PHARMACY

in Practice

Original research

Preservatives can produce harmful effects in

paediatric drug preparations

Introduction
Pharmacists working in hospital or
community pharmacies often calion
their experience to prepare medications extemporaneously (extemp
preparations).
In the UK, NHS hospital trusts especially those
with
product
manufacturing
facilities
are
responsible for preparing pharmaceutical preparations for hospital use
where there
are shortages In
commercial sources to meet clinical
needs. This is often done for those
paediatric products where it IS
common practiceto take an adult dose
and turn it into preparations suitablefor
children - such as the preparation of
ciprofloxacin suspensionfrom tablets or
the preparation of unit dose by a
pharmacy Central IntravenousAdditive
Service (ClVAS), Some other products
are also produced under speciallicence
for rare therapies or in support of
clinical investigations,

Most of the extemporaneous preparations are aqueous liquids'and. as a

result they are susceptibleto microbial
contamination" which Ca.R lead to
spoilage and undesirable effects in
patients,These products thus need to
be preserved to maintain their
microbial integrity during storage and
when in-use, However; the type and
quantity of preservatives must be
carefully selected
in
paediatric
preparations because of the possible
pharmacologicalactions or toxic effects
from this formulation ingredient.
Current practice
A list of preservatives currently used
within the London region NHS
pharmacy manufacturingunits,obtained'
from a survey, is given in Table I, The
sur\/ey revealedthat chloroform is used
widely as a preservative, especiallyfor
extemporaneously prepared oral liquid
medicines,Chloroform is active against
a wide range of microorganisms and it
is one of the oldest preservatives used

r------_..;;.---------------------------'----------------------j,,r,.
y

I'

PHARMACY
in Practice
in pharmacy. Of concern, therefore, is
the reported chloroform toxicity in
animals that has led the US FDA and
similar agencies in some other countries
to ban its use in medicines and cosmetics.

Chloroform has been found to

oroduce hepatocellular carcinomas Jer cancers in mice and rats, and
renal tumours in male rats after oral
aoministration Aside from the toxic
#iects there is a possibility of reduction
"'\me preservative effect as a result of

Original

evaporation of chloroform from medicinal preparations during storage and

routine use.

research

Despite these unfavourable reports,

the British Pharmacopoeia (200 I) and
Martindale Extra (36th Edition) still
allow the inclusion of chloroform in
drug preparations up to a concentration of O.5%w/w or v/v.

ans. Some believe there is a genuine

reason for concern because results
from animal studies have been used to
predict the toxicity profile of substances
in humans - and chloroform is no
exception. In our opinion chloroform
should not be employed as a preservative for pharmaceutical preparations - especially those. intended
for use in children.

Few scientists would argue that the

reported adverse effects of chloroform
have not been demonstrated in hum-

Methyl and propyl parabens, including

their salt combinations, are also used as
preservatives for extemps and products

PHARMACY
in Practice

Original research

that are produced as batches.

In our survey benzyl alcohol was used
in one cream preparation. Comments
from the survey revealed that the use
of phenyl mercuric nitrate (0.004%) and
thiomersal (0.005%) as preservatives in
ophthalmic preparations is diminishing
because of side-effects. Future formulation objectives may therefore include
the production of ophthalmics without
a need for chemical preservation.
Other

preservatives,

such

as

propylene glycol, ethanol and benzalkonium chloride are also being used
to a varying extents and they also have
potential to cause harm when used for
the preparation of paediatric medicines.

Review
Some preservatives
are toxic and
should be restricted
in paediatric
formulations while others are less toxic
but effective. This paper is a concise
review of the properties of some of the
preservatives frequently used in the
preparation of pharmaceutical dosage

forms and includes a thorough assessment of their potential

risks and
benefits, especially in medicines intended for neonates and children. It is
hoped that the information we provide
will assist formulation pharmacists to
select an optimum preservation system
for their products.
Benzyl Alcohol
Benzyl alcohol is commonly used at
concentrations
up to 2.0%v/v as
preservative in solutions and injectable
drugs. Optimum
activity occurs at

PHARMACY
in Practice

Original

research

solution pH values of less than pH 5. It

is active against gram positive bacteria,
moulds, fungi and yeast and possesses
modest bactericidal activity. It is less
effective against gram negative bacteria
and ineffective against spores. It IS
incompatible with methylcellulose.
A number of neonatal deaths and
severe respiratory
and metabolic
complications - especially in low-birth
weight premature infants - have been
associated with the use of this agent in
bacteriostatic saline intravascular flush
and
endotracheal
tube
lavage
sol utions.!"

