Prescribing and sale of ophthalmic chloramphenicol following reclassification to over-the-counter...

Prescribing and sale of ophthalmic chloramphenicolfollowing reclassification to over-the-counter availabilityijpp_46 269..274

Roger Walkera,b and Anne Hinchliffea

a Public Health Wales, Temple of Peace and Health and b Welsh School of Pharmacy, Cardiff University,Redwood Building, Cathays Park, Cardiff, UK

Abstract

Objectives The impact of over-the-counter (OTC) availability of chloramphenicol eyedrops and eye ointment was investigated on the prescribing and overall supply of ophthalmicchloramphenicol in primary care.Methods Primary care prescription data for ophthalmic chloramphenicol and ophthalmicantibacterials in England and Wales were analysed from December 2003 (month 1) toSeptember 2008 (month 58). OTC data were analysed from June 2005 when the first OTCproduct was launched (months 19 to 58).Key findings In the 40 months following reclassification more than 2.9 million packs(53.9 per 1000 population) of chloramphenicol were sold in England and 152 024 (51.7 per1000 population) in Wales. In the 12 months to September 2008 sales of the drops andointment were 67 and 40% of their respective prescription volumes in England. In Walessales of drops were 52% and ointment 26% of their respective prescription volumes. Thenumber of chloramphenicol packs sold was 2.2 times greater than the calculated reductionin ophthalmic antibacterial prescription items in England and 2.9 times greater than thereduction seen in Wales.Conclusion Following the reclassification of chloramphenicol there have been significantincreases in the supply of the ophthalmic antibacterials in both England and Wales.Keywords chloramphenicol; conjunctivitis; over-the-counter; pharmacosurveillance

Introduction

Chloramphenicol is a broad-spectrum antibiotic that was introduced into clinical practice in1948 and has been widely used by the topical, oral and parenteral routes. Administration bythe oral or parenteral route is now reserved for life-threatening conditions because of the riskof serious haematological side effects such as reversible and irreversible aplastic anaemia.[1]

Chloramphenicol continues to be widely used when administered by the topical route and iscurrently the drug of choice for the treatment of bacterial conjunctivitis.[1] Along with othertopical antibiotics it has been shown to be of benefit and improve early (days 2–5) clinicaland microbiological remission in bacterial conjunctivitis.[2] This effect, although diminished,persists at days 7–10 and has been interpreted to indicate that early treatment with chloram-phenicol may reduce the risk of transmission, permit an earlier return to work, school orchildcare as appropriate, and reduce secondary infections.

In June 2005 chloramphenicol eye drops were reclassified in the UK from a PrescriptionOnly Medicine (POM) to Pharmacy (P) status for the treatment of bacterial conjunctivitis.This reclassification, which thereby allowed sale of the eye drops over the counter (OTC)from community pharmacy, occurred after widespread consultation with professionals andthe public and despite a number of objections.[3] Among the objections were concerns aboutthe appropriateness of the training of pharmacists, the risk of misdiagnosis, safety, thelikelihood of overuse and the emergence of increased resistance. Overall, those in favour ofthe reclassification considered any risk to be minimal and more than offset by improved andtimely access for patients. In July 2007 chloramphenicol eye ointment was also reclassifiedto P status.

We have previously undertaken a preliminary investigation of the use of OTC chloram-phenicol in Wales.[4] In the present study we have quantified the sales of OTC chlorampheni-col in England and Wales and investigated whether OTC availability had an impact onprescriptions for ophthalmic chloramphenicol.

Research Paper

Correspondence: Roger Walker,Consultant in PharmaceuticalPublic Health, Public HealthWales, Temple of Peace andHealth, Cathays Park, Cardiff,CF10 3NW, UK.E-mail: roger.walker@wales.nhs.uk

Methods

The study had an ecological design and involved a retrospec-tive analysis of primary care prescription data for the periodDecember 2003 (month 1) to September 2008 (month 58) andOTC sale data from June 2005 (month 19) to September 2008.

