2010 Drug Packaging Review. Identifying

Outlook

Translated from Rev Prescrire February 2011; 30 (328): 142-145

2010 drug packaging review: identifying problems to prevent errors

G Prescrire’s analyses showed that the quality of drug packaging in 2010 still left much to be desired.

G Potentially dangerous packaging remains a significant problem: unclear labelling is source of medication errors; dosing devices for some psychotropic drugs create a risk of overdose; child-proof caps are often lacking; and too many patient information leaflets are misleading or difficult to understand.

G Everything that is needed for safe drug packaging is available; it is now up to regulatory agencies and drug companies to act responsibly.

G In the meantime, health professionals can help their patients by learning to identify the pitfalls of drug packaging and providing safe information to help prevent medication errors. Rev Prescrire 2011; 31 (328): 142-145.

n recent years, the beneficial impact of include saxagliptin (Prescrire Int n°113); dual graduations, this represents a source Inew regulatory measures has emerged prasugrel (Rev Prescrire n°317); and a of confusion (Rev Prescrire n°315). The in Prescrire’s annual reviews of drug child-proof blister pack for fentanyl, an bulk bottles of doxylamine-Lidene°, a self- packaging. These measures include opiate (Rev Prescrire n°319). medication product, that lacked a child- amendments to the European Directive Among the packaging examined in proof cap, were replaced by blister packs on human medicines (in 2004), that 2010, several bottles containing large (Rev Prescrire n°315); this was also the extended the use of international non- amounts of dangerous substances were case with indoramin (Rev Prescrire n°318). proprietary names (INNs) on drug equipped with child-proof caps, includ- labelling, required the use of Braille on ing oral haloperidol solution (Rev Prescrire boxes, and provided for user testing of n° 320). Misleading and confusing patient information leaflets. The French A few products that require the use of labelling drug regulatory agency (Afssaps) issued devices for their preparation or adminis- new regulations on the labelling of dan- tration are sold in a ready-to-use format, In 2010, there remained widespread gerous injectable drugs. with the necessary items included in the flaws in drug packaging, along with some We also welcomed the decision by sev- packaging. Examples include: sodium unpleasant surprises. eral generics manufacturers to highlight phosphate + bisacodyl (Rev Prescrire n°315); the INN on their boxes (1,2). This article certolizumab (Rev Prescrire n°325); C1 INN not highlighted. The INN (inter- reviews the packaging quality of the esterase inhibitor (Rev Prescrire n°321); and national nonproprietary name) is often drugs we analysed in 2010. icatibant (Prescrire Int n°110). not clearly visible, making the drug more In 2010, there were a few improve- difficult to identify, thus increasing the ments in the packaging of existing prod- risk of medication errors. In particular, Welcome efforts ucts. The new oral syringe provided for the INN is missing from the front of the Fluanxol° is now graduated in milligrams box and from the bottle of a solution for As in previous years, none of the 300 of flupentixol, a neuroleptic, rather than in inhalation rich in terpene derivatives drug packagings we examined in 2010 the number of drops of solution (Rev (levomenthol + benzoin tincture + eucalyptus included all the important features Prescrire n°318). Similarly, the new tincture + Peru balsam + essential oils of required for optimal drug use. syringe provided for Depakine° oral solu- lavender and thyme) (Rev Prescrire n°318). Prescrire’s Packaging Working Group tion is now graduated solely in mil- The INN on the label of Isofebryl vita- found too few single-unit blisters or ligrams of sodium valproate, rather than in min C° is printed in thin grey letters 1 mm quasi-single-unit blisters (a): examples both milligrams and millilitres; like all high, while the “vitamin C” contained in

