Abstract
- Every year, Prescrire's analysis of drug packaging confirms the importance of taking packaging into account in assessing a drug's harm-benefit balance.
- Safe, tried and true options are available, yet the quality of most of the drug packaging Prescrire examined in 2011 left much to be desired.
- Few of the packaging items examined help prevent medication errors and many actually increase the risks: misleading and confusing labelling, dosing devices that create a risk of overdose, bottles without a child-proof cap, and inadequate or dangerous patient information leaflets. Umbrella brands continue to expand and are a potential source of medication errors.
- Some patients are at greater risk: the patient leaflets for NSAIDs endanger pregnant women and their unborn babies; children are insufficiently protected by paediatric packaging and are at risk due to the lack of child-proof caps on too many bottles.
- The raft of regulatory measures taken by the French drug regulatory agency (Afssaps) in the aftermath of the Mediator° disaster overlooked the importance of packaging.
- Until drug regulatory agencies tackle the vast issue of drug packaging, it is up to healthcare professionals to protect patients from harm.
Patients need to have easy access to high quality care. Drug packaging represents one aspect of quality care. Every year, Prescrire publishes a review of its systematic analyses of the packaging of the drugs examined in its “New Products” section (a). These analyses regularly lead us to issue warnings, when we identify packaging items that are a potential source of medication errors or serious incidents, although safe, tried and true options are available.
What is Prescrire’s verdict on the quality of the packaging it examined in 2011?
High quality drug packaging exists
Tablets and capsules account for three-quarters of the pharmaceutical market. All that is required to package them correctly are: a brand name that includes the international nonproprietary name (INN); plain and effective labelling in which the INN and dose strength are given adequate prominence and not overshadowed by superfluous graphics; single-unit blisters, i.e. each blister pocket is labelled with the INN, dosage form, dose strength, batch number and expiry date, and is pre-cut, with each unit dose still fully labelled after separation; and a clear patient leaflet.
In 2011, only one of the medicinal products we examined satisfied all of these criteria: Mexilétine AP-HP° (mexiletine) (Rev Prescrire n° 330).
A few interesting examples. Single-unit blisters make it possible to clearly identify each tablet, e.g. sirolimus 0.5 mg - Rapamune° (Rev Prescrire n° 336), amlodipine + telmisartan - Twynsta° (Rev Prescrire n° 335) and bilastine - Bilaska°, Inorial° (Rev Prescrire n° 338).
Some blister packs are sealed with a safety film, making it difficult for young children to gain access to the tablets or capsules inside the blister pockets, e.g. miglustat - Zavesca° (Rev Prescrire n° 328) and bosentan 32 mg - Tracleer° (Rev Prescrire n° 329).
The outer surface of the medicated plaster lidocaine - Versatis° (Rev Prescrire n° 330) is directly labelled with its INN and dose strength: a rare but welcome feature.
The INN progesterone is displayed in a central position in large lettering on the front of the outer packaging of the brand-name generic drug Progestan° (Rev Prescrire n° 333). Several generic manufacturers have made a similar effort (b).
The outer packaging also sometimes displays useful warnings. For example, the outer packaging of the oral immunosuppressant methotrexate - Novatrex° (Rev Prescrire n° 331) has a centrally positioned warning that the drug is not to be taken every day. The message is repeated on the bottle cap, which unfortunately is not child-proof.
Only a minority of multidose bottles containing oral liquid formulations have a child-proof safety cap, e.g. valsartan - Tareg° (Rev Prescrire n° 338) and paracetamol - Doliprane°, Dafalgan° (Rev Prescrire n° 334).
Several improvements. We noticed several improvements in 2011: ustekinumab - Stelara° (Rev Prescrire n° 327) now only comes in prefilled syringes with a needle stick protection device, rather than in bottles; terlipressin - Glypressine° is now available as a ready-to-use solution as well as in the form of a bottle of powder + solvent (Rev Prescrire n° 328); ritonavir - Norvir° tablets can be stored at room temperature, so are more convenient than the older capsules that required refrigeration (Rev Prescrire n° 331); the etonogestrel implant - Nexplanon° comes with an applicator for easier, safer insertion and is also easier to locate for removal (Rev Prescrire n° 332); more prefilled syringes containing injectable drugs are equipped with a needle stick protection device, e.g. darbepoetin alfa - Aranesp° and pegfilgrastim - Neulasta° (Rev Prescrire n° 333) and dalteparin - Fragmine° 2500 IU and 5000 IU (Rev Prescrire n° 335); the first somatropin multidose prefilled pen - Norditropine Nordiflex° (Rev Prescrire n° 335) is a ready-to-use option (but must be refrigerated).