Data for ophthalmic antibacterials (British National For-mulary section 11.3.1) and chloramphenicol preparations (eyedrops and eye ointment) supplied on prescription in Englandand Wales were obtained from the Prescription PricingAuthority and Health Solutions Wales, respectively. Thenumber of packs of chloramphenicol-containing OptrexInfected Eyes, Galpharm Vision, Brochlor and Golden Eyeophthalmic drops and ointment along with propamidine- anddibromopropamidine-containing ophthalmic preparationssupplied through 8640 out of 9712 (89%) and 622 out of 714(87%) community pharmacies in England and Wales, respec-tively, were obtained from IMS Health.

The volumes of chloramphenicol eye drops or ointmentprescribed or sold OTC are presented as the total number ofitems supplied over each 12-month period together with themedian (and interquartile range, x, y) for the componentmonths. Data were standardised per 1000 patients using 2006mid-year population estimates[5] to allow comparison betweenEngland and Wales. The Mann–Whitney U test was used toexplore year-on-year changes in prescribing and determinethe impact of the availability of OTC chloramphenicol eyedrops (marketed June 2005) and ointment (marketed July2007) on respective prescription volume.

Linear regression was used to predict the number and rateof prescriptions for all ophthalmic antibacterials (chloram-phenicol, ciprofloxacin, fusidic acid, gentamicin, levofloxa-

cin, neomycin, ofloxacin and polymyxin B sulphate)dispensed at month 58 of the study using the equationy = a + bx, where a is the intercept on the y axis, b is theregression coefficient and x is the number of study months(i.e. 58). The regression model was based on the quantitiesprescribed in the first 18 months of data collection (December2003 to May 2005), the period prior to the launch of OTCchloramphenicol, and used to predict prescription rates atmonth 58. Statistical analyses were performed using SPSSversion 14 (SPSS, Chicago, IL, USA).

Results

The number of prescription items dispensed each month forophthalmic chloramphenicol from December 2003 to Septem-ber 2008 showed similar trends in England and Wales(Figure 1). In both countries there was a marked seasonalvariation for chloramphenicol eye drops with a peak each yearbetween January to March and a nadir in August to October.Between the peak and nadir a steady decline was interruptedeach year in May or June by a transient increase in prescrib-ing. A seasonal variation was also observed with OTC sales ofchloramphenicol eye drops with a peak in May or June eachyear and a nadir in August to November The seasonal varia-tion for both prescribing and OTC sales of chloramphenicoleye ointment was less marked.

In each complete calendar year for 2004, 2005, 2006 and2007 the numbers of prescriptions for chloramphenicol oint-ment were significantly lower than prescriptions for eye dropsin both England (47, 50, 44 and 50% lower, respectively; allP < 0.0001) and Wales (31, 35, 31 and 41% lower, respec-tively; all P < 0.0001). OTC sales of chloramphenicol eye

Jul-04

Jul-05

Jul-06

Jul-07

Jul-08

Wales eye drops Wales ointment England eye drops England ointment

Figure 1 Items of chloramphenicol eye drops and ointment prescribed in primary care in Wales and England.

270 International Journal of Pharmacy Practice 2010; 18: 269–274

ointment were also lower than sales of the eye drops (72%lower in England and 69% lower in Wales, for the 12-monthperiod October 2007 to September 2008; both P < 0.0001).

By month 58 of the study, chloramphenicol eye drops hadbeen available OTC for 40 months and the ointment for 15months. During this 40-month period 2 941 118 (53.9 per1000 population) OTC packs of chloramphenicol were sold inEngland and 152 024 (51.7 per 1000 population) packs sold inWales. In the final 12 months for which data were available(October 2007 to September 2008) sales of OTC chloram-phenicol eye drops in England were equivalent to 67%(864 350/1 287 063) of the prescription volume with sales ofthe ointment at 40% (245 438/610 790) of their respectiveprescription volume. In Wales, sales of chloramphenicol eyedrops were 52% (42 194/81 005) of prescription volume withsales of the ointment at 26% (12 939/49 069). Despite thevolume of these sales, no significant change was observed in

the year on year figures from 2004 to 2007 for the number ofprescriptions dispensed per 1000 population for chloram-phenicol eye drops or ointment in either England or Wales(Table 1).