PAGE 162 • PRESCRIRE INTERNATIONAL JUNE 2010/VOLUME 20 N° 117 Downloaded from english.prescrire.org on 27/09/2021 Copyright(c)Prescrire. For personal use only. the brand name is printed in thick orange risk that patients may inadvertently take letters 5 mm high. Yet this product also a double dose (1,2). Regulatory agencies Inseparable contains aspirin and paracetamol. have thus far failed to take action. On the blister packs of Temeritduo° box/blister pack/leaﬂet: (nebivolol 5 mg + hydrochlorothiazide Confusion in expression of con- an interesting 12.5 mg or 25 mg), the INNs are so small centrations. In 2010, patients remained new concept that they can be mistaken for simple at risk from the confusing way in which underlining of the brand name (Rev Pre- the concentrations of some multidose oral scrire n°320). and injectable products were expressed. In 2010, Prescrire’s Packaging Work- One particularly shocking example ing Group noted that the box, blister Graphic designs of product lines: noted in 2010 concerns two oral solutions pack and patient information leaflet for too easily confused. The use of similar of sodium valproate, both marketed in DolipraneLib° paracetamol OTC tablets graphics for different dose strengths France by Sanofi Aventis, that differ in (Rev Prescrire n°325) could not be sep- intended to reinforce the brand image the way in which their concentrations are arated. represents another source of confusion. expressed. The front of the box and bot- This design ensures that the patient The front sides of the boxes containing tle of the reference product (Depakine°) information leaflet remains on hand the 2 dose strengths of Temeritduo° are bears the expression “200 mg/ml”, while throughout the use of the product, and a noteworthy example. “20%” is used on the only generic version that a blister pack containing another On the front of boxes containing the (Valproate de sodium Winthrop°). This drug cannot accidentally be put in the 4 dose strengths of the Exforge HCT° difference can cause confusion if the ref- box of DolipraneLib° in the family med- product line (amlodipine + valsartan + erence drug is replaced by the generic. icine cabinet. hydrochlorothiazide), the colour strip This is a significant issue with an Unfortunately, the printing of the prod- intended to differentiate between the antiepileptic drug. uct identifier is systematically spread dose strengths is largely overshadowed by For several years now, the labelling of over 2 blister pockets, each of which the other graphics (Prescrire Int n°114), many injectable products has created a contains one 500-mg tablet, a dose that thus increasing the risk of medication risk of medication errors because of Euro- often suffices. errors with this combination of three pean guidelines requiring the inclusion of In addition, the information printed antihypertensive drugs. the concentration or dose in the name of on the back of the box does not warn of The differences between the labelling on each proprietary drug. This information the risk of serious liver damage when blister packs of the various doses of Exforge may help regulatory agencies to distin- paracetamol is taken at the same time HCT° (aliskiren + hydrochlorothiazide guish between different products, but as large quantities of alcohol. Rev Prescrire n°315, 320) and rufinamide they in no way help health professionals This is why Prescrire was unable to (Inovelon°) are also inadequately high- and patients to use drugs correctly (see grant the yearly Packaging Award to ligted (Rev Prescrire n°319). inset page 165). For example, the SPC for this product. The graphics for the umbrella range temsirolimus (Prescrire Int n°111) states ©Prescrire Codotussyl° (Rev Prescrire n°317) are that a dose of 25 mg should be injected. another example of poor-quality label- The front of the box highlights the ling: a bright fuchsia background and administrative information, including superfluous graphics, such as face of a the concentration “25 mg/ml”. However, Boxes protect drugs from light, heat child or adult (actually resembling an the bottle contains 30 mg of the drug in and humidity. They also serve as a con- adolescent) in the background. The brand a volume of 1.2 ml, creating a risk of con- tainer for the patient information leaflet name is far too prominently displayed fusion between the total amount of the and dosing device. They are, by defini- on products with very different compo- drug contained in the bottle (30 mg) tion, larger than the bottle, blister pack or sitions (acetylcysteine, cetylpyridinium, and the dose to administer (25 mg). syringe they contain, meaning that their lidocaine or pholcodine). labelling can be larger and easier to read. The boxes and bottles of pholcodine Regulatory agencies must ensure that syrups show a double-ended spoon, with Bottles sold without a box: dangerous substances are not sold with- a large spoon at one end (5 ml) and a an exception, or a new trend? out an outer packaging. small one at the other end (2.5 ml). In this illustration, only the large spoon is In 2010, 3 drugs marketed in bulk full, yet the unit dose recommended in bottles were sold without a box as outer Protecting children the patient information leaflets for chil- packaging (i.e. secondary packaging): dren weighing between 20 and 35 kg is calcium polystyrene sulfonate (Resikali° Rev Too many dangerous substances are 2.5 ml. Community pharmacists should Prescrire n°319); calcium acetate (Phos- still sold without an adequate child- avoid placing this product line on their phosorb° Rev Prescrire n°323); and seve- proof device. This represents a poten- OTC shelves. lamer carbonate (Renvela° Rev Prescrire tially serious problem with OTC products n°326). like cough syrups with psychotropic Poor identification of individual These bottles have a folded sheet effects, such as Codotussyl° (a product blister pockets. Some blister packs attached to their side. The user detaches line described above); and the Clarix° examined in 2010 are still associated one end in order to read the information product line, containing drugs such as with a well-known risk: for example, it contains. However, the sheet can be dif- pholcodine and pentoxyverine (Prescrire the name and dose of pramipexole 0.26 mg ficult to reattach after several uses, and n°318). (Rev Prescrire n°323) span two pre-cut it sometimes has to be detached com- blister pockets. pletely in order to be read (Phospho- Blister packs of DolipraneLib° exhibit a sorb°). a- similar flaw (see inset opposite). In the case of Resikali°, it is necessary to For further information on the activities of Prescrire’s Packaging Working Group, and for explanations on tech- Prescrire has been drawing attention to insert one’s fingers into the powder in order nical terms such as “ single-unit blisters “ and “quasi sin- this issue for several years, because of the to find and pull out the measuring spoon. gle-unit blisters”, see reference 2.

