

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).


394

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).


395

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.



396

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


CLASS IHighly permeableHighly soluble

Eligible

CLASS IIHighly permeablePoorly soluble

Not eligible

CLASS IIIPoorly permeableHighly soluble

Not eligible

CLASS IVPoorly permeablePoorly soluble

Not eligible


397

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



398

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.


399

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


400

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.



401

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



402

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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.


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.


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

.


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

.


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.


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.


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.


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.


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


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

.


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


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.


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

.


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

.


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


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)


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

.


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

.


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

.


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

.


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

.


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.


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

.


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.


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

.


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

.


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

.


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.


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.


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

.


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

.


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

).


436

1.

Sw

eetm

an S

. Mar

tind

ale:

the

com

ple

te d

rug

refe

renc

e, 3

4th

ed. L

ond

on, P

harm

aceu

tical

Pre

ss, 2

004.

2.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.

3.

Kris

hna

S, W

hite

NJ.

Pha

rmac

okin

etic

s of

qui

nine

, chl

oroq

uine

and

am

odia

qui

ne. C

linic

al im

plic

atio

ns. C

linic

al P

harm

acok

inet

ics,

199

6,30

:263

–299

.4.

N

aisb

itt D

J et

al.

Met

abol

ism

-dep

end

ent n

eutro

phi

l cyt

otox

icity

of a

mod

iaq

uine

: A c

omp

aris

on w

ith p

yron

arid

ine

and

rel

ated

ant

imal

aria

l dru

gs.

Che

mic

al R

esea

rch

in T

oxic

olog

y,19

98, 1

1:15

86–1

595.

5.

Bol

ton

GC

et a

l. Th

e d

isp

ositi

on o

f cla

vula

nic

acid

in m

an. X

enob

iotic

a, 1

986,

16:

853–

863.

6.Th

e In

tern

atio

nal P

harm

acop

oeia

, 3rd

ed

. Gen

eral

met

hod

s of

ana

lysi

s, q

ualit

y sp

ecifi

catio

ns fo

r p

harm

aceu

tical

sub

stan

ces,

exc

ipie

nts

and

dos

age

form

s. G

enev

a, W

orld

Hea

lth

Org

aniz

atio

n, 2

004.

7.

New

ton

PN

et a

l. C

omp

aris

on o

f ora

l art

esun

ate

and

dih

ydro

arte

mis

inin

ant

imal

aria

l bio

avai

lab

ilitie

s in

acu

te fa

lcip

arum

mal

aria

.Ant

imic

rob

ial A

gen

ts C

hem

othe

rap

y, 2

002,

46:

1125

–11

27.

8.

New

ton

P e

t al.

Ant

imal

aria

l bio

avai

lab

ility

and

dis

pos

ition

of a

rtes

unat

e in

acu

te fa

lcip

arum

mal

aria

. Ant

imic

rob

ial A

gen

ts C

hem

othe

rap

y, 2

000,

44:

972–

977.

9.

Luke

DR

, Fou

lds

G. D

isp

ositi

on o

f ora

l azi

thro

myc

in in

hum

ans.

Clin

ical

Pha

rmac

olog

y an

d T

hera

peu

tics,

199

7, 6

1:64

1–64

8.10

. Sin

gla

s E

[C

linic

al p

harm

acok

inet

ics

of a

zith

rom

ycin

]. P

atho

log

ie-b

iolo

gie

(P

aris

), 1

995,

43:

505–

511

(in F

renc

h).

11. L

alak

NJ,

Mor

ris D

L. A

zith

rom

ycin

clin

ical

pha

rmac

okin

etic

s. C

linic

al P

harm

acok

inet

ics,

199

3, 2

5:37

0–37

4.12

. McG

uire

BW

et a

l. A

bso

rptio

n ki

netic

s of

ora

lly a

dm

inis

tere

d le

ucov

orin

cal

cium

. NC

I Mon

ogra

phs

, 198

7, 5

:47–

56.

13. M

cGui

re B

W e

t al.

Pha

rmac

okin

etic

s of

leuc

ovor

in c

alci

um a

fter

intr

aven

ous,

intr

amus

cula

r, an

d o

ral a

dm

inis

trat

ion.

Clin

ical

Pha

rmac

y, 1

988,

7:5

2–58

.14

. DeV

ito J

M e

t al.

Bio

equi

vale

nce

of o

ral a

nd in

ject

able

levo

leuc

ovor

in a

nd le

ucov

orin

. Clin

ical

Pha

rmac

y, 1

993,

12:

293–

299.

15. G

rein

er P

O e

t al.

Pha

rmac

okin

etic

s of

(-)

-fol

inic

aci

d a

fter

oral

and

intr

aven

ous

adm

inis

trat

ion

of th

e ra

cem

ate.

Brit

ish

Jour

nal o

f Clin

ical

Pha

rmac

olog

y, 1

989,

28:

289–

295.

16. Y

eh K

C e

t al.

Pha

rmac

okin

etic

s an

d b

ioav

aila

bili

ty o

f Sin

emet

CR

: a s

umm

ary

of h

uman

stu

die

s. N

euro

log

y, 1

989,

39

(11

Sup

pl 2

):25

–38.

