…and sometimes, entirely the wrong drug is found in the packet. In a case that has had UK media reports aflame, a prescription only antipsychotic drug was found in certain packets of a common pain medication that was manufactured by a completely different company. Is it a repackaging mistake? Or are more sinister intentions at work? Either way, it’s clear there are could be a few security holes in pharma’s distribution chains.

Late yesterday afternoon, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) issued a statement warning the public to be cautious when using Neruofen Plus (made by Reckitt Benckiser) because AstraZeneca’s Seroquel XL 50 mg, had been found in certain packets. Seroquel XL is indicated for the treatment of schizophrenia and bipolar disorder.

It’s a pretty big mistake. In fact, it’s so major that some media reports led themselves to the conclusion that it could be sabotage. In its own statement, the MHRA also believes that a manufacturing error is unlikely. “Seroquel XL tablets are made by a different company (AstraZeneca) at a different site. Manufacturing errors by Reckitt Benckiser and AstraZeneca are not considered to be part of the cause at this stage.”

Three packets have been identified so far—all in south London. The MHRA believes that three different batches may be affected, which equates to anywhere between 4000–7500 packs, according to a report from the UK’s BBC. The MHRA statement says that the packs contained “rogue” cut-down blisters of Seroquel that included both parallel-imported tablets (from different companies) and originator product.

Several media reports have claimed that the swap may have happened in a wholesale warehouse. Whatever the cause, the situation raises issues about the integrity of pharmaceutical packaging. For instance, in the UK, many non-prescription medicines are not wrapped in cellophane and do not have protective seals, which means that anyone can open them and, if their intentions are malicious, tamper with the contents. Should these packages be more secure? And, in the event that medicines are swapped, should blister packs be more clearly labelled?

According to the MHRA, there is a clear difference in the design of the blister packaging of Nurofen (silver and black) and Seroquel (gold and black). But the question is, how many people out there actually double-check that they’re taking the right medicine after they’ve opened the carton? In addition, text on blister packaging can often be small, which doesn’t encourage people to take notice.

The case also raises issues about the distribution and wholesale chain. In particular, if parallel importing was involved, it will reinforce long-cited concerns about this “grey market”. Parallel trade and the repackaging of drugs—to the frustration of many stakeholders—is legal in the EU. If you’re unfamiliar with parallel trade then the article “Who’s afraid of parallel trade?” is a good introduction, or you can take a look at the EUROPA website.

At the moment, there’s no solid information as to the exact cause, and the MHRA has warned that we may never know the full story, saying: “We have some information to suggest possible links between these cases. It is possible that these problems are linked to product consolidation and/or erroneous examination of returns. Work is ongoing to obtain more information but the full facts may never be fully established.”

However, the situation has also highlighted something that pharma companies are reluctant to use in this kind of situation: communication.

I’ve read reports on The Drum and PRWeek suggesting that Reckitt Benckiser could have provided more information to consumers.

Writing for The Drum, Jonathan Hemus said: “Crucial to effective reputation protection is filling the information vacuum and reassuring your stakeholders… But Reckitt Benckiser – parent company of Nurofen Plus – has appeared slow to activate these communication channels. Hours after the Medicines and Healthcare products Regulatory Agency (MHRA) had issued its announcement about the issue, there was:

no information on the Nurofen website
no information on the Reckitt Benckiser website
no information on the Nurofen Facebook page
no one manning the consumer helpline.”

At the time of writing this blog, there was still very little information available outside of the MHRA and third-party news sites, but this may change.

Unfortunately, mistakes do happen and product recalls will continue. And in the EU, at least for the foreseeable future, there will be continued concerns over parallel trade and repackaging. But in comparison to the complexity of these issues, you’d think that disseminating information to the public was relatively easy.

The weight of children, and all individuals for that matter, varies within certain age ranges. Drugs are formulated based on age and weight, so it makes sense that dosing instructions address both. A major concern regarding dosing labels for children, in particular, is that if a child falls into a certain age range but weighs less than average for that age range, then that child could be overdosed when given a dose based on age alone.