PRESCRIRE INTERNATIONAL JUNE 2010/VOLUME 20 N° 117 • PAGE 163 Downloaded from english.prescrire.org on 27/09/2021 Copyright(c)Prescrire. For personal use only. Outlook 2010 drug packaging review

Bottles of Dolirhume aux huiles Patient information leaflets: FDA: inaccurate essentielles°, a product rich in terpene too often inadequate derivatives, have aluminium caps that are dosing devices easy to unscrew. A young child ingesting Although readability tests of patient a large amount would be at risk for the information leaflets have led to improve- In 2009, the US Food and Drug neurological adverse effects of terpene ments, too many leaflets are still mis- Administration (FDA) examined the dos- derivatives, such as seizures, hallucina- leading or difficult to understand (1,2). ing devices for 200 oral multidose OTC tions, and drowsiness (3). Leaflets for OTC cough syrups exam- products intended for pain, cough, aller- In 2010, a new combination of anti- ined in 2010 (the Codotussyl° and Clar- gy and some gastrointestinal disorders hypertensive drugs was sold in bulk bot- ix° product lines, for example) do not in children under 12 years of age (1). tles with easily removable stoppers explain the natural course of normal, The results, published in 2010, are wor- (amlodipine + perindopril, Rev Prescrire mild cough, or (adequately) deal with thy of note. n°316). non-drug options. Yet antitussives are The first fentanyl nasal spray (Prescrire Int barely, if at all, more effective than sim- In line with Prescrire’s findings. n°110) was marketed in France in plas- ply sucking a sweet or drinking liquids Only three-quarters of the products tic boxes designed to make it harder for (4,5). This information is not specified in examined by the FDA included a dosing children to access the multidose bottles. the patient leaflets. device. Four out of five devices were Yet our tests showed they were not dif- Patient leaflets for some OTC NSAIDs dosage cups, 13.5% were droppers, ficult to open. In addition, the bottles are incomplete or ambiguous in terms of and only 2.7% were oral syringes, which have a simple push-button spray and the risks to the unborn child in pregnant are more precise than dosage cups are not equipped with a safety cap. How- women. The leaflet for ibuprofen tablets and droppers (1). ever, patients are unlikely to put the (Nurofenfem° Rev Prescrire n°320) does At least one inconsistency was found bottle back in the inconvenient “tamper- not clearly mention that NSAIDs are between the instructions for use and the proof” box between uses. contraindicated during the first trimester graduations on the dosing device for of pregnancy, even though the data point nearly all of the products examined. At to an increased risk of miscarriage (6). least one necessary graduation was miss- Dosing devices: The leaflet simply states (our transla- ing in nearly one-quarter of cases, while worrisome trend towards tion): “during the first trimester of pregnan- about 8 in 10 devices bore unnecessary the use of pump bottles cy (…), your physician may, if necessary, pre- graduations. Eleven devices bore atypical scribe this drug”. units of measurement such as cm3, and In 2010, few dosing devices were grad- A greater problem exists with the 2 different graduated scales were found uated in units corresponding to the leaflet for VoltarenPlast° diclofenac plasters on half of the dosing devices (1). weight of drug. Most were graduated in (Rev Prescrire n°320) that states (our In November 2009, the FDA issued a millilitres, requiring the user to calculate translation): “during the first 6 months of guidance for manufacturers on the the weight equivalent, another potential pregnancy, VoltarenPlast° (...) may only be design of dosing devices for OTC oral source of error. Worse yet, the dosing used if recommended by your physician”. medicines (2). It included the following device for levetiracetam, an antiepileptic This is particularly dangerous: NSAID recommendations: all such products drug (Rev Prescrire n° 321), is now grad- use during the second trimester can cause should be sold with a dosing device; the uated in ml whereas it used to be grad- severe renal and cardiovascular disor- instructions for use should be compati- uated in mg (see also Rev Prescrire n°327). ders in the foetus (7). ble with the graduations; the highest The use of droppers, which are obso- What are patients likely to make of standards for packaging should become lete and imprecise, is especially danger- these ambiguous statements? Why do the the norm (for example, the capacity of ous with psychotropic drugs such as leaflets for all NSAIDs not simply con- dosing devices should be limited to the haloperidol and escitalopram (Rev Prescrire traindicate their use in self-medication maximum recommended dose); and n°319). throughout pregnancy (8), as in some user tests should be conducted. In 2010, oral memantine (Rev Prescrire direct-to-consumer advertisements? The FDA’s example should be fol- n°323), previously available in dropper Some injectable drugs must be pre- lowed in Europe. bottles, was sold instead in spray bottles pared and administered by a healthcare ©Prescrire equipped with a metered pump that has professional, but not all the relevant to be primed and has no refractory peri- leaflets contain complete instructions 1- Yin SH et al. “Evaluation of consistency in od (minimum time between 2 puffs). (e.g. tocilizumab, Rev Prescrire n°320). This dosing directions and measuring devices for One push delivers 5 mg of memantine, i.e. information is sometimes contained in pediatric nonprescription liquid medications” 10 times more than a drop with the use detailed brochures provided to health JAMA 2010; 304 (23): 2595-2602. 2- Food and Drug Administration “Draft guid- of the old bottles. As expected, soon after professionals by the company. These ance for industry. Dosage delivery devices for the new packaging of the oral form was brochures should be read with a critical OTC liquid drug products” November 2009: released, errors, including cases of over- eye. It would be simpler if the boxes 13 pages. dose, occurred. In late 2010, the compa- contained the information required by all ny made the labelling clearer but did those concerned. not change the dosing device. Instanyl° is also delivered via a spray pump that needs to be primed and has no In practice refractory period. The company that mar- kets it has announced it will provide a Overall, the poor quality of drug pack- single-dose safety bottle. In the mean- aging continues to undermine patient time, there remains a risk of potentially safety (see our comment opposite). fatal overdose (see above). While waiting for drug companies and regulatory agencies to take this issue seriously, health professionals seeking

