PHARMACYOriginal research in Practice

Preservatives can produce harmful effects inpaediatric drug preparations

I

.IntroductionPharmacists working in hospital orcommunity pharmacies often caliontheir experience to prepare med-ications extemporaneously (extemppreparations).

In the UK, NHS hospital trusts -especially those with productmanufacturing facilities areresponsible for preparing pharma-ceutical preparations for hospital usewhere there are shortages Incommercial sources to meet clinicalneeds.This is often done for thosepaediatric products where it IScommon practiceto take an adult doseand turn it into preparationssuitableforchildren - such as the preparation ofciprofloxacinsuspensionfrom tablets orthe preparation of unit dose by apharmacy Central IntravenousAdditiveService (ClVAS),Some other productsare also produced under speciallicencefor rare therapies or in support ofclinical investigations,

Most of the extemporaneous prep-arations are aqueous liquids'and. as aresult they are susceptibleto microbialcontamination" which Ca.R lead tospoilage and undesirable effects inpatients,These products thus need tobe preserved to maintain theirmicrobial integrity during storage andwhen in-use, However; the type andquantity of preservatives must becarefully selected in paediatricpreparations because of the possiblepharmacologicalactions or toxic effectsfrom this formulation ingredient.

Current practice

A list of preservativeswithin the London

currently usedregion NHS

pharmacymanufacturingunits,obtained'from a survey, is given in Table I, Thesur\/eyrevealedthat chloroform is usedwidely as a preservative, especiallyforextemporaneously prepared oral liquidmedicines,Chloroform is active againsta wide range of microorganismsand itis one of the oldest preservativesused

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PHARMACYin Practice Original research

in pharmacy. Of concern, therefore, isthe reported chloroform toxicity inanimals that has led the US FDA andsimilaragencies in some other countriesto ban its use in medicines and cos-metics.

Chloroform has been found tooroduce hepatocellular carcinomas -Jer cancers - in mice and rats, and

renal tumours in male rats after oralaoministration Aside from the toxic#iects there is a possibility of reduction"'\me preservative effect as a result of

evaporation of chloroform from med-icinal preparations during storage androutine use.

Despite these unfavourable reports,the British Pharmacopoeia (200 I) andMartindale Extra (36th Edition) stillallow the inclusion of chloroform indrug preparations up to a concent-ration of O.5%w/w or v/v.

Few scientists would argue that thereported adverse effects of chloroformhave not been demonstrated in hum-

ans. Some believe there is a genuinereason for concern because resultsfrom animal studies have been used topredict the toxicity profile of substancesin humans - and chloroform is noexception. In our opinion chloroformshould not be employed as a pres-ervative for pharmaceutical prep-arations - especially those. intendedfor use in children.

Methyl and propyl parabens, includingtheir salt combinations, are also used aspreservatives for extemps and products

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that are produced as batches.

In our survey benzyl alcohol was usedin one cream preparation. Commentsfrom the survey revealed that the useof phenyl mercuric nitrate (0.004%) andthiomersal (0.005%) as preservatives inophthalmic preparations is diminishingbecause of side-effects. Future formul-ation objectives may therefore includethe production of ophthalmics withouta need for chemical preservation.

Other preservatives, such as

propylene glycol, ethanol and benz-alkonium chloride are also being usedto a varying extents and they also havepotential to cause harm when used forthe preparation of paediatric medicines.

ReviewSome preservatives are toxic andshould be restricted in paediatricformulations while others are less toxicbut effective. This paper is a concisereview of the properties of some of thepreservatives frequently used in thepreparation of pharmaceutical dosage

forms and includes a thorough assess-ment of their potential risks andbenefits, especially in medicines intend-ed for neonates and children. It ishoped that the information we providewill assist formulation pharmacists toselect an optimum preservation systemfor their products.

Benzyl Alcohol

Benzyl alcohol is commonly used atconcentrations up to 2.0%v/v aspreservative in solutions and injectabledrugs. Optimum activity occurs at

PHARMACYin Practice Original research

solution pH values of less than pH 5. Itis active against gram positive bacteria,moulds, fungi and yeast and possessesmodest bactericidal activity. It is lesseffective against gram negative bacteriaand ineffective against spores. It IS

incompatible with methylcellulose.