According to the FDA briefing materials, “It has been reported that seventy percent of emergency department visits, across all age groups, related to single ingredient acetaminophen were due to unintentional overdose and two-thirds of those overdoses occurred in children less than 12 years of age.” In addition to unclear labels and labeling, causes of overdosing include: “general knowledge deficits, varying dosing devices, varying formulations and concentrations… and inadequate provision of dosing instructions to patients by their providers.”

Currently, the under-age-2 labels for OTC medications containing acetaminophen say, “Consult a doctor.” Labeling instructions for children under 6 months of age may retain the “Consult a doctor” statement, but weights and ages should be provided for children 6 months to 24 months, according to the committee recommendations.

The official minutes of the joint advisory committee meeting should be published in the Federal Register in the coming days and will contain additional details. Briefing materials used for the meeting were provided by officials within FDA, the Consumer Healthcare Products Association, and McNeil Consumer Healthcare; they are available online. The committees reviewed available pharmacokinetic, efficacy, and safety information as well.

FDA is not required to accept the committees’ recommendations but typically does.

The goal, according to an agency press release, is to avoid accidental overdose, a problem often associated with administering medicines to children. The guidance, officially titled, Dosage Delivery Devices for Orally Ingested OTC Liquid Drug Products, provides information about easy-to-use dosage delivery devices and devices that minimize the risk of unintentional overdose, and how these types of devices can be provided for OTC liquid pain relievers, cold medicine, cough syrups, and more.

Key recommendations for industry according to the guidance include: dosage delivery devices should be included for all orally ingested OTC liquid drug products; devices should be marked with calibrated units of liquid measurement (e.g., teaspoon) that are the same as the units of liquid measure specified in the directions for the product and there should not be any unnecessary markings; manufacturers should ensure that dosage delivery devices are used only with the products they are packaged with; liquid measure markings on dosage delivery devices should be clearly visible and not obscured when the liquid product is added to the device.

The release about the guidance also includes tips for parents and caregivers regarding dosage and administration of liquid OTC products. I’m happy to report that FDA is asking manufacturers via the guidance to make these changes to their OTC liquid products and alerting consumers to potential overdosing problems. Accidents with improper dosing and overdosing of OTCs have been a problem for some time now, and it’s nice to see action being taken at a high level.

Standard-setting bodies, regulatory authorities, and industry have been battling this challenge for years. Because they can’t come into our homes to help us take medication properly, they have gone over in painstaking detail the way a label should read so that it can be easily understood by the average consumer. They are constantly revising the way labels and information packages should be written, designed, and distributed.

Most recently, FDA is considering the use of one-page information sheets for prescription products (say goodbye to those multiple page inserts found in pharmacy prescription bags) and USP is looking toward a national standard for prescription labels. FDA also recently released a guidance for industry to help improve label comprehension studies (drug manufacturers perform these studies to test consumer understanding of product labels).  Across the Atlantic, EMA is considering better harmonizing drug labels and package leaflets across the European Union.

These efforts are important and may help consumers in self-selecting OTC as well as self-administering OTC and prescription products, but consumers also need to be more vigilant. How many times, for example, have you thrown away a medication’s packaging or prescription leaflet simply because you’ve taken it before and know exactly how much to take, and how often? I certainly have. What if the drug’s dosage or strength changed since the last time you took it, however? You would never know and could end up taking too much, or too little of the product. What if you are taking a new drug, and there are drug interactions that you need to be aware of, but don’t because you didn’t read the fine print on the label?

A pharmacist can help answer questions and a doctor can prescribe the right dosage, but once we as consumers bring home a medication, there’s no one there to help make sure we administer the drug properly. This is our responsibility.

You might want to rethink buying that bulk-sized hand sanitizer if you’re trying to protect you and your family from Methicillin Resistant Staphylococcus Aureus bacteria (MRSA) and other diseases. FDA is cracking down on over-the-counter (OTC) drug companies that are claiming their products prevent infection from MRSA.  The agency has sent letters to firms Tec Laboratories, JD Nelson and Associates, Dr. G.H. Tichenor Antiseptic Co., and Oh So Clean, Inc. (who also does business as “CleanWell Company”), among others.