Other improvements are only relative. The ready-to-use solution and prefilled syringe forms of omalizumab - Xolair° (Prescrire Int n° 121) are more convenient than the former bottle of powder + solvent, but should still be avoided due to the drug's unfavourable harm-benefit balance. Romiplostim - Nplate° (Rev Prescrire n° 332) now comes with the devices required for its preparation, but the labelling of its dose strength remains a potential source of confusion.
Identify misleading and confusing labelling before errors occur
The usual labelling flaws were particularly pronounced in 2011.
INNs absent or barely legible. The INN is a drug's true name, yet it was not mentioned on the labelling of several blister packs: racecadotril - Diarfix° (Rev Prescrire n° 328); meprobamate + aceprometazine - Mépronizine° (Rev Prescrire n° 333) until its withdrawal from the French market in January 2012; quinine + thiamine - Hexaquine° (Rev Prescrire n° 337) (c); Timothy grass (Phleum pratense) pollen extract - Grazax° (Rev Prescrire 328). The single-dose containers of levocabastine - Levofree° eye drops only display the brand name, in lower-case lettering, which can be rubbed off with a finger (Rev Prescrire n° 328).
When the INN is present (which is mandatory), it is commonly not given adequate prominence: it is barely legible on the embossed, shiny film of the blister pack of the ethinylestradiol + levonorgestrel generic Lovavulo° (Rev Prescrire n° 327), and printed in tiny lettering on the blister pack of tianeptine - Stablon° (Rev Prescrire n° 337) and Actifedsign° (paracetamol + chlorphenamine + vitamin C) (Rev Prescrire n° 338). On some outer packaging, the INN is printed underneath the brand name as if simply to underline it, e.g. isothipendyl - Apaisylgel° (Rev Prescrire n° 335), injectable cloxacillin - Orbénine° (Rev Prescrire n° 336) and mequitazine - Primalan° (Rev Prescrire n° 337).
Sometimes the INN and dose strength are difficult to read due to insufficient contrast with the background: yellow print on the aluminium film of blisters containing octreotide 0.1 mg - Siroctid° (Rev Prescrire n° 332); pale pink on white blisters containing morniflumate suppositories - Nifluril Enfants° (Rev Prescrire n° 336); white print against a yellow background for paracetamol oral solution - Dolko° (Rev Prescrire n° 334).
INNs printed separately from dose strengths. Most labelling conforms to a layout that separates the INN from its dose strength, in accordance with regulations. For example, the box and bottle of Daivobet° (Rev Prescrire n° 331) display the following information, from top to bottom:
- the brand name;
- the dose strength as "50 micrograms/0.5 mg/g";
- the term "gel";
- then the INNs "calcipotriol/betamethasone".
Yet it would be more logical and, more importantly, less conducive to medication errors if each INN were displayed next to its dose strength. In the example cited above: "calcipotriol 50 micrograms/g" and "betamethasone 0.5 mg/g".
Stickers to warn users of a change: advantages and limitations. In 2011, changes were made to the marketing authorisations (MAs) for injectable oxacillin - Bristopen° (Rev Prescrire n° 336) and mequitazine - Primalan° (Rev Prescrire n° 337). In the first case, intramuscular administration was no longer authorised; in the second, the drug was no longer available without a prescription. The outer packaging examined had already been manufactured at the time of the MA variation; therefore, the new information was added to the boxes in the form of a sticker. However, the contents of the boxes, the internal labelling and patient leaflet were not modified, creating a risk of error due to contradictory information. It is imperative that all packaging items be rapidly updated after changes in the marketing authorisation. If it would compromise access to the drug in the short term to withdraw batches that were manufactured before the variation or that are already stocked in pharmacies, measures to modify the packaging already present on the market must be comprehensive: all of the outer and inner labelling must be amended and an up-to-date patient leaflet provided.