A number of neonatal deaths andsevere respiratory and metaboliccomplications - especially in low-birthweight premature infants - have beenassociated with the use of this agent inbacteriostatic saline intravascular flushand endotracheal tube lavagesol utions.!"

Benzyl alcohol toxicity has beenascribed to the build-up of benzoic acid- exacerbated by the immature con-jugation pathway in neonates. Thus, thesame caution should be applied topreparations containing benzoic acid orsodium benzoate. Benzoates sub-stantially increase the unbound bilirubinconcentration (UBC), but this isattenuated after a 42-fold dilution.'

The use of benzyl alcohol should beavoided in neonates if possible. If benzylalcohol is present in a paediatricpreparation and its use is essential, thetotal dose should not exceed IOmg/kgper day.This is an arbitrary figure basedon the knowledge that 100mg/kg/dayhas caused death from gaspingsyndrome in very low birth-weightpremature babies.'

Many commercially available neonatalpreparations contain sodium benzoateor benzoic acid but the amount ofpreservatives ingested from normaldoses in these preparations is~wellbelow 10mg/kg/day. It is advisable toavoid administration of preparationscontaining these preservatives toseverely ill neonates such as prematureinfants with metabolic acidosis orrespiratory distress.

Parabens

Methyl and propyl hydroxy benzoatesare generally safe in neonates. Parabensare included in some parenteralproducts that have been usedextensively in neonates, such as

Benzoic acid (BA)

Ethanol (ET)

Table I. List of Preservstive« being used within the London region NHS pharmaceutical manufacturing units"= ophthalmic products

gentamicin injection. methyl and propyl paraben bind toalbumin and methyl paraben displacesbilirubin from albumin." Despite thisdisplacement, hyperbilirubinaemia hasnever been demonstrated in vivo whenpreparations containing the preserv-atives are given in normal doses.'

The concentrations used inpharmaceutical formulations varydepending on the dosage form withinjectable or parenteral preparationhaving the lowest. Methyl parabens(0. 18%) and propyl parabens (0.02%)have been used to preserve variousparenteral formulations. The parabensare most active at a pH range of 4-8and their activity decreases withincreasing pH. They are most activeagainst yeast, mould and gram positivebacteria and less against gram negativebacteria Their activity is enhanced insome formulations when combinedwith propylene glycol or phenyl ethylalcohol.

The excretion of methyl paraben bythe urinary route in preterm infants isvariable during the first few days ofextrauterine life. Whether there is anaccumulation of preservatives in thebody and whether after repeatedinjections the albumin binding capacityfor bilirubin' is affected, remains to bedetermined. It is not uncommon forpreterm infants to have neonataljaundice," However, as a precaution,products containing parabens should beavoided as much as possible in acutely illIn vitro studies indicate that both

I04 Pharmacy in Practice - May 2004

PHARMACYin Practice Original research

neonates presenting with jaundice,kernicterus or hyperbilirubinaemia.

BenzalkoniumChlorideBenzalkoniumchloride is a commonlyused bactericidal preservative insuspensions,nasalsprays,eye drops andnebuliser solutions. In ophthalmicpreparations benzalkonium is effectiveat concentrations of 0.01-0.02%w/v.

In nasal and otic preparationsbenzalkonium is effective at a conc-entration range of 0.002-0.02%.Disodium edetate (0.1%) is usuallyadded to enhance antibacterial activityagainstPseudomonas spp.

When benzalkonium chloride hasbeen used as a preservative innebulised solutions of anti-asthmaticagents,it has been reported to causebronchoconstriction and was assoc-iated with the precipitation of arespiratory attack? 10. II

In nasal sprays this product canexacerbate rhinitis and it can induceirritation or keratitis in eyepreparations.It isworth noting that these propertiesare not peculiar to benzalkonium andthey could be manifest by other pres-ervatives. It is advisable,therefore, toavoid the useof benzalkoniumchloridein paediatric products especiallyin anti-asthmapreparations." Potentialsourcesof benzalkonium in products forchildren with asthma and concurrentsinusitis include nasal saline, nasalcorticosteriods and nasaldecongestantsolutions.

