Overall, only slight progress was made in 2009.
INNs need to be more legible
Pharmaceutical companies that are not targeting the generics market often put the emphasis on invented brand names on the labelling, at the expense of the international nonproprietary name (INN). For example, the INN is displayed under the brand name on blister packs in a virtually illegible form (small, widely spaced print), as though it is simply underlining the brand name (racecadotril - Tiorfast° Rev Prescrire 304 and 308, inside front cover). In another example, the INN was one-tenth the size of the brand name and compressed to fit under the first two letters of the latter (nifuroxazide - Imoseptyl° Rev Prescrire 307). The INN is mentioned after a variety of other particulars on the front of the box (ziconotide - Prialt° Rev Prescrire 312; biclotymol - Humex mal de gorge miel citron° Rev Prescrire 308; chlorphenamine- paracetamol - Humex état grippal° Rev Prescrire 314). As a final example, the INN disappears from the blister pack when the patient has to tear the film that covers the only identified blister in order to remove a tablet (vildagliptin - Galvus° Rev Prescrire 313).
Labelling cluttered with company graphics and multilingualism
Other factors make it harder to read the information that is useful for patient care, such as the INN and dose strengths: company graphics reproduced on the various product- line extensions (telmisartanhydrochlorothiazide - Micardisplus°, Pritorplus ° Rev Prescrire 306), particularly those of “umbrella” brands (loperamide - Imodiumcaps° Rev Prescrire 312; pheniramine-paracetamol-vitamin C - Fervex° Rev Prescrire 306); the use of shimmering colours (guaifenesin - Vicks Expectorant sirop adultes° Rev Prescrire 306), making it difficult to read the therapeutic indications, which are useful when selecting this over-the-counter drug, due to reflection from the metallic finish on some parts of the box.
The inclusion of multiple languages on blister packs or bottles leaves less size for the printed information, making it harder to read (sitagliptin + metformin - Janumet°, Velmetia° Rev Prescrire 304 and 314; doripenem - Doribax° Rev Prescrire 304) (a).
Lack of clarity in expression of dose strength and concentration
Too many labels in 2009 expressed dose strength or concentration in a complex way that was a dangerous source of confusion. For example, a change in the expression of dose strength of perindopril, alone or in combination with indapamide, led to overdoses (Coversyl° Rev Prescrire 309, Bipreterax° and Preterax° Rev Prescrire 313). The total quantity of the active ingredient was still absent from the main parts of the labelling, such as the front of the box or the bottle label for some injectable drugs (ziconotide - Prialt° Rev Prescrire 312; cetuximab - Erbitux° Rev Prescrire 303; triamcinolone (hexacetonide) - Hexatrione° Rev Prescrire 308).
The risk of confusing concentration and total quantity is a concern with injectable drugs that require dilution or reconstitution. For example, in the case of romiplostim (Nplate° Rev Prescrire 311), the dose strength mentioned on the box and the bottle (250 µg) differ from the quantity contained in the bottle (375 µg) and from the target concentration for the reconstituted solution (500 µg/ml).
Another example: although the box for Mycamine° (Rev Prescrire 305) does prominently display the total quantity of micafungin contained in each bottle of powder for reconstitution (50 mg or 100 mg), the target concentration for the reconstituted solution is only displayed in small print on one side of the box: 10 mg/ml or 20 mg/ml respectively. And this information is not present on the bottles (b).
Colours: still no guidelines
The use of colours, particularly to distinguish between various dose strengths within a product line, continues to expand. In 2009, several examples were analysed: fentanyl - Abstral° Rev Prescrire 313; oxycodone - Oxynorm°, OxyNormOro° Rev Prescrire 313; lacosamide - Vimpat° Rev Prescrire 307 + 311 inside front cover and 314; levodopa + carbidopa-entacapone - Stalevo° Rev Prescrire 309 and 314. Yet the risk-benefit balance of this practice has sometimes proved unfavourable (2). There is an urgent need for European directives aimed at improving these practices.
Inaccurate dosing devices
In 2009, psychotropic drugs were still supplied with inaccurate dosing devices: one antiepileptic (diazepam - Valium°, Rev Prescrire 306) comes with a dropper and another (lacosamide - Vimpat° Rev Prescrire 307 + 311 inside front cover and 314) comes with a measuring cup with barely legible graduations. And a simple measuring spoon was provided to prepare the dose of the cough suppressant pentoxyverine - Pectosan° (Rev Prescrire 306).