Dangerous proliferation of pictograms and dosing schedules. Colokit° tablets of sodium phosphate salts are used to cleanse the bowel before a colorectal investigation. The patient leaflet includes a comprehensive, detailed dosing schedule (see footnote a on page 133) explaining when to administer the 8 doses, each consisting of 4 tablets taken with 250 ml of water, i.e. 32 tablets in total. Taking the tablets with a large volume of water is crucial, because the drug can cause renal damage and sometimes fatal electrolyte disturbances. However, the outer packaging shows a different dosing schedule, consisting of only 2 dose squares along with some other information. Users who read this dosing schedule but not the patient leaflet could take the wrong number of tablets at the wrong frequency, potentially resulting in an overdose (Rev Prescrire n° 329).
In 2011, Pérubore° tablets for inhalation (essential oils of lavender, rosemary and red thyme + thymol) (2 tablets per dose) were replaced by capsules containing twice the dose (1 capsule per dose). The small dosing schedule on the outer packaging of Pérubore° for inhalation (Rev Prescrire n° 335) has an illustration of 2 capsules and a pair of scissors. It is not readily obvious that the 2 capsules are separated by the word "or" in small print that barely stands out against the background. The 2 capsules actually illustrate 2 alternative preparation methods: either the capsule is placed in hot water, or the tip of the capsule is cut and its contents poured into the water. Patients who had previously been using 2 tablets could be confused by this dosing schedule and use 2 capsules, resulting in an overdose.
The pictogram on the single-dose containers of cutaneous chlorhexidine - Septidose° (Rev Prescrire n° 336) shows a row of 4 boxes in increasingly lighter shades of green. The first shows a large-headed child of indeterminate age, the second probably represents an adult, the third depicts two superimposed single-dose containers, and the fourth is empty. What is the intended message? The drug company could have made better use of this space by increasing the INN and route of administration on the labelling, in order to prevent confusion with the plethora of similar single-use containers marketed for use in babies, including hygiene products and physiological saline. Dangerous errors involving these types of containers have already occurred, in which the wrong route of administration was used (Rev Prescrire n° 284 and n° 326).
Dosing schedules and pictograms are used to convey complex information. It would be better to reserve their use for essential messages and to conduct comprehension tests among patients and pharmacists before they are displayed on marketed products.
Umbrella brands: a growing problem. Medicines containing very different active ingredients can be marketed under the same umbrella brand. Their packaging includes prominent graphics designed to be easily recognisable by users. But these graphics make very different medicines look alike, with the potential for confusion and medication errors. Umbrella brands gain ground every year, for example the "Doli" product line, which expanded again in 2011 (Rev Prescrire n° 331) as well as the Vicks product line (Rev Prescrire n° 338).
Some cold remedies are authorised when a number of symptoms coexist, such as fever, nasal discharge, headache and watery eyes. But these symptoms are sometimes mentioned separately on the front of the box, as optional alternatives. For example, the labelling on the boxes of Actifed états grippaux° (Rev Prescrire n° 332) and Actifedsign° (Rev Prescrire n° 338) (paracetamol + chlorphenamine + vitamin C) implies that these medicines are suitable for the treatment of an isolated symptom, such as fever. However, in this case, paracetamol alone would be a more appropriate choice.
Oxomemazine of the Humex° product line (Rev Prescrire n° 337) is a shocking example of inappropriate, umbrella-brand packaging. This phenothiazine antihistamine syrup is marketed in a bottle without a child-proof cap. The box contains a measuring cup, a dosing device known in practice to carry a risk of overdose. The outer packaging and bottle show a caramel liquid that resembles a creamy dessert. The term "night-time" is prominently displayed next to a moon on a midnight blue background. It is easy to assume that this is a treatment for insomnia, yet that is not its approved indication.
The graphics on the box of the antihistamine niaprazine - Nopron° were amended after the French drug regulatory agency noticed a starry, midnight blue sky that trivialised the use of an antihistamine in childhood insomnia (Rev Prescrire n° 243).