The cumulative number of prescriptions dispensed orpacks sold for chloramphenicol eye drops or ointment fromDecember 2003 to September 2008 are presented for England(Figure 2) and Wales (Figure 3).

When the actual number of prescriptions for all oph-thalmic antibacterial prescriptions dispensed over the58-month study period was compared with that predictedfrom the first 18 months of data (R2 = 0.998) the observedvalues were 8.6 and 5.7% less than predicted in England andWales, respectively. Comparison of the number of OTCchloramphenicol packs sold with the apparent reduction inprescribed ophthalmic antibacterial items revealed that thenumber of OTC chloramphenicol packs sold was 2.2 times

Table 1 Number of ophthalmic chloramphenicol prescriptions dispensed per 1000 population (median [interquartile range]) in Wales and England

Wales England

Drops Ointment Drops Ointment

2004 2.05 (1.80, 2.20) 1.40 (1.35, 1.48) 2.51 (2.10, 2.79) 1.33 (1.25, 1.39)2005 2.19 (1.80, 2.54) 1.42 (1.38, 1.49) 2.52 (1.88, 3.11) 1.26 (1.18, 1.38)

P = 0.371* P = 0.56* P = 0.91* P = 0.18*2006 2.07 (1.80, 2.20) 1.44 (1.38, 1.46) 2.11 (1.77, 2.40) 1.19 (1.13, 1.26)

P = 0.507* P = 0.73* P = 0.17* P = 0.08*2007 2.26 (2.11, 2.30) 1.36 (1.14, 1.52) 2.20 (1.94, 2.32) 1.10 (0.95, 1.25)

P = 0.083* P = 0.44* P = 0.91* P = 0.17*

*Comparison of prescriptions dispensed with previous year.

Jul-04

Jul-05

Jul-06

Jul-07

Jul-08

Prescribed chloramphenicol eye ointment Prescribed chloramphenicol eye drops OTC chloramphenicol drops OTC chloramphenicol ointment

Figure 2 Cumulative prescribed and OTC sales of chloramphenicol eye drops and ointment in England.

Prescribing and sale of ophthalmic chloramphenicol Roger Walker and Anne Hinchliffe 271

(2 941 118/1 336 879) greater than the calculated reductionin prescription items in England and 2.9 times (152 024/52 277) greater than the reduction seen in Wales.

Prior to the availability of OTC chloramphenicol theonly ophthalmic anti-infectives available for sale werepropamidine- and dibromopropamidine-containing eye dropsand ointment. During the first 12 months following the launchof OTC chloramphenicol there was a 26% reduction (equiva-lent to 83 551 packs) in combined sales of propamidine anddibromopropamidine in England. This compared with a 28%reduction (13 336 packs) in Wales. In the 12 months toSeptember 2008 combined sales of propamidine- anddibromopropamidine-containing ophthalmic preparations inEngland were 83% (197 280/237 799) of pack sales in 2005,a reduction of 40 519 packs per year. In Wales, sales in the 12months to September 2008 were 93% (31 872/34 292) of the2005 figure, a reduction of 2420 packs per year.

Discussion

Main findingsThis is the first study to examine in detail the impact of thereclassification of ophthalmic chloramphenicol on prescribingand OTC supply in England and Wales. The results indicate amarked increase in overall use against a backdrop where totalprescription use of chloramphenicol appeared, year on year, toremain steady. Attempts to justify the additional quantity ofOTC chloramphenicol sold on the basis that there was aswitch from other prescribed ophthalmic antibacterials orOTC ophthalmic preparations, such as propamidine- ordibromopropamidine-containing preparations, failed to

explain the increase in sales. More than 1.4 million additionalpacks of antibacterial eye drops and ointment were supplied inEngland and more than 90 000 extra packs were supplied inWales in the 40 months after chloramphenicol became avail-able OTC.