Benzoic acid (BA)

Ethanol (ET)

Benzyl alcohol toxicity

has been
ascribed to the build-up of benzoic acid
- exacerbated by the immature conjugation pathway in neonates. Thus, the
same caution should be applied to
preparations containing benzoic acid or
sodium
benzoate.
Benzoates
substantially increase the unbound bilirubin
concentration
(UBC),
but this is
attenuated after a 42-fold dilution.'
The use of benzyl alcohol should be
avoided in neonates if possible. If benzyl
alcohol is present in a paediatric
preparation and its use is essential, the
total dose should not exceed I Omg/kg
per day.This is an arbitrary figure based
on the knowledge that 100mg/kg/day
has caused
death
from
gasping
syndrome in very low birth-weight
premature babies.'
Many commercially available neonatal
preparations contain sodium benzoate
or benzoic acid but the amount of
preservatives
ingested from normal
doses in these preparations is~well
below 10mg/kg/day. It is advisable to
avoid administration
of preparations
containing
these
preservatives
to
severely ill neonates such as premature
infants with metabolic
acidosis or
respiratory distress.
Parabens
Methyl and propyl hydroxy benzoates
are generally safe in neonates. Parabens
are included
in some
parenteral
products
that
have
been
used
extensively
in neonates,
such as

I04

Pharmacy in Practice - May 2004

Table I. List of Preservstive being used within the London region NHS pharmaceutical manufacturing units

"=

ophthalmic products

gentamicin injection.
The
concentrations
used
in
pharmaceutical
formulations
vary
depending on the dosage form with
injectable or parenteral preparation
having the lowest. Methyl parabens
(0. 18%) and propyl parabens (0.02%)
have been used to preserve various
parenteral formulations. The parabens
are most active at a pH range of 4-8
and their
activity
decreases
with
increasing pH. They are most active
against yeast, mould and gram positive
bacteria and less against gram negative
bacteria Their activity is enhanced in
some formulations
when combined
with propylene glycol or phenyl ethyl
alcohol.

In vitro studies indicate that both

methyl and propyl paraben bind to

albumin and methyl paraben displaces
bilirubin from albumin." Despite this
displacement, hyperbilirubinaemia
has
never been demonstrated in vivo when
preparations containing the preservatives are given in normal doses.'
The excretion of methyl paraben by
the urinary route in preterm infants is
variable during the first few days of
extrauterine life. Whether there is an
accumulation of preservatives in the
body and whether
after repeated
injections the albumin binding capacity
for bilirubin' is affected, remains to be
determined. It is not uncommon for
preterm
infants to have neonatal
jaundice," However, as a precaution,
products containing parabens should be
avoided as much as possible in acutely ill

PHARMACY
in Practice
neonates presenting with jaundice,
kernicterus or hyperbilirubinaemia.
BenzalkoniumChloride
Benzalkonium chloride is a commonly
used bactericidal preservative in
suspensions,nasalsprays,eye drops and
nebuliser solutions. In ophthalmic
preparations benzalkonium is effective
at concentrations of 0.01-0.02%w/v.
In nasal and otic preparations
benzalkonium is effective at a concentration range of 0.002-0.02%.
Disodium edetate (0.1%) is usually
added to enhance antibacterial activity
againstPseudomonas spp.
When benzalkonium chloride has
been used as a preservative in
nebulised solutions of anti-asthmatic
agents,it has been reported to cause
bronchoconstriction and was associated with the precipitation of a
respiratory attack? 10. II
In nasal sprays this product can
exacerbate rhinitis and it can induce
irritation or keratitis in eye preparations.
It is worth noting that these properties
are not peculiar to benzalkonium and
they could be manifest by other preservatives. It is advisable,therefore, to
avoid the use of benzalkoniumchloride
in paediatric products especiallyin antiasthma preparations." Potential sources
of benzalkonium in products for
children with asthma and concurrent
sinusitis include nasal saline, nasal
corticosteriods and nasaldecongestant
solutions.
Chlorobutanol (Chlorbutol)
Chlorobutanol has antibacterial and
antifungal properties and it is used at a
preservative concentration of 0.5% in
injections and in eye drops. Patients
who were given high doses of
salicylamide or morphine infusions
preserved with chlorobutanol showed
chlorbutol-induced somnolence. '3.14

Original

Chlorobutanol should not be usedto

preserve injectable preparations that
are intended for neonatesand children.
Eye drops,
nasal and
dental
preparations may be preserved with
chlorobutanol especially where their
sedativeand analgesicproperties are of
advantage.