Worse yet, the packaging of the antiepileptic drug ethosuximide - Zarontin° (Rev Prescrire 309) does not contain a dosing device - the package leaflet recommends using a household teaspoon, which is a known source of dosing errors. Lack of safety devices. In 2009, multidose bottles containing large quantities of psychotropic drugs were still available on the French market without a childproof safety cap: diazepam - Valium° (Rev Prescrire 306), ethosuximide - Zarontin° (Rev Prescrire 309) and pentoxyverine - Pectosan° (Rev Prescrire 306).
In addition, the packaging for three drugs containing perindopril, alone or in combination with indapamide, was worse in 2009 than in previous years: blister packs were replaced by bulk bottles with no childproof safety cap. This makes it possible for a child to rapidly ingest an overdose, and imposes restrictions and repackaging costs on hospitals and healthcare institutions (Rev Prescrire 309 and 313).
Okimus° tablets (dry hawthorn extractquinine, Rev Prescrire 309) have changed colour but the bulk bottle still has no childproof safety cap (for which it was given a red card in the 2008 Prescrire Packaging awards).
Two other cases represent a step backwards: injectable aciclovir - Zovirax° (Rev Prescrire 308) no longer comes with a drug transfer device and the syringe for the papillomavirus vaccine types 6, 11, 16, 18 - Gardasil° (Rev Prescrire 306) is no longer equipped with an automatic needle guard. These devices were included in the packaging to reduce the risk of contamination through needle stick injuries.
Uninformative package leaflets
The patient information leaflets for self-medication products, including those available over the counter, often contain insufficient information. The natural course of the symptoms and non-drug options are only addressed briefly or not at all, for both cough (guaifenesin - Vicks Expectorant adultes° Rev Prescrire 306; pentoxyverine - Pectosan° Rev Prescrire 306) and fever (pheniramine-paracetamolvitamin C - Fervex° Rev Prescrire 306).
Another example: it is difficult to judge when a burn is serious enough to require medical attention on the basis of the package leaflet for trolamine - Biafineact° (Rev Prescrire 309), which recommends consulting a doctor for burns covering more than 2% of total body surface area.
Package leaflets start with a section describing the action of the drug. These sections have become more detailed, but they do not weigh the benefits against the adverse effects, which are only listed at the end of the leaflet. Some sections even contain promotional statements. For example, in 2009, the French package leaflet for racecadotril - Tiorfanor° (Rev Prescrire 307) mentions that the drug is "very effective", yet the reduction in the number of stools is modest at best.
In 2009, the Prescrire Packaging Working Group even analysed a drug that had no package leaflet per se: betaine citrate - Citrate de bétaïne Cristers° granules (Rev Prescrire 311). The information is spread around on the outer and inner surfaces of the box. The only information displayed on the sachet of granules is the batch number and expiry date. Once it has been removed from the box, this sachet becomes unidentifiable.
Furthermore, delays in updating package leaflets interfere with information about adverse effects reaching patients. For example, Prescrire obtained aliskiren - Rasilez° (Rev Prescrire 311) when it was introduced in May 2009. The package leaflet only mentioned two adverse effects: diarrhoea and skin rash. The risk of angioedema was not mentioned. This adverse effect was already known in 2007 and officially listed in the marketing authorisation dated 3 April 2009. Furthermore, when Rasilez° was introduced in France, a version of the package leaflet that mentioned this adverse effect was available on the European Commission’s website.
© Prescrire June 2010
"Drug packaging in 2009: a few advances" Prescrire Int 2010; 19 (107): 135-137
Notes:
a- In January 2009, the European Commission finally updated its guidelines on labelling and packaging leaflets (ref. 4). This new version includes useful recommendations such as displaying the INN in a prominent way. As of late 2009, it was still too soon to evaluate their impact. We will return to this issue in the future.
b- In 2009, the European Medicines Agency (EMA) released draft guidelines for public consultation on the expression of concentrations and strengths on packaging. The comments Prescrire sent to EMA are presented in reference 5. Selected references from Prescrire’s literature search.
References:
1- Prescrire Editorial Staff "Drug packaging in 2008: not enough progress" Prescrire Int 2009; 18 (101): 134-135.
2- Prescrire Editorial Staff "Packaging of pharmaceuticals: still too many dangers but several encouraging initiatives" Prescrire Int 2007; 16 (89): 126.
3- Prescrire Editorial Staff "European Directive: drug packaging provisions finally transposed into French law" Prescrire Int 2009; 18 (102): 183-1.
4- European Commission "Guideline on the readability of the labelling and package leaflet of medicinal products for human use. Revision 1" 12 January 2009: 27 pages.
5- Prescrire Editorial Staff "Preventing errors related to the expression of strength on drug packaging" Comments on draft guidelines EMEA/208304/2009 28 May 2009: 9 pages.
