bromhexina info total

8/11/2019 Bromhexina Info Total

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DRUGDEX DRUG EVALUATIONS

BROMHEXINE

0.0 OVERVIEW

A. BROMHEXINE is an expectorant/mucolytic agent.

B. DOSIN IN!ORMA"ION# $sual %oses o& BROMHEXINE

in c'ronic (ronc'itis 'a)e (een * to +, milligrams -mg

orally t'ree times %aily or 0 mg t1ice %aily2 'ig'er %oses

-30 mg %aily 'a)e (een use% 1it' anti(iotics in

(ronc'iectasis2 in patients 1it' S4ogren5s syn%rome6 %oses

o& +, mg orally t'ree times %aily 'a)e (een a%ministere%.

7. 8HARMA7O9INE"I7S# !ollo1ing oral a%ministration o&

BROMHEXINE6 pea: serum concentrations occur in

approximately + 'our2 t'e %rug is meta(oli;e% in t'e li)er

an% excrete% in t'e urine primarily as meta(olites2 t'e

elimination 'al&


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(ronc'iectasis6 S4ogren5s syn%rome6 an% in com(ination use

1it' anti(iotics.

1.0 DOSING INFORMATION

1.1 DOSAGE FORMS

A. In&ormation on speci@c pro%ucts an% %osage &orms

can (e o(taine% (y re&erring to t'e 8ro%uct In%ex.

B. SNONMS

1. NA-274

2. NA-872

3. Bisolvon(R)

7. OR8HAN DR$ S"A"$S

+. BROMHEXINE 'as (een %esignate% an

orp'an pro%uct &or use in t'e treatment o& mil%ecti)e in t'e treatment o& O"I"IS

MEDIA 1it' e>usion in c'il%ren - to +0

years o& age -Ste1art et al6 +3*=2 Elcoc:

F ?or%6 +3.

2.0 PHARMACOKINETICS

2.2 DRUG CONCENTRATION LEVELS

2.2.1 THERAPEUTIC

A. "IME "O 8EA9 7ON7EN"RA"ION#

+. Oral6 un:no1n# + 'our -Bec'gaar% F

Nielsen6 +3*2 auc' F Han:1it;6 +3=.

a. 8ea: serum concentrations o&

BROMHEXINE occur approximately +

'our &ollo1ing oral a%ministration

-Bec'gaar% F Nielsen6 +3*2 auc' F

Han:1it;6 +3=.

(. !ollo1ing a G mg oral %ose o&

BROMHEXINE6 plasma le)els %ecline%

to approximately 0.+G an% 0.=

mcg/m? at * an% G 'ours postects 'a)e necessitate%

1it'%ra1al o& t'erapy in some patients

-?anglan%s6 +302 Ayl1ar%6 +32

"'ompson F Ree)e6 +32 Armstrong6

+3,2 alenti F Marenco6 +3*3.

3.3.! KIDNEY"GENITOURINARY

A. ENURESIS

+. Enuresis -1it' or 1it'out %iarr'ea

necessitate% %iscontinuation o&

BROMHEXINE t'erapy in o& c'il%ren

1it' otitis me%ia in + stu%y -Ste1art et al6

+3*=. Ho1e)er6 it is unclear i& t'is e>ect

1as %e@nitely attri(uta(le to BROMHEXINE.

3.3.# LIVER

A. HEPATOTOXICITY

+. "ransient ele)ations in serum aspartate

aminotrans&erase -SO" le)els 'a)e (een


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%escri(e% in&reJuently %uring BROMHEXINE

t'erapy -Hamilton et al6 +302 Anon6 +3+2

Se'gal F Mo'an6 +330. Some

in)estigators suggest t'at SO" rises are

attri(uta(le to an e>ect o& BROMHEXINE

on (ronc'ial glan%s as oppose% to 'epatic

%ys&unction -Anon6 +3+.

3.3.$ OCULAR

A. OCULAR EFFECTS

+. Brom'exine - mg/%ay &or + %ays

'a% NO E!!E7" on rate o& tear secretion

in =, 'ealt'y )olunteers 1it' normal tear

secretion. alues on Sc'irmer5s test I 1ere

t'e same -+. mm/= min (e&ore an% a&ter

(rom'exine use -A)isar et al6 +33,.

3.3.10 SKIN

A. RASH

+. Rarely6 S9IN RASH 'as (een reporte%

in BROMHEXINE


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. Australian Drug E)aluation 7ommittee -ADE7

7ategory A -ADE76 +33,.

4.0 CLINICAL APPLICATIONS

4.1 MONITORING PARAMETERS

4.1.1 THERAPEUTIC

A. 8HSI7A? EXAMINA"ION

+. In patients 1it' c'ronic (ronc'itis6

%ecrease% %iLculty o& expectoration6

increase% sputum )olume6 a re%uction in

coug' an% %yspnea6 an% impro)ement in

pulmonary &unction tests are in%icati)e o& a

t'erapeutic response to BROMHEXINE.

4.1.2 TOXIC

A. ?ABORA"OR 8ARAME"ERS

+. Hepatic &unction tests -especially %uring

long


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or Necti)e

in se)ere %isease. "'e use o& t'is agent mig't t'us

(e consi%ere% in com(ination t'erapy an% in less

se)erely a>ecte% patients to en'ance expectoration

an% possi(ly )entilatory capacity. Ho1e)er6 it 1ill not

replace more con)entional mo%es o& t'erapy. "'e

a%%ition o& BROMHEXINE to t'e 'ospital &ormulary &or

t'is in%ication mig't (e 4usti@e% i& excessi)e cost is

not a &actor. !urt'er stu%ies in)estigating t'e use o&

'ig'er %oses o& BROMHEXINE -eg6 to 30 mg

%aily in (ot' mo%erate an% se)ere (ronc'itis appear

1arrante%. A%%itional comparati)e stu%ies 1it' ot'er

mucolytic agents -eg6 Secti)e in otitis me%ia 1it' e>usion.

4.4 MECHANISM OF ACTION"PHARMACOLOGY

A. MECHANISM OF ACTION


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+. BROMHEXINE is an expectorant/mucolytic

agent 1'ic' 'as (een in)estigate% in t'e

treatment o& respiratory %isor%ers6 S4ogren5s

syn%rome6 an% otitis me%ia -Se'gal F Mo'an6

+3302 Mant'orpe F 8rause6 +3*,2 Anon6 +3+.

"'e %rug is a (en;ylamine %eri)ati)e -


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(ronc'itis patients appear secon%ary to easier

expectoration -alenti F Marenco6 +3*3.

. Ot'er p'armacological e>ects o&

BROMHEXINE 'a)e (een reporte%6 inclu%ing

en'ancement o& secretion &rom exocrine glan%s

-eg6 tear pro%uction -Se'gal F Mo'an6 +3302

!rost


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+. A (rie& re)ie1 o& t'e mec'anism o& action6

eLcacy6 an% toxicity o& BROMHEXINE is

a)aila(le -Be'gal F Mo'an6 +330.

. An in&ormati)e e%itorial regar%ing t'e use o&

BROMHEXINE in c'ronic (ronc'itis is a)aila(le

-Anon6 +3+.

4.5 THERAPEUTIC USES

A. ASTHMA

+. OERIE#FDA APPROVAL: Adult no! "#di$t%i& no

'FFA*: Adult in#++#&tiv#

DO,'NAON: Adult "oo%

. S$MMAR#

- '++i&$&/ is &ont%ov#%si$l

. AD$?"#

a. Oral or intra)enous BROMHEXINE 'as

not (een associate% 1it' clinical or

)entilatory impro)ement in patients 1it'

mo%erate


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. S$MMAR#

- Aus&ult$to%/ +indins $nd +o%d

#"i%$to%/

volu# in 1 s#&ond (F'V-1) ("ositiv#

&$n#

o+ $""%oi$t#l/ 155 illilit#%s) &$n#sdo not

$""#$% &lini&$ll/ %#l#v$nt

. AD$?"#

a. "'e com(ination o& oral BROMHEXINE

0 milligrams t'ree times %aily &or += %ays

in com(ination 1it' intramuscular

7E!"ACIDIME -+ gram t1ice %aily &or t'e

@rst %ays 1as reporte% more e>ecti)e

t'an t'e intramuscular 7E!"ACIDIME

regimen alone in t'e treatment o& acute

exacer(ations o& (ronc'iectasis in a

%ou(le


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not %i>er (et1een groups. !urt'er stu%ies

are nee%e% to con@rm t'e potential (ene@ts

o& 'ig'ecti)e in increasing )entilatory

capacity6 re%ucing %iLculty in

expectoration6 an% pro%ucing clinical

impro)ement as compare% to place(o

in patients 1it' c'ronic (ronc'itis an%


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some patients 1it' (ronc'itis an%