LimitationsPrior to the reclassification of chloramphenicol there wereconcerns that OTC availability would result in excessive andinappropriate use and increase antibiotic resistance. In thepresent study we did not assess whether sales were appropri-ate, nor investigate resistance to chloramphenicol.

Prescribing data for England and Wales was comprehen-sive and included NHS prescriptions dispensed by all phar-macies or dispensing doctors in primary care. In contrast, theOTC data were only available for 89 and 87% of communitypharmacies in England and Wales, respectively, and conse-quently the OTC data presented in this study are an underes-timate of the overall supply picture.

Unlike prescribing data, which are a measure of dispensedprescriptions, the OTC data utilised were for the purchase ofstock by pharmacies rather than sale to customers. Thus phar-macy buy-in data are assumed to be a good proxy for sales incommunity pharmacy due to their limited storage facilitiesand need to optimise turnover of stock to facilitate cash flow.The OTC data could have been skewed if pharmacies hadbeen offered a particularly good purchasing deal at any pointduring the year or had made advanced bulk purchases topredict an increase in demand ahead of a seasonal outbreakand/or an advertising campaign. However, the available datadid not support the occurrence of either of these scenarios.

OTC chloramphenicol drops 0.5% OTC chloramphenicol ointment Prescribed chloramphenicol eye drops 0.5% Prescribed chloramphenicol eye ointment

Figure 3 Cumulative prescribed and OTC sales of chloramphenicol eye drops and ointment in Wales.

In the data analysis prescribed quantities were presented asprescription items whereas the unit for OTC data was a pack.OTC pack sizes of chloramphenicol eye drops and ointmentwere 10 ml and 4 g, respectively. Although prescribers canrequest more than one pack on a prescription, a single pack isthe norm (mean amounts supplied per prescription item inWales between October 2007 and September 2008 were10.3 ml and 4.2 g, respectively). Our assumption that a singlepack was issued for each prescription item may have affectedthe results but we consider the likely impact small.

The ecological nature of the study meant we were unableto clearly identify the factors driving the significant increasein ophthalmic chloramphenicol observed nor were we able todetermine whether prescribing or OTC sales of ophthalmicchloramphenicol were appropriate. The launch of some OTCophthalmic chloramphenicol preparations has been accompa-nied by advertising and this is likely to have raised publicawareness and promoted sales. The increase in demand forchloramphenicol may have been appropriate and could haveinvolved use by individuals with bacterial conjunctivitis whohad previously managed without chloramphenicol. This addi-tional usage may have resulted in reduced spread to others andearlier recovery of symptoms. However, there are also anec-dotal reports of patients with sore, but not infected, eyesseeking to purchase ophthalmic chloramphenicol. In suchsituations the pharmacist plays an important role in refusinginappropriate sales. The extent to which the apparent, addi-tional demand for chloramphenicol demonstrated in this studyrepresents previously unmet need, as opposed to inappropriateuse, requires further research.

What is already known on this topicConjunctivitis is one of the most frequent ocular problemsseen in the community and is usually caused by viral orbacterial infection of the eye following an upper respiratoryinfection.[6] The variation in demand for chloramphenicol eyedrops throughout the year corresponded to the winter coughand cold season and the spring/early summer allergy season.The results of this study also demonstrated a preference forchloramphenicol drops over ointment, which was not surpris-ing as the ointment is considered more likely to cause tempo-rary blurring of vision than the drops and therefore less likelyto be used during the day.