Cumulative intake of
preservatives
The cumulative or concomitant intake
of preservatives from multiple drug
therapy given to neonatesand children,
should be calculated.The very ill neonates and premature babies,especially
those with kernicterus or conditions
predisposing to hyperbilirubinaemia,
should not be given products
containing parabens,at least until their
condition resolves.

Conclusion
There is considerable risk associated
with the extemporaneous preparation
of pharmaceutical products especially
those meant for use in neonates and
young children.
Pharmacists must assessthese risks
and make efforts to transfer extemp
products to batch manufacture. This
transition will involve formulation study,
scale-up and stability surveillance.
Adequate information must also be
sought on all formulation ingredients so
that the problems of incompatibility
and toxicity to patients can be resolved
before formulation.

research

patients should not be preserved with

benzalkonium chloride and injections
intended for neonates should not
contain
chlorbutanol.
However,
chlorbutanol is useful as preservative in
eye drops, nasal and dental preparations where their sedative and
analgesic properties may be an
advantage.
To improve the delivery of a professional pharmacy servrce,
we
recommend mandatory labelling of all
inactive ingredients such as preservatives in all formulations.This must be
included on the packagingmaterials of
all prescription and over the counter
drugs, whether produced extemporaneously or commercially This would
facillitate an evaluation of the risks
associated with specific formulation
ingredients and thus speed up the
decision-making process on the
suitability of medications for neonates
and children.

Acknowledgement
The authors are grateful to all the
London
region NHS pharmacy
manufacturing units that participated in
the survey.
References
I. Gershanik

JJ,

Boeder B, George W, Sola A,_

Leitner M. Kapadia C. The gaspingsyndrome:

benzyl alcohol poisoning? Clin Res 1981;29;
895A.

2. Brown WJ, Buist NR, Gipson HT, Huston RK,

Kennaway NG. Fatal benzyl alcohol poisoning
in a neonatal intensive care unit. Lancet 1982;

We recommend that chloroform

should not be used as a preservative in
medicines that are intended for use in
children becauseof its toxicity.The next
edition of the British Pharmacopoeia
should consider this recommendation
and delete chloroform from the list of
preservatives allowed for inclusion in
drug preparations intended for human
consumption. There are other, equally
effective and lesstoxic, alternatives.

I: 1250.
3. Anderson ON, Ng Kj,Andresen B,Cordera L
Benzyl alcohol poisoning in a premature new
born infant Am

Obstet Gynecol 1984; 148:

344-6.
4. Ahlfors CEo Benzyl alcohol, kernicterus and
unbound bilirubin. Journal of Pediatrics 200 I ;

139: 317-9.
5. Woods

D. The

safety

of

antimicrobial

preservatives in oral liquids for neonates.

New Zealand Pharmacy 1996;4: 22.

6. Rasmussen LF, Ahlfors CE, Wennberg. The

A delayed cellular type of hypersensitivity reaction to chlorbutol used

to preserve heparin when it was given
by subcutaneous injection, has also
been reported."

Parabensand benzyl alcohol can be

used as preservatives in childrens'
medicines, but should be used with
caution in children with jaundice.
Nebulised solutions for asthmatic

effects of paraben preservatives on albumin

binding of bilirubin. journal of Pediatrics 1976;

89: 475-8.
7. Woods

JT. Bryan LE, Chan G, Sciff D.

Gentamicin and albumin-bilirubin binding -

PHARMACY
in Practice

Original

research

A neonate in an acute-care unit receiving an aqueous infusion. Special care must be

taken in the choice of preservatives for neonatal aqueous drug preparaifons

7. Woods

J1; Bryan LEo Chan G, Sciff D.

Gentamicin and albumin-bilirubin binding An in-vivo ~udy.Joumal of Pediatrics 1976; 89:

483-6.

dependence. Med J Aust 1979; I: 288.