ast'ma -ent et al6 +3,32 alenti F

Marenco6 +3*3. Ho1e)er6 ot'er

similarly %esigne% stu%ies &aile% to

%emonstrate signi@cant or consistent

(ene@ts 1it' oral BROMHEXINE G

to G* milligrams %aily in c'ronic

(ronc'itis patients -Armstrong6 +3,2

Anon6 +32 "'ompson F Ree)e6

+32 7lar:e et al6 +32 ?anglan%s6

+302 Hamilton et al6 +30. In some

o& t'ese latter stu%ies6 lac: o& (ene@t

1as o(ser)e% %espite signi@cant

increases in sputum )olume an%

%ecreases in sputum )iscosity

-Hamilton et al6 +30. 7linical

response to t'e %rug is usually seen

only in patients 1it' slig't


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- Discrepancies in t'ese trials are

most li:ely explaine% (y patient

selection. Most stu%ies reporting no

signi@cant (ene@t o& BROMHEXINE

enrolle% patients 1it' more se)ere

c'ronic (ronc'itis6 as e)i%ence% (y

lo1 (aseline &orce% expiratory )olume

-!E


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some (ut not all patients 1it' slig'tect o&

mucoi% secretions6 an% possi(ly

&acilitate a more rapi% response

-Matts6 +3G2 Boner et al6 +3*G2

Dattoli F ?ec'i6 +3*. Some stu%ies

'a)e also reporte% t'at

BROMHEXINE can increase sputum


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concentrations o& )arious anti(iotics

-Bergogne


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BROMHEXINE an% 7E8HA?EXIN 1as

reporte% superior to 7E8HA?EXIN

alone in treating acute exacer(ations

o& c'ronic (ronc'opulmonary %iseases

in + comparati)e trial2 )entilatory

&unction an% clinical symptoms 1ere

impro)e% to a greater %egree in t'e

com(ination group -8almieri et al6

+3*.

-G A &urt'er stu%y reporte%

statistically similar response rates 1it'

t'e com(ination o&

OX"E"RA77?INE =0 milligrams

&our times %aily plus BROMHEXINE *

milligrams &our times %aily -, an%

OX"E"RA77?INE alone -=+ in

patients 1it' exacer(ations o& c'ronic

(ronc'itis or acute (ronc'itis2 'ospital

stay 1as s'ortene% in t'e

BROMHEXINE group -3 )ersus ++

%ays -Matts6 +3G. Ho1e)er6

met'o%s o& treatment allocation an%

(aseline clinical c'aracteristics o&

eac' treatment group 1ere not

pro)i%e%2 it 1as unclear i& t'e se)erity

o& %isease in eac' group 1as


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compara(le6 1'ic' coul% 'a)e

a>ecte% 'ospital stay. Ot'ers reporte%

poor response to (ot' t'e

com(ination o& ER"HROM7IN an%

BROMHEXINE an% ER"HROM7IN

alone in c'ronic (ronc'itis patients2

BROMHEXINE %i% not &acilitate

sputum penetration o&

ER"HROM7IN in t'is stu%y

-Maesen et al6 +3*. 7linical

response in relation to pulmonary

&unction 1as not a%%resse% in any o&

t'ese stu%ies.

D. OTITIS MEDIA

+. OERIE#

FDA APPROVAL: Adult no! "#di$t%i& no



. S$MMAR#

- n#++#&tiv#

. AD$?"#

a. In t1o controlle% stu%ies6 oral

BROMHEXINE in %oses o& +, to G*

milligrams %aily &or G to , 1ee:s 1as

ine>ecti)e in t'e treatment o& otitis me%ia

1it' e>usion -secretory otitis me%ia in

c'il%ren - to +0 years o& age -Ste1art et

al6 +3*=2 Elcoc: F ?or%6 +3.

E. POSTOPERATIVE RESPIRATORY INFECTIONS


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+. OERIE#


'FFA*: Adult #++#&tiv#


. S$MMAR#- $/ #n$n $nti0ioti& $&tivit/ 0/ its

u&ol/ti& "%o"#%ti#s #n$0lin i#%

0%on&i$l &onnt%$tions to 0# $&i#v#d

- $/ "%#v#nt u&us "luin $nd %#sult$nt

"$%#n&/$l &o"li&$tions

. AD$?"#

a. 7om(ination t'erapy 1it' 7E8HA?EXIN

an% BROMHEXINE 'as (een reporte%

e>ecti)e in treating an% pre)enting

respiratory in&ections &ollo1ing surgery

-primarily a(%ominal in uncontrolle% stu%ies

in)ol)ing patients 1it' acute or c'ronic

(ronc'itis or ot'ers at ris: o& respiratory

complications -Busca et al6 +3*2 8almieri

et al6 +3*. BROMHEXINE may en'ance

anti(iotic acti)ity in t'ese patients (y its

mucolytic properties6 ena(ling 'ig'er

(ronc'ial concentrations to (e ac'ie)e%6

an% pre)ent mucus plugging an% resultant

parenc'ymal complications. Ho1e)er6 in t'e

a(sence o& a control group recei)ing

anti(iotic t'erapy alone6 it is %iLcult to

assess t'e eLcacy o& com(ination t'erapy.

(. One stu%y 'as reporte% t'e eLcacy o&

intramuscular &ollo1e% (y oralBROMHEXINE in re%ucing t'e inci%ence o&


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postoperati)e (ronc'opneumonia in 'ig'ects 1ere o(ser)e%6

it is unclear i& t'e com(ination o>ers a

signi@cant a%)antage o)er 7E8HA?EXIN

alone6 an% controlle% stu%ies are nee%e%.

G. S%OGREN&S SYNDROME

+. OERIE#


'FFA*: Adult #++#&tiv#


. S$MMAR#

- 'n$nd l$&%i$l s#&%#tion $s 0##n

o0s#%v#d in "$ti#nts 6it 9o%#ns s/nd%o# in so#

&ont%oll#d studi#s 0ut not ot#%s

. AD$?"#

a. An impro)ement in op't'almological

tests in%icati)e o& en'ance% lacrimal

secretion 'as (een o(ser)e% in patients

1it' S4ogren5s syn%rome %uring oral

BROMHEXINE t'erapy in some controlle%

stu%ies (ut not ot'ers2 su(4ecti)e


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impro)ement 1as not reporte% (y t'e

patient in any o& t'ese stu%ies6 nor 1as

t'e rate o& tear secretion in 'ealt'y

su(4ects a>ecte% (y (rom'exine -A)isar et

al6 +33,. AMBROXO?6 a meta(olite o&

BROMHEXINE6 'as not (een e>ecti)e in

pro%ucing o(4ecti)e impro)ement2 a%%itional

stu%ies are nee%e% to clari&y t'e role o&

BROMHEXINE in S4ogren5s syn%rome.

"1o place(o


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impro)ement in t'is parameter 1it' place(o.

BROMHEXINE 1as not associate% 1it'

su(4ecti)e impro)ement.

c. Early stu%ies employe% relati)ely small

num(ers o& patients6 an% o& t'e stu%ies

-"apper


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1. RESPIRATORY TRACT INFECTIONS

a. 7om(ination BROMHEXINE plus

AMOXI7I??IN is more e>ecti)e t'an

AMOXI7I??IN alone in t'e treatment o&

(ronc'itis or pneumonia.

(. A%%ing BROMHEXINE to AMOXI7I??IN

pro%uces a 'ig'er cure rate an% &aster

resolution o& symptoms t'an AMOXI7I??IN

alone in patients 1it' acute (ronc'itis

-n3+ or pneumonia -n+0+ -1it' clinical

assessment &or (acterial etiology6

accor%ing to a multi


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an% sputum )olume 1ere signi@cantly (etter

among t'ose treate% 1it'

(rom'exine/amoxicillin -)isual analog scale2

p less t'an 0.00+. Six patients in t'e

com(ination group experience% a%)erse

e)ents6 compare% 1it' = patients in t'e

amoxicillin only group.

B. CARBOXYMETHYLCYSTEINE

1. BRONCHITIS

a. ENERA? IN!ORMA"ION# 7ysteine

compoun%s6 suc' as N


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(. Secti)e

as (rom'exine syrup -+, mg t'ree times

%aily in impro)ing sputum consistency an%

some clinical symptoms. "ren%s to1ar% t'e

superiority o& S< car(oxymet'ylcysteine

1ere o(ser)e% in t'is stu%y6 inclu%ing a

more rapi% onset o& action. Ho1e)er6

neit'er agent pro%uce% impro)ement in

)entilatory )olumes or pea: expiratory o1

rates -Ayl1ar%6 +3.

C. CEPHALEXIN

1. SUMMARY

a. 7om(inations o& (rom'exine an%

cep'alexin 1ere more e>ecti)e t'an

cep'alexin alone.