Chlorobutanol (Chlorbutol)Chlorobutanol has antibacterial andantifungalproperties and it is used at apreservative concentration of 0.5% ininjections and in eye drops. Patientswho were given high doses ofsalicylamide or morphine infusionspreserved with chlorobutanol showedchlorbutol-induced somnolence. '3.14

A delayed cellular type of hyper-sensitivity reaction to chlorbutol usedto preserve heparin when it was givenby subcutaneous injection, has alsobeen reported."

Chlorobutanol should not be usedtopreserve injectable preparations thatare intended for neonatesand children.Eye drops, nasal and dentalpreparations may be preserved withchlorobutanol especially where theirsedativeand analgesicproperties are ofadvantage.

Cumulative intake ofpreservativesThe cumulative or concomitant intakeof preservatives from multiple drugtherapy given to neonatesand children,should be calculated.The very ill neo-nates and premature babies,especiallythose with kernicterus or conditionspredisposing to hyperbilirubinaemia,should not be given productscontaining parabens,at least until theircondition resolves.

ConclusionThere is considerable risk associatedwith the extemporaneous preparationof pharmaceutical products especiallythose meant for use in neonates andyoung children.

Pharmacistsmust assessthese risksand make efforts to transfer extempproducts to batch manufacture. Thistransition will involve formulation study,scale-up and stability surveillance.Adequate information must also besought on all formulation ingredientssothat the problems of incompatibilityand toxicity to patients canbe resolvedbefore formulation.

We recommend that chloroformshould not be usedasa preservative inmedicines that are intended for use inchildren becauseof its toxicity.The nextedition of the British Pharmacopoeiashould consider this recommendationand delete chloroform from the list ofpreservatives allowed for inclusion indrug preparations intended for humanconsumption.There are other, equallyeffective and lesstoxic, alternatives.

Parabensand benzyl alcohol can beused as preservatives in childrens'medicines, but should be used withcaution in children with jaundice.Nebulised solutions for asthmatic

patients should not be preserved withbenzalkonium chloride and injectionsintended for neonates should notcontain chlorbutanol. However,chlorbutanol is usefulaspreservative ineye drops, nasal and dental pre-parations where their sedative andanalgesic properties may be anadvantage.

To improve the delivery of a prof-essional pharmacy servrce, werecommend mandatory labelling of allinactive ingredients such as preser-vatives in all formulations.This must beincluded on the packagingmaterials ofall prescription and over the counterdrugs, whether produced extempor-aneously or commercially This wouldfacillitate an evaluation of the risksassociated with specific formulationingredients and thus speed up thedecision-making process on thesuitability of medications for neonatesand children.

AcknowledgementThe authors are grateful to all theLondon region NHS pharmacymanufacturingunits that participated inthe survey.

ReferencesI. Gershanik JJ, Boeder B, George W, Sola A,_

Leitner M. KapadiaC.The gaspingsyndrome:benzyl alcohol poisoning? Clin Res 1981;29;895A.

2. Brown WJ, Buist NR, Gipson HT, Huston RK,KennawayNG. Fatal benzyl alcohol poisoningin a neonatal intensive care unit. Lancet 1982;

I: 1250.3. Anderson ON, Ng Kj,Andresen B,Cordera L

Benzylalcohol poisoning in a premature newborn infant Am J Obstet Gynecol 1984; 148:344-6.

4. Ahlfors CEoBenzyl alcohol, kernicterus andunbound bilirubin. Journal of Pediatrics 200 I ;139: 317-9.

5. Woods D. The safety of antimicrobialpreservatives in oral liquids for neonates.

New Zealand Pharmacy 1996;4: 22.6. Rasmussen LF, Ahlfors CE, Wennberg. The

effects of paraben preservatives on albuminbinding of bilirubin. journal of Pediatrics 1976;89: 475-8.

7. Woods JT. Bryan LE, Chan G, Sciff D.Gentamicin and albumin-bilirubin binding -

PHARMACYin Practice Original research

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

8. Hindmarsh KW. John E,Asali LA, French IN,Williams GL, McBride WG. Urinary excretion

of methylparaben and its metabolites inpreterm infants. Joumal of Pharm Sciences1983; 72: 1039-41.