No outer packaging: a trend to be monitored
The outer packaging is an excellent medium for clearly displaying important information about the drug (INN, dose strength, route of administration, storage conditions). It is by definition larger than the items it contains and a higher level of contrast is possible than on a transparent bottle or a metallic blister pack. It also protects the drug from light and variations in temperature when necessary. It is also a reliable way of keeping the dosing devices and patient leaflet with the drug.
Two types of product packaging for the over-the-counter mouthwash Eludrilpro° (chlorhexidine + chlorobutanol) (Rev Prescrire n° 338) have been authorised without a box. The dosing device, a cup, fits over the neck of the bottle. The text for the patient leaflet is printed in small white letters on a transparent label around the bottle; it is difficult to read on the 200 ml bottle. It is worth reading though, to learn that the solution contains 42.8% alcohol, for example.
A drug without outer packaging is cheaper to produce. It may appear practical and more environmentally friendly, but the quality of the examples examined in 2010 and 2011 left much to be desired.
Too many bottles are easily opened by children
The three oral forms of methotrexate available in France come in bulk bottles without a child-proof cap (Rev Prescrire n° 331). Yet massive ingestion of this cytotoxic drug could be fatal for a child.
Bottles of candy-pink betamethasone + dexchlorpheniramine tablets - Célestamine° are closed with a simple stopper, of the sort found on tubes of aspirin in the last century (Rev Prescrire n° 331). Perindopril arginine 10 mg + indapamide 2.5 mg - Bipreterax° comes in the same type of bottle (Rev Prescrire n° 327), as does the quinine + cratagus (dry hawthorn extract) combination Okimus° (Rev Prescrire n° 337), which contains a sufficient quantity to kill a child.
The following drugs come in bottles with easily unscrewed caps: metoclopramide paediatric oral solution - Primpéran° (Rev Prescrire n° 328); the opioids pholcodine - Flucalyptol toux sèche pholcodine° (Rev Prescrire n° 327 and n° 333) and dextromethorphan - Euphonyll° (Rev Prescrire n° 330); the antiepileptic ethosuximide - Zarontin° (Rev Prescrire n° 338); the benzodiazepines clonazepam - Rivotril° (Rev Prescrire n° 337) and diazepam - Valium° (Rev Prescrire n° 338); and mequitazine - Primalan° (Rev Prescrire n° 337).
Like Eludrilpro°, the chlorhexidine + chlorobutanol mouthwash - Buccosoin° (Rev Prescrire n° 335) comes in a bottle with no child-proof cap and contains a high proportion of alcohol (42.8%).
Until drug regulatory agencies systematically address the risks associated with children ingesting drugs and safeguard the public by imposing stricter MA requirements, we must all follow a few basic rules: keep drugs and drug waste out of the reach of children, and take care not to drop any tablets from bulk bottles.
Dosing devices: delicate situations
Almost all of the dosing devices examined in 2011 were flawed or even dangerous. The labelling of memantine oral solution - Ebixa° has improved, but the dosing pump on the bottle must be primed before use, which remains a source of error (Rev Prescrire n° 328); in any case, this drug is best avoided. Doses of ethosuximide - Zarontin° (Rev Prescrire n° 338) no longer have to be measured with an ordinary spoon, but the measuring cup that is now provided is a poor choice, since cups are known in practice to lead to overdose. As of late 2011, nasal fentanyl - Instanyl° was still marketed in dangerous multidose bottles with a dosing pump. Slightly less dangerous single-dose bottles became available at the end of 2011, but only in hospitals (Prescrire Int n° 123).
Droppers are still marketed: diazepam - Valium° (Rev Prescrire n° 338) and clonazepam - Rivotril° (Rev Prescrire n° 337). A welcome feature is a diagram on the opening tab of their outer packaging, showing that the dropper should be held vertically during use. Failing the provision of an accurate, suitable oral delivery syringe, it is high time that patient leaflets include information and diagrams on the proper use of droppers.
The oral delivery syringe for Vitamin K1 Roche nourrissons° 2 mg oral or injectable solution (phytomenadione) was one of the rare examples examined of an oral syringe graduated in milligrams, but it includes a superfluous 1 mg graduation that could create confusion (Rev Prescrire n° 337): according to the summary of product characteristics (SPC), the 1 mg dose is only administered by injection.