2. RESPIRATORY DISORDERS


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)ersus ++ %ays -Matts6 +3G. Ho1e)er6

met'o%s o& treatment allocation an%

(aseline clinical c'aracteristics o& eac'

treatment group 1ere not pro)i%e%2 it 1as

unclear i& t'e se)erity o& %isease in eac'

group 1as compara(le6 1'ic' coul% 'a)e

a>ecte% 'ospital stay.

E. SALINE SOLUTION

1. SINUSITIS

a. A small ran%omi;e%6 %ou(le


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impro)ement t'an (rom'exine -p less t'an

0.0=.

F. SOBREROL

1. RESPIRATORY DISORDERS PEDIATRICS

a. So(rerol %rops in %oses o& =0 to +00

milligrams -mg t1ice %aily 1as reporte% at

least as e>ecti)e as (rom'exine %rops -

to G mg orally t'ree times %aily in treating

c'il%ren un%er = years o& age 1it' acute

'ypersecretory (ronc'opulmonary %isease

-A;;ollini et al6 +330.

!.0 REFERENCES

+. ADE7# Australian Drug E)aluation 7ommittee# Me%icines

in 8regnancy < An Australian 7ategorisation o& Ris: o& Drug

$se in 8regnancy6 r% e%. Australian o)ernment

8u(lis'ing Ser)ice6 7an(erra6 Australia2 +33,.

. AMA Department o& Drugs# Drug E)aluations

Su(scription. American Me%ical Association6 7'icago6 I?6

+33+.

. Anon# A controlle% trial o& t'e e>ects o& (rom'exine on

t'e symptoms o& out


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=. Armstrong M?# Dou(leect on tear secretion in 'ealt'y su(4ects -letter.

Ann 8'armacot'erapy +33,2 0#+G3*.

. Ayl1ar% M# A (et1een


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com(ination o& cep'alexin plus (rom'exine# a report on +00

cases. Drugs Exptl 7lin Res +3*G2 +0#G==


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+. ent M6 9no1lson 8A F 8rime !# E>ect o&

(rom'exine on )entilatory capacity in patients 1it' a )ariety

o& c'est %iseases. ?ancet +3,32 #+03G


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*. ?anglan%s HM# Dou(le


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G. Se'gal S9 F Mo'an M# Brom'exine -re)ie1. In%ian

8e%iatr +3302 #G3


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E'( )* D)+,-'/

DRUGDEX DRUG EVALUATIONS

ACETYLCYSTEINE

0.0 OVERVIEW

A. Acetylcysteine is a %eri)ati)e o& t'e amino aci% cysteine.

B. DOSIN IN!ORMA"ION# As a mucolytic6 t'e &ollo1ing

%osing is recommen%e%# ne(uli;e% %oses o& to = m? o&

a +0 solution2 orally &or a%ults an% a%olescents o)er +G

years o& age6 ,00 mg %aily in + to %i)i%e% %oses. !or

acetaminop'en o)er%ose6 an oral loa%ing %ose o& +G0

mg/:g is &ollo1e% (y 0 mg/:g e)ery G 'ours &or +

a%%itional %oses in a%ult an% pe%iatric patients2 alternati)ely6

t'e erman manu&acturer recommen%s I a%ministration o&

a +=0 mg/:g loa%ing %ose6 &ollo1e% (y =0 mg/:g in&use%

o)er G 'ours6 &ollo1e% (y +00 mg/:g in&use% o)er +, 'ours

&or a total %ose o& 00 mg/:g in&use% o)er 0 'ours an%

+= minutes.

7. 8HARMA7O9INE"I7S# "'e %rug is 1ellects occur 1it'in G= min an% persist &or +00

min2 some %egree o& 'epatic meta(olism occurs6 1it' renal

excretion o& meta(olites an% unc'ange% compoun%.

D. 7A$"IONS# "'e primary toxicity o& N


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reporte%. A%)erse e>ects primarily consist o& allergic

reactions6 ras'6 nausea6 'ypotension6 (ronc'oconstriction6

(ronc'ospasm6 angioe%ema6 tac'ycar%ia6 an% respiratory

%istress.

E. 7?INI7A? A88?I7A"IONS# Acetylcysteine is a mucolytic

agent use% in t'e treatment o& pulmonary %iseases

associate% 1it' increase% )iscosity o& (ronc'ial secretions.

More importantly6 acetylcysteine is )ery e>ecti)e an%

extensi)ely use% in re)ersing t'e 'epatotoxicity in%uce% (y

acetaminop'en poisoning2 it is also recommen%e% as a

secon% line agent in acrylonitrile an% met'acrylonitrile

poisonings.

1.0 DOSING INFORMATION

1.1 DOSAGE FORMS

A. In&ormation on speci@c pro%ucts an% %osage &orms

can (e o(taine% (y re&erring to t'e 8ro%uct In%ex.

B. SNONMS#

1. Atil&ist#in$

2. At/l&/st#in n$t%iu

3. A ?1?-


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+. Acetylcysteine is inacti)ate% (y pure O-

-?a1son F Saggers6 +3,=6 (ut t'is is pre)ente%

in t'e commercial pro%uct (y inclu%ing ED"A.

. Solutions &or oral use retain t'eir potency &or

at least 3, 'ours un%er re&rigeration 1'en preecti)e an% to

re%uce t'e mean treatment %uration

to + 'ours -oo et al6 000.

2. MUCOLYTIC

a. Oral acetylcysteine e>er)escent

ta(lets are recommen%e% &or a%ults

an% a%olescents &rom age +G years in

a %ose o& G00 to ,00 milligrams -mg

%aily in + to %i)i%e% %oses

-!ac'in&o !luimucil-R a:ut6 +33.

B. ORAL SOLUTION PREPARATION

+. "'e 0 acetylcysteine solution s'oul%

(e %ilute% 1it' cola %rin:s6 !resca-R6 or

ot'er so&t %rin:s to a @nal concentration o&

=. I& a%ministere% )ia gastric tu(e or


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Miller


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D. INTERPRETATION OF ACETAMINOPHEN

ASSAY

+. 'en results o& t'e plasma

acetaminop'en assay are a)aila(le6 t'e

Rumac:/Matt'e1 nomogram -a)aila(le in

Mucomyst-R pac:age inserts s'oul% (e

utili;e% to %etermine i& plasma

concentrations are in t'e potentially toxic

range. alues a(o)e t'e soli% line

connecting 00 micrograms/milliliter at G

'ours 1it' =0 micrograms/milliliter at +

'ours are associate% 1it' a possi(ility o&

'epatic toxicity i& acetylcysteine is not

a%ministere%. I& t'e plasma le)el is a(o)e

t'e (ro:en line on t'e nomogram6 continue

1it' maintenance %oses o& acetylcysteine.

I& t'e initial plasma le)el is (elo1 t'e

(ro:en line on t'e nomogram6 t'ere is

minimal ris: o& 'epatic toxicity an%

acetylcysteine treatment can (e

%iscontinue% -8ro% In&o Mucomyst-R6

+33,.

E. INTRAVENOUS

1. ACETAMINOPHEN POISONING

. SUMMARY


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-+ "'ere is NO !DA


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- "EN" HO$R

8RO"O7O?# A%minister +=0

milligrams/:ilogram in 00

milliliters = %extrose -D=

o)er += minutes6 &ollo1e% (y =0

milligrams/:ilogram in =00

milliliters D= o)er G 'ours6

&ollo1e% (y +00

milligrams/:ilogram in + liter

D= o)er t'e next +, 'ours

-8rescott et al6 +332 estman6

+3*3.

-G "'ere %oes appear to (e a

slig't increase% ris: o& a%)erse

reactions &ollo1ing intra)enous

a%ministration -primarily urticaria

an%/or (ronc'ospasm 1'ic' are

rate


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Base% on a)aila(le %ata6 it is eJual

to


56/231

presenting early 1it' toxic le)els o&

acetaminop'en an% se)ere aci%osis6

presenting early 1it' extremely 'ig'

le)els o& acetaminop'en -G000

nmol/liter or more an% patients

presenting more t'an += 'ours a&ter

t'e ingestion 1it' serum le)els

excee%ing +000 nmol/liter.

%. "'e manu&acturer o& !luimucil-R

Anti%ot recommen%s t'e &ollo1ing

intra)enous %osing# +=0

milligrams/:ilogram -mg/:g in 00 m?

= Dextrose 1it' electrolyte a%%iti)e

o)er += minutes6 &ollo1e% (y =0

mg/:g in =00 m? = Dextrose 1it'

electrolyte a%%iti)e o)er G 'ours6

&ollo1e% (y +00 mg/:g in +000 m?