14. DeChristoforo R Corden BJ,Hood JC Narang
PK, Magrath IT High-dose morphine infusion
complicated by chlorobutanol-induced somn-

8. Hindmarsh KW. John E, Asali LA, French IN,

olence. Annals of Internal Medicine 1983; 98:

Williams GL, McBride WG. Urinary excretion

335-6.
15. Dux 5 Pitlik S, Perry G, Rosenfeld JB.

of methylparaben and its metabolites

in

preterm infants. Joumal of Pharm Sciences

Hypersensitivity

1983; 72: 1039-41.

preserved heparin. Lancet 1981; i: 149.

9. Boucher M Roy MT. Henderson

association

of

benzalkoniun

J.

Possible

chloride

in

nebuliser solution with respiratory arrest. Ann

Pharmacother 1992; 26: 772-4.
I O. Beasley CR Rafferty

P.

reaction to chlorbutanol-

Holgate S. Benz-

Olufemi Rabid *, technical R&D

manager, Paul Forset, production
manager, Sanjay Pate?, senior aseptic
services pharmacist

alkonium chloride and bronchoconstriction.

* Corresponding

Lancet 1986 ij: 1227.

I I. Beasley CR. Rafferty

P.

constrictor

properties

ipratropium

bromide

Holgate ST.Bronchoof preservatives in

(Atrovent)

nebuliser

author
Department of Pharmacy. Guys and St
Thomas' Hospital Trust, Lambeth
Palace Road. London, Sf I 7fH

solution. 8MJ 1987: 294: I 197-8.

12. Excipients: Review of adverse reaction. WHO

Pharmaceutical News Letter. NovemberDecember 1998.
13.Borody T Chinwah PM, Graham GG, Wade
ON, Williams KM. Chlorbutol toxicity and

IA()

'""'

_,___~._--..L! _

We will be very pleased to recieve

readers' views on this and other article
in Pharmacy in Practice. These may be
emailedto:pip@medicomgroup.com