Published studies that track sales of a medicine followingreclassification from prescription only status to pharmacysales in the UK are limited. Presumably this has arisenbecause the UK National Health Service does not have readyaccess to OTC data, although it can be purchased from com-panies such as IMS Health. This lack of post-reclassificationdata appears to be a weakness of the current reclassificationprocess and needs to be addressed, particularly where prod-ucts with a significant public health dimension, such aschloramphenicol, are involved. Of the studies published, Ryanand Yule[7] explored changes in prescribing following thereclassification of both oral loperamide and hydrocortisone1% cream to OTC status and found no reduction in prescrip-tion numbers. Similarly, Dhippayom and Walker[8] investi-gated the impact of the reclassification of omeprazole andfound no impact on prescribing rates of ulcer-healing drugs.

In both studies OTC sales were a small percentage ofprescription volume and therefore unlikely to impact on pre-scription volume. In the present study the scenario is some-what different given the high volume of sales compared toprescription volume and the high, overall, volume of use.

What this study addsThe present study has demonstrated a substantial growth inthe market for ophthalmic chloramphenicol preparations fol-lowing reclassification, and has quantified that growth. Thismarket growth could not be explained by patients switchingfrom the prescribed to OTC supply route or from an alternateOTC ophthalmic anti-infective preparation.

Whereas increasing the range of medicines available OTCforms part of Government strategy[9] to increase self-care,improve access and reduce demand on the National HealthService, post-reclassification monitoring is a neglected area ofstudy. This study highlights the need to routinely monitorsales following reclassification in a more systematic waygiven the escalation in use of chloramphenicol observed.

ConclusionFollowing the reclassification of ophthalmic chloramphenicolthere was a marked increase in OTC supply. This increasecould not be accounted for by a corresponding reduction inprescriptions for ophthalmic antibacterials or a switch fromanother OTC anti-infective agent. Overall 1.5 million extrapacks of ophthalmic chloramphenicol were supplied inEngland and Wales during the first 40 months followingreclassification.

Declarations

Conflicts of interestThe Author(s) declare(s) that they have no conflicts of interestto disclose.

FundingThis research received no specific grant from any fundingagency in the public, commercial or not-for-profit sectors.

AcknowledgementsWe are grateful to Marilyn Meecham for data extraction andmanipulation, Isabel Puscas for library service support andIMS Health for OTC data supply.

References1. Martin J. British National Formulary, 57th edn. London: British

Medical Association, Royal Pharmaceutical Society of GreatBritain, 2009.

2. Sheikh A, Hurwitz B. Topical antibiotics for acute bacterialconjunctivitis. Cochrane systematic review and meta-analysisupdate. Br J Gen Pract 2005; 55: 962–964.

3. Medicines and Healthcare Products Regulatory Agency.The reclassification of chloramphenicol eye drops. ARM25. 2004. http://www.mhra.gov.uk/Publications/Consultations/Medicinesconsultations/ARMs/CON007689 (accessed 13 April2010).

Prescribing and sale of ophthalmic chloramphenicol Roger Walker and Anne Hinchliffe 273

4. Walker R, Hinchliffe A. Impact of the reclassification of chloram-phenicol eye drops and ointment on prescriptions for chloram-phenicol. Int J Pharm Pract 2009; 17: B67–B68.

5. Office of National Statistics. Population estimates mid-2006UK, England and Wales, Scotland and Northern Ireland. 2007.http://www.statistics.gov.uk/statbase/Product.asp?vlnk=15106(accessed 13 April 2010).

6. Denniston A, Murray P. Oxford Handbook of Ophthalmology.Oxford: Oxford University Press, 2006.

7. Ryan M, Yule B. Switching drugs from prescription only to over-the-counter availability; economic benefits in the UnitedKingdom. Health Policy 1990; 16: 233–239.

8. Dhippayom T, Walker R. Impact of the reclassification of ome-prazole on the prescribing and sales of ulcer healing drugs. PharmWorld Sci 2006; 28: 194–198.

9. Department of Health. Building on the Best: Choice, Responsive-ness and Equity in the NHS. London: Department of Health,2003.

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