= Dextrose 1it' electrolyte a%%iti)e

o)er +, 'ours6 &or a total %ose o&

00 mg/:g o)er 0 'ours an% +=

minutes. IM8OR"AN" NO"E# "'e

amount o& = Dextrose 1it'

electrolyte a%%iti)e is calculate% &or a

0 :g person6 s'oul% t'e patient

1eig' less6 t'is amount must (e

a%4uste% accor%ing to t'e gui%elines


57/231

&or intra)enous glucose a%ministration

-!ac'in&o !luimucil-R Anti%ote6 +33.

e. "'e manu&acturer o& !luimucil-R

Anti%ot recommen%s treatment 1it'in

+0 'ours o& acetaminop'en o)er%ose2

a%ministration o& acetylcysteine +=

'ours a&ter t'e o)er%ose 1ill most

li:ely not pro%uce %esire% results6

alt'oug' reports o& &a)ora(le results

to a%ministration +, to G 'ours a&ter

o)er%ose can (e &oun% in t'e

literature. "'e anti%ote protocol s'oul%

(e &ollo1e%6 i& acetaminop'en serum

le)els excee% 00 nanograms per

milliliter -ng/m? a&ter G 'ours or 0

ng/m? += 'ours a&ter acetaminop'en

ingestion2 as long as t'e se)erity o&

t'e poisoning is un:no1n6 anti%ote

t'erapy s'oul% (e initiate% -!ac'in&o

!luimucil-R Anti%ot6 +33.

2. ACRYLONITRILE POISONING

. INHALATIVE OR DERMAL

POISONING

1 NONSEVERE POISONING

-a "reatment o& nonecti)e in

pre)enting acetaminop'en


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ingestion o& an o)er%ose. Do not 1ait

&or t'e result o& la(oratory assays &or

acetaminop'en le)els. "'e &ollo1ing

proce%ures are recommen%e% -8ro%

In&o Mucomyst-R6 +33,#

-+ "'e stomac' s'oul% (e

emptie% (y la)age or emesis

1it' syrup o& ipecac. Syrup o&

ipecac s'oul% (e gi)en in a

%ose o& += to 0 milliliters &or

c'il%ren an% 0 to G0 milliliters

&or a%ults accompanie% (y G to

, ounces o& 1ater. "'e %ose

s'oul% (e repeate% i& emesis

%oes not occur in 0 minutes.

- In t'e cases o& a mixe%

%rug o)er%ose6 acti)ate%

c'arcoal may (e in%icate%. I&

acti)ate% c'arcoal is

a%ministere%6 it is recommen%e%

t'at t'e patient (e la)age%

(e&ore a%ministration o&

acetylcysteine since acti)ate%

c'arcoal a%sor(s acetylcysteine

in )itro an% may also %o so in

)i)o.


66/231

- Bloo% s'oul% (e %ra1n &or

acetaminop'en plasma assay

an% &or (aseline SO"6 S8"6

(iliru(in6 prot'rom(in time6

creatinine6 B$N6 (loo% sugar6

an% electrolytes. 8lasma or

serum acetaminop'en

concentrations s'oul% (e

%etermine% as early as possi(le

(ut no sooner t'an G 'ours

&ollo1ing acute o)er%ose. "'ese

le)els are essential in assessing

t'e potential ris: o&

'epatotoxicity. I& an assay &or

acetaminop'en cannot (e

o(taine%6 it is necessary to

assume t'e o)er%ose is

potentially toxic.

-G A%minister t'e loa%ing %ose

o& acetylcysteine -+G0

milligrams/:ilogram o& (o%y

1eig't.

-= !our 'ours a&ter t'e loa%ing

%ose6 a%minister t'e @rst

maintenance %ose o& 0

milligrams/:ilogram. Maintenance


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%oses s'oul% (e repeate% at Gers a more

rapi% onset o& action in c'ronic (ronc'itis

an% (ronc'iectasis compare% 1it' oral an%

intramuscular routes. "'e intramuscular

route is eJui)alent to t'e oral route -rassi

et al6 +3.

B. 8EA9 RES8ONSE#

+. Mucolytic6 in'alation# G= minutes -Hurst et al6

+3,.

2.1.2 DURATION

A. SIN?E DOSE#

+. Mucolytic6 in'alation# +00 minutes -Hurst et al6

+3,.

2.2 DRUG CONCENTRATION LEVELS

2.2.1 THERAPEUTIC

A. "IME "O 8EA9 7ON7EN"RA"ION#

+. In'alation6 ne(uli;er# + to 'ours -Hol%iness6

+33+.


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a. An intra)enous %ose o& +=0 mg/:g gi)en

in += minutes resulte% in a mean

maximum plasma concentration o& ==G

mg/? -8rescott et al6 +3*3.

B. AREA $NDER "HE 7$RE -A$7# 3.3 mg/?/'r

-'ealt'y su(4ects -ones et al6 +33.

+. Mean A$7 1as +=. mg/?/'r in patients

1it' cirr'osis as compare% to 3.3 mg/?/'r in

'ealt'y controls6 &ollo1ing an intra)enous %ose

o& ,00 mg in&use% o)er minutes -ones et al6

+33.

2.3 ADME

2.3.1 ABSORPTION

A. BIOAAI?ABI?I" -!#

+. Oral6 ta(lets# , to +0 -Hol%iness6 +33+.

a. Oral (ioa)aila(ility is similar &or a single

,00ect o& acti)ate% c'arcoal on oral

(ioa)aila(ility -atson F Mc9inney6 +33+.

One stu%y &oun% no %i>erence in total area

un%er t'e cur)e -Nort' et al6 +3*+. In

)itro %ata %emonstrate% signi@cant

a%sorption o& t'e %rug to acti)ate% c'arcoal


79/231

-9lein


80/231

A. DIS"RIB$"ION HA?! ?I!E# 0.++ ?/:g/'our

-Olsson et al6 +3**.

B. O?$ME O! DIS"RIB$"ION -%# 0. to

0.G ?/:g -Olsson et al6 +3**2 Borgstrom et al6

+3*,.

2.3.3 METABOLISM

2.3.3.1 METABOLISM SITES AND KINETICS

A. ?i)er6 rapi% an% extensi)e -Hol%iness6 +33+.

+. !ollo1ing %e


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7. It is not precisely :no1n 'o1 muc' o& t'e

%rug is excrete% unc'ange% )ersus meta(oli;e%.

"'e ma4or excretory meta(olite is inorganic

sul&ate2 t'e sul&ate eJuate% to * o& t'e

a%ministere% %ose an% some taurine 1as also

present -Hol%iness6 +33+2 Barte: et al6 +32

S'i' F Sc'ulman6 +3,3.

D. !ollo1ing intra)enous %oses o& ra%ioacti)ely

la(ele% acetylcysteine6 urinary ra%ioacti)ity coul%

(e %etecte% &or up to = %ays -Barte: et al6

+32 S'i' F Sc'ulman6 +3,3.

2.3.4.3 OTHER

A. "O"A? BOD 7?EARAN7E# ,.= ?/'r -'ealt'y

su(4ects -ones et al6 +33.

+. A)erage o& G.= ?/'r in patients 1it'

cirr'osis as compare% to ,.= ?/'our in

'ealt'y controls6 &ollo1ing an intra)enous

%ose o& ,00 mg in&use% o)er minutes

-ones et al6 +33.

B. O"HER EX7RE"ION#

+. !eces6 -Hol%iness6 +33+.

a. In animal mo%els6 only o& Nect# loss o& anti(iotic eLcacy

. Se)erity# not speci@e%

. Onset# not speci@e%

G. Documentation# poor

=. ?iterature Reports#

a. A signi@cant increase in MI7 1as

o(ser)e% in an in )itro stu%y o& t'e

com(ine% use o& acetylcysteine an%

ampicillin6 penicillin 6 cloxacillin6 met'icillin6

oxacillin6 Juinacillin6 cep'alori%ine6 or

tetracycline -?a1son F Saggers6 +3,=.

Ho1e)er6 t'e results o& one in )i)o stu%y


117/231

on t'e use o& com(ination t'erapy in

respiratory tract in&ections &oun% no

inacti)ation o& t'e anti(iotic 1'en

aerosoli;e% acetylcysteine 1as use% 1it'

ampicillin6 cep'alori%ine6 cloxacillin6

eryt'romycin6 &usi%ic aci%6 gentamicin6

lincomycin6 met'icillin6 no)o(iocin6

sul&a%ia;ine6 sul&amet'a;ine6 or tetracycline

-Saggers F ?a1son6 +3,*. 7linical reports

o& suc' an interaction are lac:ing6

suggesting t'at it is unli:ely to (e o&

clinical importance.

L. 6UINACILLIN

+. 7linical Management# Acetylcysteine s'oul%

not (e mixe% in t'e same solution as Juinacillin

&or ne(uli;ation.