9. Boucher M Roy MT. Henderson J. Possibleassociation of benzalkoniun chloride innebuliser solution with respiratory arrest. AnnPharmacother 1992; 26: 772-4.

I O. Beasley CR Rafferty P. Holgate S. Benz-alkonium chloride and bronchoconstriction.Lancet 1986 ij: 1227.

I I. Beasley CR. Rafferty P. Holgate ST.Broncho-constrictor properties of preservatives inipratropium bromide (Atrovent) nebulisersolution. 8MJ 1987: 294: I 197-8.

12.Excipients:Review of adverse reaction. WHOPharmaceutical News Letter. November-December 1998.

13.Borody T Chinwah PM, Graham GG, WadeON, Williams KM. Chlorbutol toxicity and

dependence.Med J Aust 1979; I: 288.14.DeChristoforo R Corden BJ,Hood JC Narang

PK,Magrath IT High-dose morphine infusioncomplicated by chlorobutanol-induced somn-olence. Annals of Internal Medicine 1983; 98:335-6.

15.Dux 5 Pitlik S, Perry G, Rosenfeld JB.Hypersensitivity reaction to chlorbutanol-

preserved heparin. Lancet 1981; i: 149.

Olufemi Rabid *, technical R&Dmanager, Paul Forset, productionmanager, Sanjay Pate?, senior asepticservices pharmacist

* Corresponding authorDepartment of Pharmacy. Guys and StThomas' Hospital Trust, LambethPalace Road. London, Sf I 7fH

We will be very pleased to recievereaders' views on this and other articlein Pharmacy in Practice. These may beemailedto:pip@medicomgroup.com

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ACE inhibitors.fibrates. fluoxetine. salicylatas and sulphonamide antibiotics.Substances that may reduce the blood·glucose-Iowering effectinclude 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 hlood-glucose-Jowering effect of iilSujlh. Under the inilu.ence ofsympatholytic medicinal products the ,Signs of alldrenergiccounter·regulation may be reduced or absent Pregnancy BndLactation: No clinical data O(l flXllOSedpregnancies are available.Lactating women may require adjustinents in insulin dose anddiet. Advel1le Reactions: Hypoglycaemia may occur if the insulindose is too high in relation to requirement. A marked change inglycaemlc COntrol may cause temporary visual impairmentalthough long term improved glycaemic control decreases therata of prlll!ression of diabotic retinop_athy. UpOlIystroplly mayoccur 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~ skinr!lllctlons. angio·oedema. bronchospasm. hypotension and shock-and may be life threatening, Insulin administrntion may causeinsulin antibodies to form and may. in fare cases, necessitateadjustment of tile insulin dose. Insulin may. rarely, cause sodi.umretention and oedema, Overdose may lead to severe and.sometimes long·te.rm and IIle threatening hypoglycaemifl. Mild'episodes can usually be treated with pral carbohydrates. Motesevere episodes mav-be treated with iQualllJ.)SCular/subcutaneousglucagon or conr;entJaied intravenous glucose. PhannaceujjcalPrecautions:.Store unopened cartridges/vials/OptiSet pens at2·8"C. 00 not freeze.. O~oeopened do not. store above 25'C and.US8. within 4 wee~s. Do not refrigerate OptiSet pen once.in·us8.0.rOptiPen·Pro® 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!IICategory: POM. Marketing Authorisation Numbers: MarketAuthorisation Holder Aventis Plmrma Deutschland GmbH, 0-65926Frankfurt am Main. Germany. Lantus 100 IU/ml solution forinje,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 flbA1cwith Insulln'Glargine t Insulin Lispro in Comparison with NPHInsulin +Unmodified Homan Insulin in People with Type 1 Diabetes.Clinical TherapeuliCS/New TactmoIIll!Y. Abstract 1914-1'0 andposter presented at 6311lAmerican DIabetes Association AnnualMeeting. Now Orleans. June 13th·17th.Z003. 2.. Riddle Me.Rosenstock J. Gerich J. The treat·to-targst trial: randomizedaddition of glargine or human NPH inslilin to qral therapy forlype 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