PAGE 164 • PRESCRIRE INTERNATIONAL JUNE 2010/VOLUME 20 N° 117 Downloaded from english.prescrire.org on 27/09/2021 Copyright(c)Prescrire. For personal use only. to improve patient care can help by Editors’ opinion learning to assess the quality of packaging items, reporting poorly designed drug packaging, and providing information Regulatory agencies and companies must take and advice to their patients, thus reduc- packaging more seriously ing the risk of medication errors. ©Prescrire Everything that is needed to produce help health professionals and patients safe and convenient drug packaging is use drugs correctly (1). Selected references from Prescrire’s literature already available on the market (see search. opposite), yet the quality of most pack- More stringent controls. Some 1- Prescrire Editorial Staff “Drug packaging in 2009: aging remains mediocre. As a result, drugs with dangerous packaging still a few advances” Prescrire Int 2010; 19 (107): 135-137. 2- Prescrire Editorial Staff “Packaging of pharma- some products carry a risk of potential- reach the market despite controls put in ceuticals: still too many dangers but several encour- ly dangerous medication errors. place by European or national regulatory aging initiatives” Prescrire Int 2007; 16 (89): 126. authorities and pharmacovigilance com- 3- Afssaps “Commission nationale de Pharma- covigilance - Compte rendu de la réunion du mardi Guidelines needed. Guidelines are mittees. The French Transparency com- 25 mai 2010” 6 July 2010: 6-14. needed for packaging safety, including: mittee is supposed to weigh the advan- 4- Prescrire Rédaction “Toux gênantes“ Rev Prescrire quality criteria for unit-dose packaging; tages and disadvantages of new drugs 2008; 28 (299): 676-677. 5- Prescrire Rédaction “Médicaments de la toux et the design of dosing devices; safety relative to existing products; this includes rhume: effets indésirables trop graves face à des trou- guidelines for dangerous substances; the packaging. Ineffective controls cre- bles bénins” Rev Prescrire 2009; 29 (312): 751-753. careful use of colour on the labelling in ate an unacceptable risk of confusion 6- Prescrire Rédaction “AINS topiques: gare en cas order to distinguish between different and medication errors in practice. de grossesse” Rev Prescrire 2008; 28 (299): 664. 7- Prescrire Rédaction “Gare aux AINS en deuxième dose strengths belonging to the same Making drug packaging safer and more partie de grossesse” Rev Prescrire 2007; 26 (270): product line; specific recommendations convenient to use is a means of improv- 188-191. for paediatric drug packaging; and key ing the quality of health care. Regulato- 8- Prescrire Rédaction “Infos-patients - Pas d’anti- inflammatoire pendant la grossesse” www. information for patients, according to ry agencies and drug companies must prescrire.org: 1 page. the nature of the medication, its indica- take this issue more seriously. tions, route of administration, pharma- ceutical form, and devices for prepara- ©Prescrire tion and administration. Rev Prescrire 2011; 31 (328): 145. Existing guidelines tend to focus on administrative requirements and cost 1- European Medicines Agency “QRD Recom- rather than on the quality of patient mendations on the expression of strength in the care. For example, European recom- name of centrally authorised human medicinal mendations on the expression of drug products” 18 November 2009 + “Submission of comments - Comments from International concentrations and dose strengths exist Medication Safety Network” 28 May 2009: 5 + solely for administrative purposes, not to 9 pages.

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