. Onset# not speci@e%


=. ?iterature Reports#








118/231









sul&a%ia;ine6 sul&a%imi%ine6 or tetracycline





M. TETRACYCLINE

+. A%)erse E>ect# loss o& anti(iotic eLcacy

. 7linical Management# Acetylcysteine s'oul%

not (e mixe% in t'e same solution as

tetracycline &or ne(uli;ation.


G. Onset# not speci@e%

=. Documentation# poor

,. 8ro(a(le Mec'anism# un:no1n

. ?iterature Reports#





119/231












sul&a%ia;ine6 sul&a%imi%ine6 or tetracycline





3.5.3 DRUGLAB MODIFICATIONS

A. NITROPRUSSIDE TEST

+. Summary# Acetylcysteine may inter&ere 1it'

t'e nitroprussi%e test6 resulting in a &alse


120/231

1it' suspecte% 'epatocellular in4ury -7sa:o F

Elin6 +33.

. Se)erity# minor

. Onset# rapi%


B. SALICYLATE ASSAY

+. Summary# "'e e>ects o& =G commonly use%

me%ications on t'e assay o& salicylate

concentration 1ere e)aluate%. Only acetylcysteine

an% cysteamine cause% a signi@cant inter&erence

1it' t'e salicylate measurement. "'e assay

met'o% &or salicylate 1as colorimetric -a reaction

1it' Gect# unrelia(le salicylate

concentrations

. 7linical Management# "'e colorimetric assay

met'o% &or salicylate measurement s'oul% not

(e use% in patients recei)ing acetylcysteine.

G. Se)erity# minor

=. Onset# rapi%

,. Documentation# &air

. 8ro(a(le Mec'anism# salicylate assay

inter&erence

3.5.4 INTRAVENOUS ADMIXTURES

3.5.4.2 COMPATIBILITIES DRUGS


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A. BACITRACIN

+. Acetylcysteine +0 1it' (acitracin =000

$/m?6 compati(le (ut mixture s'oul% (e

use% at once -8ro% In&o Mucomyst-R6

+33+

B. CARBENICILLIN

+. 7ar(enicillin -+= mg/m? 1it'

acetylcysteine +06 compati(le (ut mixture

s'oul% (e use% at once -8ro% In&o

Mucomyst-R6 +33,

C. CEPHALORIDINE

+. Acetylcysteine +0 1it' cep'alori%ine G,

mg/m?6 compati(le (ut mixture (ecame a

slig'tly %ar:er yello1 color t'an a control

solution -8ro% In&o Mucomyst-R6 +33+

D. CEPHALOTHIN

+. Acetylcysteine +0 1it' cep'alot'in ++0

mg/m?6 compati(le (ut mixture s'oul% (e


+33+

E. CHLORAMPHENICOL

+. Acetylcysteine 0 1it' c'loramp'enicol

0 mg/m?6 compati(le2 con%itions not

speci@e% -8ro% In&o Mucomyst-R6 +33+

F. COCAINE


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+. Acetylcysteine +0 1it' cocaine =6

compati(le2 con%itions not speci@e% -8ro%

In&o Mucomyst-R6 +33+

G. COLISTIN

+. Acetylcysteine +0 1it' colistin .=



+33+

H. CROMOLYN

+. Acetylcysteine 1it' cromolyn so%ium

ne(uli;er solution +6 p'ysically an%

c'emically compati(le -sta(le &or up to ,0

minutes 1'en mixe% in )itro -?es:o F

Miller6 +3*G

I. DEXAMETHASONE

+. Acetylcysteine +, 1it' %examet'asone

0.* mg/m?6 compati(le2 con%itions not


%. EPINEPHRINE

+. Acetylcysteine +. - parts 1it'

epinep'rine 0. -+ part6 compati(le2

con%itions not speci@e% -8ro% In&o

Mucomyst-R6 +33+

K. GENTAMICIN


123/231

+. Acetylcysteine +0 1it' gentamicin 0

mg/m?6 compati(le2 con%itions not speci@e%

-8ro% In&o Mucomyst-R6 +33+

L. ISOPROTERENOL

+. Acetylcysteine 1it' isoproterenol

0.=6 compati(le2 con%itions not speci@e%

an% %rug concentrations liste% (elo1 -8ro%


. Acetylcysteine +0 1it' isoproterenol

0.0=6 compati(le2 con%itions not speci@e%



. Acetylcysteine 0 1it' isoproterenol

0.0=6 compati(le2 con%itions not speci@e%



G. Acetylcysteine +. - parts 1it'

isoproterenol 0. -+ part6 compati(le2

con%itions not speci@e% an% %rug

concentrations liste% (elo1 -8ro% In&o

Mucomyst-R6 +33+

M. KANAMYCIN

+. Acetylcysteine +0 1it' :anamycin +,



+33+


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. Acetylcysteine + 1it' :anamycin *=



+33+

N. LIDOCAINE

+. Acetylcysteine +0 1it' li%ocaine 6



O. LINCOMYCIN

+. Acetylcysteine +0 1it' lincomycin +=0



P. NEOMYCIN

+. Acetylcysteine +0 1it' neomycin +00



6. NOVOBIOCIN

+. Acetylcysteine +0 1it' no)o(iocin =



R. PANCREATIC DORNASE

+. Acetylcysteine +,. 1it' pancreatic

%ornase *000 $/m?6 compati(le (ut mixture

s'oul% (e use% at once -8ro% In&o

Mucomyst-R6 +33+

S. PENICILLIN G


125/231


126/231

+. Acetylcysteine 0 1it' so%ium

(icar(onate G.6 compati(le2 con%itions

not speci@e% -8ro% In&o Mucomyst-R6

+33+

Y. TETRACAINE

+. Acetylcysteine +0 1it' tetracaine +6



. VANCOMYCIN

+. Acetylcysteine +0 1it' )ancomycin =



+33+

3.5.4.4 INCOMPATIBILITIES DRUGS

A. AMPHOTERICIN B

+. Acetylcysteine G to += 1it'

amp'otericin B + to G mg/m?6 incompati(le2

con%itions not speci@e% -8ro% In&o

Mucomyst-R6 +33+

B. AMPICILLIN

+. Acetylcysteine +0 1it' ampicillin =0

mg/m?6 incompati(le2 con%itions not


C. CHLORTETRACYCLINE


127/231

+. Acetylcysteine +0 1it' c'lortetracycline

+.= mg/m?6 incompati(le2 con%itions not


D. ERYTHROMYCIN

1. ERYTHROMYCIN LACTOBIONATE

a. Acetylcysteine +0 1it'

eryt'romycin lacto(ionate += mg/m?6

incompati(le2 con%itions not speci@e%


E. IODIED OI

+. Acetylcysteine 0 m? o& a 0 solution

1it' io%i;e% oil +0 m? o& a G0 solution6

incompati(le2 con%itions not speci@e% -8ro%


F. OXYTETRACYCLINE

+. Acetylcysteine +0 1it' oxytetracycline

+.= mg/m?6 incompati(le2 con%itions not


G. TETRACYCLINE

+. Acetylcysteine +0 1it' tetracycline +.=

mg/m?6 incompati(le2 con%itions not


4.0 CLINICAL APPLICATIONS

4.1 MONITORING PARAMETERS

4.1.1 THERAPEUTIC

A. A7E"AMINO8HEN OERDOSE


128/231

+. ?i)er &unction tests

4.1.2 TOXIC

A. A7E"AMINO8HEN OERDOSE

+. Nausea6 )omiting

4.2 PATIENT INSTRUCTIONS

A'*L*'N' ($-s#-t##l--t##n) (NALAON):

#l"s /ou to 0%#$t# 0#tt#% 0/ tinnin o% dissolvin

ti& lun u&us &$us#d 0/ #"/s#$ "n#uoni$

&/sti& +i0%osis o% ot#% lun "%o0l#s.

BRAND NA'(): u&o/st(R) u&osil(R)

'N *O, O,LD NO ,' 'DN':

*ou sould not us# tis #di&in# i+ /ou $v# $d $n

$ll#%i& %#$&tion to $t/l&/st#in#.O O ,' AND OR' 'DN'

olution:

- *ou% do&to% 6ill t#ll /ou o6 u& #di&in# to us#

$nd o6 o+t#n to $v# /ou% t%#$t#nts.

- $%#+ull/ %#$d $nd +ollo6 t# inst%u&tions t$t

&o# 6it t# #di&in#. #/ 6ill t#ll /ou o6 to

us# t# n#0uliE#% (t# d#vi t$t /ou us# to

0%#$t# in t# #di&in#) $nd &o"%#sso% $nd o6 to

&$%# +o% $nd &l#$n t# n#0uliE#% it.