Patient leaflets: inadequate and dangerous
Package leaflets developed through European centralised MA procedures have shown a trend towards overall improvement in recent years, e.g. telaprevir - Incivo° (Rev Prescrire n° 339). But more progress is needed. One serious flaw is that brand names too often take precedence over INNs. Patient leaflets should explain that the INN is a drug's true name and encourage patients to remember INNs to facilitate their discussions with healthcare professionals and to be able to identify their drugs in the interactions sections of other patient leaflets, for example.
However, the patient leaflets for many older drugs that were approved through non-centralised procedures are inadequate.
For example, the patient leaflet for flumetasone + salicylic acid + coal tar - Alkotar° (Rev Prescrire n° 337) does not explain the uncertainty over the potential carcinogenic effect of coal tar (1).
As of 19 December 2011, the patient leaflet available on the French agency website for mephenesin + methyl nicotinate ointment - Décontractyl° (Rev Prescrire n° 328 and n° 337) still did not contain a warning about the risk of acute generalised exanthematous pustulosis reported in 2011 (2).
The patient leaflet for quinine + thiamine - Hexaquine° (Rev Prescrire n° 337) does not reflect the disproportionate risks associated with quinine, which include cardiac disturbances and prolongation of the QT interval that increase the risk of torsades de pointes, as well as hypoglycaemia and renal failure (3).
The leaflet for tianeptine - Stablon° (Rev Prescrire n° 337) does not mention its hepatic risks (4).
NSAIDs and pregnancy: enough is enough! The data on NSAIDs suggest that their administration during the first trimester of pregnancy increases the risks of miscarriage and malformations. If they are taken after the first trimester, NSAIDs expose the fetus to serious and sometimes fatal cardiovascular and renal risks (Rev Prescrire n° 301).
However, in the patient leaflets examined in 2011, regardless of dosage form and legal status, NSAIDs were only clearly contraindicated from the sixth month of pregnancy.
The products concerned are: oral ketoprofen - Bi-Profénid LP° and Profemigr° (Rev Prescrire n° 327), oral ibuprofen + codeine - Antarène Codéine° (Rev Prescrire n° 332), oral ibuprofen + pseudo-ephedrine - Adviltab rhume° (Rev Prescrire n° 332); diclofenac + heparin medicated plasters - Flector Tissugel Héparine° (Rev Prescrire n° 329); diclofenac gel - Compralfène° and Tendol° (Rev Prescrire n° 336), morniflumate suppositories - Nifluril enfants° (Rev Prescrire n° 336), and diclofenac suppositories - Voltarène enfant° (Rev Prescrire n° 338) (5-13).
The patient leaflet for mesalazine sustained release tablets - Mezavant LP° (Rev Prescrire n° 332) is more informative and states: "(…) mesalazine crosses the placenta in pregnancy (…), due caution should be taken (…) in pregnancy". The stated daily dose is 2.4 g to 4.8 g (14). However, according to the SPC for mesalazine - Pentasa° (Rev Prescrire n° 271) published on the French agency website and dated 6 January 2011 (our translation) "at doses greater then 2 g per day, the plasma concentrations of the salicylate mesalazine could expose the fetus to the risk of adverse effects, particularly renal effects (NSAID effects)". It also states that "one case of fetal renal damage (…) and renal failure at birth was reported with administration of oral mesalazine 4g/day during the second trimester of pregnancy" (15).
NSAIDs are best avoided throughout pregnancy to avoid exposing the unborn child to any risks. A clear message to this effect in patient leaflets would benefit pregnant women.
More readability tests needed. Some patient leaflets lack important information. For example, the patient leaflet for injectable iron - Venofer° (Rev Prescrire n° 331) does not mention that it must be diluted before injection. It would be better to follow the preparation instructions in the SPC.
None of the patient leaflets for the antitussives examined in 2011 described the natural course of cough or the non-drug options for relieving symptoms.
An explanation of the disorders associated with vitamin B1 deficiency would improve the leaflet for Bénerva° (Rev Prescrire n° 336) (16).