Lantus 100 IU/mI~lution

10, injection (Insulin gl.,g;ne).
Prescribing Information. Presentation,
I glass vial/pack
containing lo.ml sql~tl.on 110.0.0.IU insulin glargin~. PQuivalenl \P
3S.4mg) or 5 glass cartridges/pack each containing 3ml solution
1300 IU Insulin glargine. equivalent to lo..S2mg\ or packs 01'5
OptiSet pens each containing 3ml solution (300 IU insulin
gl.rgin&, equivalent to lo..92mg). IExcipients: zinc chloride, ''!lcresol. glycerol. hydrochloric add. sodium hydroxide and water fur
iniecriohs). Illdicirtipns: FOrthe treatmentbf adults. adolescents
.and chlldren of 6 yars or above with diabetes mellil~$, whet!!
treatment with insulin is required. Dosage'and Administration:
Lantus should be. administered subcutanllOusly once daily, at
any time. but at the same time each day: In children. the efficacy
and safety of Lantus have only been demonstrated when given in
the evening 1119' dosage of insulin glargihe should be individually
.Mjustod. Close me_taholic monito(in~ is recom.mended liutillg
transition frOl~ Olhet'insulips to Lanrus and in eircumstantenhat
increase susceptibility to hypo- or hypergiycaemia. tanus must
not bo mixed with other insulins or diltited. Contraindications:
Hypersensitivity to insulin glargine or to any of the excipients.
Precautions and Warnings: Lantus is not the insulin of choice
fbr.treatment of diab.etic ketoacidnsis. The s<,ffily and ejficflW of
Lanius has not been assessed in children.below a'years of age.
patients with impaired liver function 01 patients with moderatel
severe renaf impairment. In patients with renal impairment or
severe hepatic impairment. insulin requirements maY be
diminished. In case of insufficient glucose control or a tendency
to hypo/hyperglycaemic episodes all relevant factors must be
reviewed before dose,.adjustmont is consioered. Pa~icular caution
.s!iould be exerciseit a(ld lntensifi'ed blood monitoring is advisable
for patients in whom hypoylycaemic episOdes might be of clinical
relevance and in those with intercurrenl illness, where dose
adjustments may be required. Warning sigos of hypoglycoomja
111ay be changed. lesspronounClld or absent in certain risk groups
,including. patients in whom glycaemic control is markedly
improved. hypoglycaemia' develops gradually. an alltonomio
neuropathy is p'ri!seN,.or elderly patients. Due to more sustained
'basal insulin supply with lsntus, less 11flctoroal but more early
moming hyPlll!lycaemia can be expected. The prolonged effect
of subcutaneous insulin glargine may delay recovery from
hypoglycaernia. Interactions:.Subslances that may enhance the
bIOodglucose-lowering affect and incf!!Me susceptibiliw to
.!\ypoglycael)1ia inclu(le oral antidiabetic agents. ACE inhibitors.
fibrates. fluoxetine. salicylatas and sulphonamide antibiotics.
Substances that may reduce the bloodglucose-Iowering effect
include corticosteroids. diuretics. oestIll!len,s and Pllll!eSierones.
phenothiazine deriv3ti'/lis and thyroid Ilormones. Beta-blockers,
I1tflium salts or alcohol may potentiate .or weaken the hloodglucose-Jowering effect of iilSujlh. Under the inilu.ence of
sympatholytic medicinal products the ,Signs of alldrenergic
counterregulation may be reduced or absent Pregnancy Bnd
Lactation: No clinical data O(l flXllOSedpregnancies are available.
Lactating women may require adjustinents in insulin dose and
diet. Advel1le Reactions: Hypoglycaemia may occur if the insulin
dose is too high in relation to requirement. A marked change in
glycaemlc COntrol may cause temporary visual impairment
although long term improved glycaemic control decreases the
rata of prlll!ression of diabotic retinop_athy. UpOlIystroplly may
occur at the injection site and delay 10llal insulin absorption.
Temporary injection sile reections, inclu!ilng redness. itching,
pain, hives, swelling.or inflammation. Immediate-type allergi(}
mactlons are rare but may be associated ivith generalis.e~ skin
r!lllctlons. angiooedema. bronchospasm. hypotension and shock
-and may be life threatening, Insulin administrntion may cause
insulin antibodies to form and may. in fare cases, necessitate
adjustment of tile insulin dose. Insulin may. rarely, cause sodi.um
retention and oedema, Overdose may lead to severe and
.sometimes longte.rm and IIle threatening hypoglycaemifl. Mild
'episodes can usually be treated with pral carbohydrates. Mote
severe episodes mav-be treated with iQualllJ.)SCular/subcutaneous
glucagon or conr;entJaied intravenous glucose. Phannaceujjcal
Precautions:.Store
unopened cartridges/vials/OptiSet
pens at
28"C. 00 not freeze.. O~oe opened do not. store above 25'C and
.US8. within 4 wee~s. Do not refrigerate OptiSet pen once.inus8
.0.rOptiPenPro con\ilining.cartrldlie. NHS R;ice: 1 vial of Wml
25.00. 5 cartridges'of 3ml 39.00. 5 OptfSet of 3m1 39.0.0..L~!J!II
Category: POM. Marketing Authorisation
Numbers: Market
Authorisation Holder Aventis Plmrma Deutschland GmbH, 0-65926
Frankfurt am Main. Germany. Lantus 100 IU/ml solution for
inje,lion in a cartripga (5 calttjdges/packl EU/lJoo/l34/006,
Lantus 100 IU/ml sclution for' injection in.a 10ml vial () vial/pack)
EU/I/00/134/012.LantlJs 100 IU/ml OptiSeisolution for illJectioQ
(5 pens' EU/l/OO/134/010. Further inform~tion is available on
,equest from Medical Information Dept., Awntis Pharma,
50 Kings Hill Avenue, Kings Hill, West Mailing. KentME194AH.
Tel. 0.1732 584493. Date of Revision: June 2003.
References: 1. Ashwell S. Ami.al S. Improvement in flbA1c
with Insulln'Glargine t Insulin Lispro in Comparison with NPH
Insulin + Unmodified Homan Insulin in People with Type 1 Diabetes.
Clinical TherapeuliCS/New TactmoIIll!Y. Abstract 1914-1'0 and
poster presented at 6311lAmerican DIabetes Association Annual
Meeting. Now Orleans. June 13th17th.Z003. 2.. Riddle Me.
Rosenstock J. Gerich J. The treatto-targst trial: randomized
addition of glargine or human NPH inslilin to qral therapy for
lype 2 diabetic patients Diabetes Cajll 2003; 26{11); 3080"86.
3. lanrus Summary ot Product Characteristics.
lantus is a r"llistered trademark of the. Aventis Group.
Date of preparation: March 2004. LAN4540204