- # &o"%#sso% tu%ns t# #di&in# into $ +in#

s"%$/ t$t /ou 6ill 0%#$t into /ou% out usin

t# n#0uliE#%.

- ,s# t# out"i# t$t &o#s 6it t# n#0uliE#%.- $s /ou% $nds 6it so$" $nd 6$t#% 0#+o%# "uttin

t# n#0uliE#% to#t#%.

- O"#n t# vi$l (s$ll 0ottl# o+ #di&in#) $nd "ou%

t# #di&in# into t# n#0uliE#% &u". Put t# &$"

0$& on t# &u". # #di&in# $/ $v# $ 0$d s#ll

$t +i%st. # odo% sould o $6$/ soon $+t#% /ou

st$%t /ou% t%#$t#nt.

- u%n on t# &o"%#sso% so ist is &oin out o+

t# n#0uliE#%.

- Put t# out"i# in /ou% out &los# /ou% li"s

$%ound it $nd 0%#$t# in $nd out t%ou /ou%

out. $# su%# /ou% t##t $nd tonu# do not

0lo& t# $i%+lo6.- ##" 0%#$tin until t# n#0uliE#% &u" is #"t/ o%

no o%# ist is &oin out. *ou $/ #$% $

s"utt#%in sound 6#n t# &u" is #"t/.

- #n +inis#d tu%n o++ t# &o"%#sso% $nd &l#$n

t# n#0uliE#% $nd &o"%#sso%.

- *ou $/ n##d to &ou u" $nd s"it out u&us t$t

&oll#&ts in /ou% t%o$t.

- nst#$d o+ $ out"i# $t/l&/st#in# is

so#ti#s iv#n t%ou $ +$ $s.

- o#ti#s $ t#nt is "l$d $%ound t# #$d o%

u""#% 0od/ $nd t# #di&in# is "ut into t# $i%

o+ t# t#nt +o% 0%#$tin.

- $l to /ou% do&to% o% "$%$&ist i+ /ou $v#Gu#stions $0out /ou% #di&in# $nd 6#t#% /ou $%#

usin it &o%%#&tl/.

- to%# uno"#n#d vi$ls o+ #di&in# $t %oo


129/231

t#"#%$tu%# $6$/ +%o #$t $nd di%#&t lit.

A+t#% t# vi$l $s 0##n o"#n#d ##" it in t#

%#+%i#%$to% $nd us# it 6itin 4 d$/s. Do not

+%##E#.

- *ou sould not us# vi$ls o+ $t/l&/st#in# t$t

$v# "$ss#d t# #"i%$tion d$t#.

- ##" $ll #di&in# out o+ t# %#$& o+ &ild%#n.+ /ou iss $ dos#:

- $# t# iss#d dos# $s soon $s "ossi0l# unl#ss

it is $lost ti# +o% /ou% n#t dos#.

- i" t# iss#d dos# i+ it is $lost ti# +o% /ou%

n#t %#ul$% dos#.

- *ou sould not us# t6o dos#s $t t# s$# ti#.

DR,= AND FOOD O AVOD:

As /ou% do&to% o% "$%$&ist 0#+o%# usin $n/ ot#%

#di&in# in&ludin ov#%-t#-&ount#% #di&in#s

vit$ins $nd #%0$l "%odu&ts.

- Do not i ot#% #di&in#s in t# n#0uliE#% 6it

$t/l&/st#in# unl#ss /ou% do&to% t#lls /ou to.

ARNN=:

- + /ou $%# "%#n$nt o% 0%#$st+##din t$l to /ou%

do&to% 0#+o%# usin $t/l&/st#in#

- #ll /ou% do&to% 0#+o%# usin tis #di&in# i+ /ou

$v# $st$ o% i+ it is $%d +o% /ou to &ou.

D' 'FF'

$ll /ou% do&to% %it $6$/ i+ /ou $v# $n/ o+ t#s#

sid# #++#&ts:

- n&%#$s#d 6##Ein o% t%ou0l# 0%#$tin

- #st "$in o% titn#ss

- ouin u" 0lood

- F#v#% sin %$s o% iv#s

+ /ou $v# "%o0l#s 6it t#s# l#ss s#%ious sid#

#++#&ts t$l 6it /ou% do&to%.

- o%# out o% t%o$t

- o$%s#n#ss

- N$us#$ voitin

- Runn/ nos#

F *O, AV' AN* O'R D' 'FF' A *O, N AR'

A,'D B* 'DN' 'LL *O,R DOOR.

4.3 PLACE IN THERAPY

A. Oral acetylcysteine is consi%ere% t'e %rug o& c'oice &or

pre)ention against li)er %amage in se)ere acetaminop'en

intoxication. One clinician -Smil:stein6 +3** re)ie1e%

++6+3= cases o& suspecte% acetaminop'en o)er%ose. He

conclu%e% t'at N


130/231

as t'e 0ecti)e muco:inetic agent

an% is use&ul in %ecreasing t'e num(er o& exacer(ations in

patients 1it' c'ronic (ronc'itis. 'en gi)en in com(ination

1it' ce&uroxime6 acetylcysteine increases t'e anti(iotic5s

penetration into (ronc'ial secretion.

7. Ot'er potential uses o& acetylcysteine inclu%e protection

against oxi%ant -&ree ra%icals %amage an% as protection

against cytotoxic agents suc' as i&os&ami%e an%

cyclop'osp'ami%e.

D. Acetylcysteine s'oul% (e inclu%e% on t'e 'ospital

&ormulary.

4.4 MECHANISM OF ACTION"PHARMACOLOGY

A. MECHANISM OF ACTION

+. Acetylcysteine -NA7 is t'e N


131/231


132/231

. Nect on patients 1it' &ulminant

'epatic &ailure cause% (y acetaminop'en -Harrison et

al6 +33+.

G. Nerent %iseases6

all o& 1'ic' 'a)e one &eature in common6 t'e loss o&

SH.

=. "'e a(ility o& Nects. "'e cellular %amage associate% 1it' sepsis6

trauma6 (urns6 pancreatitis6 'epatic &ailure6

'emorr'age6 an% tissue reper&usion &ollo1ing acute

myocar%ial in&arction may (e me%iate% (y t'e

&ormation an% release o& large Juantities o& &ree


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. A re)ie1 o& t'e p'armaco:inetics an% mec'anism

o& action o& t'iol compoun%s6 inclu%ing acetylcysteine6

is pro)i%e% -Broc: et al6 +3*G.

G. Role o& cysteine an% glutat'ione in HI in&ection

an% cancer cac'exia# "'erapeutic inter)ention 1it' Nerence (et1een

NA7 an% place(o treatments 1as statistically

signi@cant -relati)e (ene@t+.=,6 3= con@%ence

inter)al6 +.ect o& long


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to (e -3= con@%ence inter)al# ering &rom

c'ronic (ronc'itis 1ere ran%omi;e% to recei)e

eit'er acetylcysteine 00 milligrams times a

%ay or place(o %uring a ,ecti)e t'an place(o in

impro)ing %iLculty in expectoration an% coug'

se)erity in c'ronic (ronc'itis patients in a

controlle% stu%y -ac:son et al6 +3*G. "oxicity

1as minimal.

e. "'e results o& a general practice stu%y o&

+,*, patients suggest t'at acetylcysteine


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a%ministere% orally -00 milligrams t'ree times

%aily &or mont's to patients 1it' c'ronic

(ronc'itis e>ecti)ely c'anges t'e )iscosity an%

c'aracter o& sputum 1it' resultant ease o&

expectoration an% coug' se)erity. "'ere 1as a

nota(le impro)ement in associate% a(normal

p'ysical signs suc' as t'e presence o& r'onc'i6

cripitations6 an% %yspnea at rest. "olera(ility 1as

goo%6 1it' *+ o& patients experiencing no si%e

e>ects2 gastrointestinal e>ects -ie6 nausea an%

)omiting 1ere most &reJuent -"attersall et al6

+3*.

H. CHRONIC OBSTRUCTIVE PULMONARY DISEASE

FDA L$0#l#d ndi&$tion

+. OERIE#

FDA APPROVAL: Adult /#s! "#di$t%i& /#s

'FFA*: Adult "ossi0l/ #++#&tiv#! "#di$t%i&

"ossi0l/ #++#&tiv#

DO,'NAON: Adult +$i%! "#di$t%i& +$i%

. S$MMAR#

- At/l&/st#in# is FDA-$""%ov#d $s $

u&ol/ti& 0/ di%#&t instill$tion o% n#0uliE$tion

- Adinist#%#d o%$ll/ o% lo&$ll/ in studi#s

- At/l&/st#in# %#dus t# &onsist#n&/ o+

s"utu in "ulon$%/ dis#$s#

- ts &ont%i0ution to i"%ov##nt in "ulon$%/+un&tion $nd &lini&$l &ondition $/ 0# liit#d

. AD$?"#

a. Once


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7O8D -(eta


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'a)e6 in general6 (een unsatis&actory. "'e only

(ene@cial response attri(uta(le to NA7 'as (een

a %ecrease in sputum consistency -Hirsc' et al6

+302 Hirsc' F 9ory6 +3,6 1it' no

impro)ement in pulmonary &unction tests or

su(4ecti)e response. NA7 'as (een s'o1n to

pro%uce 'ypoxemia an% 'ypercar(ia 1it' a

%ecrease in )ital capacity an% increase in air1ay

resistance in t'ese patients -Rao et al6 +30.