The leaflet for fosfomycin trometamol - Monuril° (Rev Prescrire n° 335) does not inform patients that in young women who are not pregnant, half of all cases of uncomplicated lower urinary tract infections resolve spontaneously within weeks without treatment. Nor does it explain that 20% to 25% of cases of uncomplicated acute cystitis resolve spontaneously within 48 hours without antibiotic therapy (Rev Prescrire n° 330) (17).
Wider application of readability tests among target patient groups or even healthcare professionals would result in more effective patient leaflets. It would also rid them of simplistic statements such as the one (our translation) from the patient leaflet for the antineoplastic bleomycin - Bléomycine Teva° (Rev Prescrire n° 335): "(…) normal cells are less sensitive to bleomycin than tumour cells. They will therefore survive whereas tumour cells will be destroyed" (18).
In summary
These shortcomings and flaws in drug packaging undermine the efficacy of treatments and patient safety. They show that convenience of use must be taken into account when evaluating drugs prior to authorisation and during their re-assessment.
Notes:
a- For additional information on Prescrire's Packaging Working Group and on technical terms such as "single-unit blister" and "dosing schedule", and to read our previous annual drug packaging reviews: for the French version, select "Les Cahiers Prescrire" from the "Libre accès" dropdown menu at www.prescrire.org, then select "Le conditionnement des spécialités pharmaceutiques"; for the English version, search for the term "packaging" at http://english.prescrire.org/en/. The 2011 packaging review builds upon Prescrire's previous annual reviews and our responses to certain public consultations on drug packaging.
b- Many generic products prominently display the INN. However, readers have pointed out that some graphic designs used on the outer packaging of different products from the same manufacturer can lead to confusion (Rev Prescrire n° 337).
c- The company has announced that its new blister packs will be labelled with the INNs.
Selected references from Prescrire's literature search.
1- Afssaps "Notice boîte-Alkotar°" 30 mars 2009: 2?pages.
2- Afssaps "Notice-Décontractyl baume" 13 juillet 2010: 6 pages.
3- Afssaps "Notice-Hexaquine" 15 juin 2007 : 5 pages + "Notice boîte " 30 novembre 2004: 2 pages.
4- Afssaps "Notice-Stablon" 2 mai 2011: 6 pages + "Notice boîte" août 2008: 2 pages.
5- Afssaps "Notice-Bi-Profénid°" 19 juillet 2011: 8 pages + "Notice boîte" janvier 2010: 2 pages.
6- Afssaps "Notice-Profémigr" 13 juillet 2010: 8 pages.
7- Afssaps "Notice-Antarène Codéine" 14 septembre 2011: 9 pages + "Notice boîte" 14 décembre 2010: 2 pages.
8- Afssaps "Notice-Flector Tissugel Héparine" 12 novembre 2010: 7 pages + "Notice boîte" août 2010: 2 pages.
9- Afssaps "Notice-Rhinadviltab°" 22 septembre 2011: 8 pages + "Notice boîte-Adviltab Rhume" 20 avril 2010: 4 pages.
10- Afssaps "Notice-Compralfène" 16 août 2010: 6 pages.
11- Afssaps "Notice-Tendol°" 28 octobre 2010: 6 pages + "Notice boîte" 14 mai 2010: 2 pages.
12- Afssaps "Notice-Nifluril Enfants suppositoire sécable" 23 août 2010 : 6 pages + "Notice boîte" 22 octobre 2004: 2 pages.
13- Afssaps "Notice-Voltarène Enfant suppositoire" 1er août 2005: 6 pages + "Notice boîte" juin 2003 : 4 pages.
14- Afssaps "Notice-Mezavant° LP" 12 mai 2011: 7 pages.
15- Afssaps "RCP-Pentasa 1 g comprimé" 6 janvier 2011: 5 pages.
16- Afssaps "Notice-Benerva° 100 mg/1 ml" 12 mars 2010 + "Notice Benerva° 500 mg/5 ml" 14 décembre 2010: 10 pages.
17- Afssaps "Notice-Monuril" 25 octobre 2010: 6 pages.
18- Afssaps "Notice-Bléomycine Teva°" 29 avril 2010: 8 pages.
©Prescrire 1 May 2012
"2011 drug packaging review: too many dangers and too many patients overlooked" Prescrire Int 2012; 21 (127): 133-138. (pdf, free)
> Return to Prescrire's annual review of drug packaging in 2011