17. O

bac

h R

, Men

arg

ues

A, V

alle

s JM

. The

pha

rmac

okin

etic

pro

fi le

of c

arb

idop

a in

dog

s. J

ourn

al o

f Pha

rmac

y an

d P

harm

acol

ogy,

198

4, 3

6:41

5–41

6.18

. McL

ean

A e

t al.

Phar

mac

okin

etic

s an

d m

etab

olis

m o

f chl

oram

buci

l in

patie

nts

with

mal

igna

nt d

isea

se. C

ance

r Tre

atm

ent R

evie

ws,

197

9, 6

(Sup

pl):3

3–42

.19

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ell D

R e

t al.

The

clin

ical

pha

rmac

olog

y of

chl

oram

buc

il an

d p

red

nim

ustin

e. B

ritis

h Jo

urna

l of C

linic

al P

harm

acol

ogy,

198

3, 1

6:76

2–76

3.20

. New

ell D

R e

t al.

Stu

die

s on

the

pha

rmac

okin

etic

s of

chl

oram

buc

il an

d p

red

nim

ustin

e in

man

. Brit

ish

Jour

nal o

f Clin

ical

Pha

rmac

olog

y, 1

983,

15:

253–

258.

21. N

icol

le A

, Pro

ctor

SJ,

Sum

mer

fi eld

GP.

Hig

h d

ose

chlo

ram

buc

il in

the

treat

men

t of l

ymp

hoid

mal

igna

ncie

s. L

euka

emia

& L

ymp

hom

a, 2

004,

45:

271–

275.

22. S

ilven

noin

en R

et a

l. P

harm

acok

inet

ics

of c

hlor

amb

ucil

in p

atie

nts

with

chr

onic

lym

pho

cytic

leuk

aem

ia: c

omp

aris

on o

f diff

eren

t day

s, c

ycle

s an

d d

oses

. Pha

rmac

olog

y &

Tox

icol

ogy,

2000

, 87:

223–

228.

23. 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.

24. D

icks

tein

K. P

harm

acok

inet

ics

of e

nala

pril

in c

ong

estiv

e he

art f

ailu

re. D

rug

s, 1

986,

32

(Sup

pl)

5:40

–44.

25. R

ipp

ley

RK

et a

l. P

harm

acok

inet

ic a

sses

smen

t of a

n or

al e

nala

pril

sus

pen

sion

for

use

in c

hild

ren.

Bio

pha

rmac

eutic

s &

Dru

g D

isp

ositi

on, 2

000,

21:

339–

344.

26. C

hen

CL

et a

l. B

ioav

aila

bili

ty a

nd p

harm

acok

inet

ic fe

atur

es o

f eto

pos

ide

in c

hild

hood

acu

te ly

mp

hob

last

ic le

ukem

ia p

atie

nts.

Leuk

aem

ia &

Lym

pho

ma,

200

1, 4

2:31

7–32

7.27

. Ver

mes

A e

t al

. P

opul

atio

n p

harm

acok

inet

ics

of fl

ucy

tosi

ne:

com

par

ison

and

val

idat

ion

of t

hree

mod

els

usin

g S

TS,

NP

EM

, an

d N

ON

ME

M.

Ther

apeu

tic D

rug

Mon

itorin

g,

2000

, 22

:676

–687

.28

. Ver

mes

A, G

uche

laar

HJ,

Dan

kert

J. F

lucy

tosi

ne: a

rev

iew

of i

ts p

harm

acol

ogy,

clin

ical

ind

icat

ions

, pha

rmac

okin

etic

s, to

xici

ty a

nd d

rug

inte

ract

ions

. Jou

rnal

of A

ntim

icro

bia

l Che

-m

othe

rap

y, 2

000,

46:

171–

179.

29. F

rick

A,

Mol

ler

H,

Wirb

itzki

E.

Bio

pha

rmac

eutic

al c

hara

cter

izat

ion

of o

ral

imm

edia

te r

elea

se d

rug

pro

duc

ts.

In v

itro/

in v

ivo

com

par

ison

of

phe

noxy

met

hylp

enic

illin

pot

assi

um,

glim

epiri

de

and

levo

fl oxa

cin.

Eur

opea

n Jo

urna

l of P

harm

aceu

tics

and

Bio

pha

rmac

eutic

s, 1

998,

46:

305–

311.

30. V

an B

amb

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

Med

icin

al P

rod

ucts

(E

ME

A),

199

9.32

. Pro

duc

t Inf

orm

atio

n Ve

rmox

®.


437

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

,20

01,1

09:1

63–1

67.

37. B

jorn

H, H

enne

ssy

DR

, Frii

s C

. The

kin

etic

dis

pos

ition

of p

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

–138

0.38

. Rob

erts

CJ.

Clin

ical

pha

rmac

okin

etic

s of

ran

itid

ine.

Clin

ical

Pha

rmac

okin

etic

s, 1

984,

9:2

11–2

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.


annex 8 proposal to waive in vivo bioequivalence

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