G. 8EDIA"RI7#

a. Intratrac'eal a%ministration o& NA7 to liJui&y

air1ay mucus neit'er impro)es t'e clinical

con%ition nor 'astens reco)ery in premature

in&ants 1it' 7HRONI7 ?$N DISEASE an% its

a%ministration may lea% to increase% total air1ay

resistance an% cyanotic spells -Bi(i et al6 +33.

I. COMMON BILE DUCT OBSTRUCTION

+. OERIE#


'FFA*: P#di$t%i& "ossi0l/ #++#&tiv#

DO,'NAON: P#di$t%i& "oo%

. S$MMAR#- $s# %#"o%ts d#s&%i0# &l#$%$n o+ 0il# du&t

o0st%u&tion usin $t/l&/st#in# in in+$nts

. 8EDIA"RI7#

a. "'e use o& N


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c'ole%oc'otomy an% may (e o& use in ot'er

in&ants 1it' %uctal o(struction.

(. N


152/231

)ital capacity -!7 (elo1 = or a pea:

expiratory o1 rate -8E!R o& 0 or lo1er

-Sta&anger et al6 +3**2 Sta&anger F 9oc'6 +3*32

Steil F Niessen6 +3*0. Most o& t'e reports

pro)i%e only su(4ecti)e e)aluations an% t'ere are

&e1 controlle% stu%ies -Denton et al6 +3,2

Stamm F Docter6 +3,=2 Reas6 +3,G. In one

stu%y6 acetylcysteine 'a% a %eleterious e>ect on

pulmonary &unction tests an% no (ene@cial e>ect

on su(4ecti)e response -"e:lin F Holscla16

+3,.

(. A systematic re)ie1 o& literature (et1een

+3,, an% +33 on t'e use o& Nerence in t'e

proportion o& patients s'o1ing greater t'an 0

impro)ement in lung &unction. it' oral NA76

t'ere 1as a ten%ency to1ar% impro)ement o&

!E+6 (ut t'e e>ect 1as small -. an% its

clinical rele)ance is Juestiona(le. !ollo1


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goo% e)i%ence t'at NA7 impro)es lung &unction

-Dui4)esti4n F Bran%6 +333.

c. "'e e>ect o& oral acetylcysteine 1as

eJui)ocal in patients 1it' cystic @(rosis an%

c'ronic pulmonary 8seu%omonas aeruginosa

in&ection. O)erall6 = patients 1ere enrolle% in a

%ou(le


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G. 8EDIA"RI7#

a. Acetylcysteine %oes not appear to impro)e

!A" MA?ABSOR8"ION in cystic @(rosis. A

%ou(leerent. "'e only conclusion 1'ic' can (e

ma%e is t'at t'e t'ic:ene% mucus co)ering t'e

)illi is an insigni@cant &actor in &at mala(sorption

associate% 1it' cystic @(rosis or t'at t'e %ose

o& acetylcysteine use% in t'is stu%y 1as

insuLcient.

K. CYSTINOSIS

+. OERIE#


'FFA*: Adult "ossi0l/ #++#&tiv#


. S$MMAR#

- At/l&/st#in# $s 0##n us#d su&ss+ull/ in

"$ti#nts 6it &/stinosis


155/231


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protect against car%iotoxicity &rom %oxoru(icin

an% a%riamycin6 lung %amage &rom (leomycin6

an% 'epatotoxicity &rom nitrogen mustar%s.

Acetylcysteine %oes NO" appear to (e e>ecti)e

in re)ersing a%)ance% le&t )entricular %ys&unction

&rom DOXOR$BI7IN


157/231


158/231

an% carries a 'ig' mortality rate. "'e cellular

%amage associate% 1it' SIRS is me%iate% (y

t'e &ormation o& large Juantities o& acti)e &ree

ra%icals (y iname% cells t'at o)er1'elm an%

%eplete en%ogenous antioxi%ants -eg6

glutat'ione. Acetylcysteine is a glutat'ione

precursor capa(le o& replenis'ing %eplete%

intracellular glutat'ione an% in t'eory augment

antioxi%ant %e&enses. A (olus %ose o& +=0 mg/:g

in %extrose = in&use% o)er 0 minutes &ollo1e%

(y += mg/:g/' &or G %ays 'as (een use% in

'umans. Initial reports appear to in%icate t'at

acetylcysteine may impro)e renal &unction6

re%uce ui% reJuirements6 an% lessen tissue

e%ema. Acetylcysteine may (e a use&ul a%4u)ant

t'erapy &or SIRS associate% 1it' se)ere sepsis

-Hen%erson F Hayes6 +33G2 Ba::er et al6 +33G2

Dinarello et al6 +332 Bone6 +332 epsen et al6

+332 el(ourn F oung6 +332 Repine F

Bee'ler6 +33+2 Rac:o1 F Asti;6 +33+2 lauser et

al6 +33+2 Ellen'orn F Barceloux6 +3**2 Bragan;a

et al6 +3*,2 9eller et al6 +3*=2 Boro;otta F 8ol:6

+3*.

e. In animals an% 'umans6 acetylcysteine 'as

(een s'o1n to %iminis' t'e extent o& reper&usion

in4ury &ollo1ing A7$"E MO7ARDIA?


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IN!AR7"ION (y re%ucing myocar%ial stunning6

re%ucing in&arct si;e (y to G36 increasing

le&t )entricular e4ection &raction6 an% re%ucing t'e

se)erity o& )entricular arr'yt'mias %uring

reper&usion -Soc'man et al6 +33,2 Arstall et al6

+33=2 rec' et al6 +332 oung et al6 +332

Da)ies et al6 +332 !ar( et al6 +332

9irs'en(aum et al6 +332 !errari et al6 +3302

Soc'man et al6 +3302 Blaustein et al6 +3*32

Sing' et al6 +3*32 Aruoma et al6 +3*32 !orman

et al6 +3**2 7econi et al6 +3**2 estlin F

Mullane6 +3**.

&. Acetylcysteine 1as not e>ecti)e treatment &or

patients 1it' AMO"RO8HI7 ?A"ERA?

S7?EROSIS -A?S. In a ran%omi;e%6 %ou(leects o& nausea an% )omiting6

compliance may 'a)e (een less t'an reporte%.

it' t'e %ose an% &ormulation use%6 NA7

cannot (e recommen%e% to pre)ent

H8ERSENSI"II" REA7"ION "O "M8


163/231

pre)ent 'emorr'agic cystitis (y neutrali;ing

t'ese al:ylating agents. Acetylcysteine

pro)i%es t'iol groups &or t'e al:ylator5s

meta(olites to react 1it'6 t'ere(y sparing

t'e (la%%er -atson6 +3*G.

- !actors contri(uting to t'e limite%

acceptance o& oral acetylcysteine as a

uroprotecti)e agent inclu%e nausea an%

)omiting associate% 1it' 'ig' %oses6 poor

taste6 an% un%esira(le p'armaco:inetic

properties -less t'an +0 is excrete% in

t'e urine -Sc'oeni:e F Dana6 +330.

7omparati)e stu%ies in%icate t'at mesna

-mercaptoet'ane sul&onate6 anot'er t'iol

compoun% capa(le o& (in%ing 1it' acrolein6

is more e>ecti)e t'an acetylcysteine &or

'emorr'agic cystitis -illiams et al6 +3302

?eg'a et al6 +330. Ho1e)er6 mesna

treatment 'as not (een s'o1n in controlle%

stu%ies to (e superior to 'yper'y%ration

1it' &orce% %iuresis &or protection against

cyclop'osp'ami%e


164/231

-+ Oral acetylcysteine 1as e>ecti)e in

pre)enting i&os&ami%e


165/231


166/231

increase% -p less t'an 0.00+6 serum creatinine

%ecrease% -p less t'an 0.06 urine output

increase% -p less t'an 0.00+6 an% so%ium

excretion increase% -p less t'an 0.0=. "'ere

1ere no signi@cant c'anges in li)er &unction or

(loo% pressure. "'e sur)i)al rates at + an%

mont's 1ere , an% =*6 respecti)ely

-inclu%ing patients 1'o 'a% recei)e% li)er

transplants a&ter impro)ement o& renal &unction.

NA7 may o>er a (ri%ging t'erapy6 exten%ing t'e

time a)aila(le &or li)er transplantation -Holt et al6

+333.

6. HIV INFECTION

+. OERIE#



DO,'NAON: Adult +$i%

. S$MMAR#

- $/ d#&%#$s# tuo% n#&%osis +$&to% l#v#ls

- $/ d#&%#$s# $&tiv$t#d su""%#sso% lls

- Do#s not $""#$% to #n$n lut$tion#

"%odu&tion

. AD$?"#

a. 'en N


167/231

asymptomatic HIects s'o1e% t'at HIecti)ely

treate% 1it' acetylcysteine +0 eye%rops -Mars'

F 7ooper6 +3*.

(. Se)enteen patients 1it' :eratocon4uncti)itis

an% corneal mucus plaJues respon%e% 1ell to

ocular a%ministration o& acetylcysteine +0 &our

times %aily. 'en acetylcysteine treatment 1as


171/231

%iscontinue%6 plaJues generally %i% not recur

-!raun&el%er et al6 +3.

c. Acetylcysteine to +0 eye%rops -%ilute%

1it' anti(iotic solution 'as also (een reporte%

to (e success&ul in one patient 1it' 9ERA"I"IS

M$7OSA (ut 1it' normal tear secretion an% no

o)ert systemic %isease -S'a1 F asset6 +3G.

"'e patient 1as also treate% 1it' a 'y%rop'ilic

contact lens.

%. Acetylcysteine 0 applie% to t'e eyes e)ery

'ours resulte% in mar:e% impro)ement in

)isual acuity6 relie& o& &oreign (o%y sensation an%

(lep'arospasm6 an% pre)ention o& mucus

accumulation in a patient 1it' :eratocon4uncti)itis

-Messner F ?ei(o1it;6 +3+.

e. A %ou(le


172/231

+. OERIE#



DO,'NAON: Adult ood

. S$MMAR#- At/l&/st#in# is not #++#&tiv# +o% %#du&in

s#%u li"o"%ot#in &onnt%$tions

. AD$?"#

a. One report in%icate% a =0 to = re%uction

in t'e plasma concentration o& lipoprotein -A

-?p-A in t1o patients gi)en an% G grams Necti)eness o&

t'e com(ination o& A7E"?7S"EINE an%7E!$ROXIME in t'e treatment o& respiratory

tract in&ections in in&ants -Rameng'i et al6 +3*36

c'il%ren -Santagelo et al6 +3*=2 Rameng'i et al6

+3*G an% a%ults -!ogliar%i et al6 +3*G2 Dal

Negro et al6 +3*=2 Bona)ita6 +3*=.

(. Acetylcysteine 1as eLcacious in com(ination

1it' ce&uroxime in curing respiratory tract

in&ections. Sixty


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com(ination o& + g ce&uroxime an% 00 mg

acetylcysteine. 8atients 1ere %i)i%e% into

groups accor%ing to t'e acute or c'ronic nature

o& t'eir respiratory tract %iseases. 8ositi)e

clinical results 1ere o(taine% in , o& t'e ,=

patients. O& a total o& = pat'ogens isolate% in

pretreatment (acteriological tests on sputum

cultures6 only 1ere still %etecta(le a&ter

treatment. "olerance o& t'e treatment 1as goo%

in all patients2 no si%e e>ects o& any :in% 1ere

o(ser)e% -Dal Negro et al6 +3*=.

c. In el%erly an%/or %e(ilitate% patients -n,6

oral N


191/231

1'at (ene@t6 i& any6 acetylcysteine mig't o>er to

patients 1'o are appropriately immuni;e% against

inuen;a -De !lora et al6 +33.

%. A7E"?7S"EINE may (e (ene@cial as an

a%4unct to anti


192/231

-IM. E)i%ence o& o(4ecti)e reco)ery or

impro)ement occurre% in +00 o& +0 c'il%ren6

1it' no toxicity (eing o(ser)e%. It is speculate%

t'at mucolytic t'erapy 1it' acetylcysteine

re%uces trac'eo(ronc'ial secretions 1'ic' coul%

accumulate in t'e perip'eral (ronc'i6 resulting in

mucus plugs 1'ic' &acilitate implantation o&

(acterial organisms -Santangelo et al6 +3*=.

Ho1e)er6 it is unclear i& t'is regimen is superior

to ce&uroxime alone.

(. In an uncontrolle% stu%y6 0 in&ants ranging in

age &rom +0 mont's to years su>ering &rom

recurrent catarr'al (ronc'ial %isease o& (acterial

origin 1ere success&ully treate% 1it' a

com(ination o& acetylcysteine an% ce&uroxime6

a%ministere% intramuscularly at %oses o& += an%

=0 milligrams/:ilogram/%ay6 respecti)ely6 &or a

mean perio% o& +0.G P/< . %ays. 7linical

controls s'o1e% t'at t'e com(ination pro%uce% a

prompt6 mar:e% re%uction in (ronc'ial

'ypersecretion. "'e clinical e>ects6 1'ic' are

%escri(e% in %etail6 an% t'e excellent local an%

systemic tolera(ility o& t'e com(ination s'o1 it

to (e a )ali% &orm o& treatment &or (acterial

(ronc'ial %isease in early in&ancy -Rameng'i et

al6 +3*G.


193/231

AF. S%OGREN&S SYNDROME

+. OERIE#



DO,'NAON: Adult ood

. S$MMAR#

- At/l&/st#in# $""#$%s to l$& #++i&$&/ in t#

t%#$t#nt o+ 9o%#ns s/nd%o#

. AD$?"#

a. One controlle% stu%y points to a limite% role

&or acetylcysteine in treating S4ogren5s syn%rome.

A trial 1as con%ucte% in +0 patients 1it'

S4ogren5s syn%rome treate% orally 1it' Nects

1ere reporte%.

(. Among 0 patients 1it' SOREN5S

SNDROME 1'ose :eratocon4uncti)itis %i% not

respon% to replacement t'erapy 1it' arti@cial

tears6 , patients impro)e% 1it' + mont's o&

topical treatment 1it' acetylcysteine =6 +

s'o1e% no c'ange6 an% one 1orsene%

-illiamson et al6 +3G.


194/231

AG. SURGERY CARDIOPULMONARY

+. OERIE#



DO,'NAON: Adult ood

. S$MMAR#

- On# stud/ so6#d "ositiv# #++#&ts o+

$t/l&/st#in# t%#$t#nt 0#+o%# su%#%/

. AD$?"#

a. 8re


195/231

AH. UNVERRICHTLUNDBORG DISEASE

+. OERIE#




. S$MMAR#

- n isol$t#d &$s#s $t/l&/st#in# t%#$t#nt $s

%#sult#d in $%#dl/ i"%ov#d +un&tion in

"$ti#nts 6it ,nv#%%i&t-Lund0o% dis#$s#

. AD$?"#

a. A G0


196/231

notice% re%uce% uency o& speec' an%

%eterioration o& 'is a(ility to 1al:. He restarte%

me%ication an% impro)ement 1as e)i%ent in

%ays. 8rior to NA7 treatment6 'e 'a%

experience% a(out +0 generali;e% sei;ures per

year2 %uring +0 mont's o& ta:ing NA76 'e 'a%

only atypical6 (rie& -=< to +0


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acetylcysteine orally G times a %ay -Ben%ere)6

+3**.

4.! COMPARATIVE EFFICACY AND EVALUATION WITH OTHER

SIMILAR THERAPEUTIC AGENTS

A. AMBROXOL

1. CYSTIC FIBROSIS

a. A clinical trial compare% t'e eLcacy o& oral

am(roxol an% N


198/231

a. Intra)enous Necti)e t'an intra)enous cysteamine in

pre)enting 'epatic complications o& se)ere

acetaminop'en o)er%ose in one stu%y -8rescott6

+3*+. Ot'er a%)antages o& Nects6 *6 t'an acetylcysteine6 * -Melica6

+3*. Bot' agents 'a% similar e>ects on

su(4ecti)e an% o(4ecti)e clinical parameters an%

respiratory &unction in patients 1it' c'ronic

(ronc'itis.

!.0 REFERENCES

+. ADE7# Australian Drug E)aluation 7ommittee# Me%icine in

8regnancy < An Australian 7ategorisation o& Ris: o& Drug A(use

in 8regnancy6 r% e%. Australian o)ernment 8u(lis'ing Ser)ice6

7an(erra6 Australia2 +33,.

. AH!S# American Hospital !ormulary Ser)ice Drug In&ormation

+3*3. American Society o& Hospital 8'armacists6 Bet'es%a6 MD6

+3*3.


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. A:erlun% B6 arstan% 76 ?in%e:e B et al# E>ect o& N

bromhexina info total

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