The products from these manufacturers range from first-aid antiseptics to hand sanitizers and wipes. Marketing campaigns and labels for the items claim that they prevent infection from MRSA and other disease-causing agents, including E.coli and/or the H1N1 influenza virus. These claims are not backed by documented evidence, according to FDA.

The agency’s letters to the manufacturers warn that marketing products with invalid claims is a violation of federal law and could result in legal action. The companies have 15 days to remove the claims from their advertising and labels or face seizure and injunction.  Deborah Autor, director of the Office of Compliance in FDA’s Center for Drug Evaluation and Research said in a press release that, “MRSA is a serious public health threat. The FDA cannot allow companies to mislead consumers by making unproven prevention claims.”

While hand sanitizers and first aid antiseptics are a good way to prevent the spread of bacteria, it’s just as important to use products whose claims are backed by proven research.  One shouldn’t be swayed by the “cure-all” preventive aspects that a product may claim to have, especially when there is possibility of safety issues.

Health professionals and consumers that have purchased products from the companies mentioned are encouraged to contact FDA through the agency’s MedWatch Safety Information and Adverse Effect Reporting program and fill out a report if any side effects are experienced.

Information that should be included on the labelling and packaging leaflet is listed in Directive 2001/83/EC, while details on display and readability are provided in the European Commission’s (EC’s) Guideline on the readability of the labelling and package leaflet of medicinal products for human use. In Europe, however, packaging and labelling presentation can vary between different Member States. The new recommendations follow a consultation with Member States about their national practices. The recommendations summarise the basic principles to guide applicants and marketing authorisation holders when preparing mock-ups and specimens of sales presentations of non-prescription medicines within the centralised procedure.

Overall, the recommendations are designed to ensure that both the labelling and packaging leaflet are suitably presented and easy to understand. Some of the basic elements included in the recommendations concern the use of a clear layout, font type, and the use of colour or graphic design. The recommendations also highlight the type of information that must be featured, which includes the usual suspects of medicine name, active substance, route of administration, indications and instructions for use. Such important information should be brought together on the pack in the same field of view in clear large font.

But what’s not to be included? The recommendations advise against using italics and capital letters for entire sentences because they are hard to read (bold type is usually better). Also, careful consideration needs to be given to the colour of the package to ensure that it does not impact readability.

Companies will also need to take care when using symbols or pictograms. Although these are allowed (if relevant), they must not be confusing; for example, the number of tablets shown must not mislead about the dose. Images that are not allowed include those of leaves and fruits (text is considered sufficient to identify a medicine’s flavour), children, toys, balloons or other images that may cause confusion with other types of products.

More specific information about the recommendations is available on the EMA website.

Pharmaceutical Technology Europe will be publishing a special feature on packaging and labelling in our next issue. If you’d like to take part by giving your opinion on the new recommendations, or by discussing any other pharma packaging topics, then why not join our LinkedIn group? Or if you prefer, send us an email with your views at ssutton@advanstar.com.

In 2001, Gladys Mensing began taking metoproclamide, a generic version of Reglan, to treat a stomach disorder. No branded versions of the drug had been available since the mid 1980s. After taking metoproclamide for four years, Mensing experienced early symptoms of tardive dyskinesia, an untreatable neurological disease. She no longer can live independently or control the muscles in her tongue, face, arms, and legs.

When Mensing began taking metoproclamide, the generic drug’s label matched that of the branded manufacturer. In 2009, FDA required generic manufacturers to include a warning that long-term use of the drug carried a 20% risk of causing tardive dyskinesia. Mensing’s lawyers argue that medical studies had identified this risk well before 2001, when she began taking the drug, but that generic manufacturers had shirked their duty to alert FDA about it.

Attorney Jay Lefkowitz told the Court that if makers of generic drugs complied with strict state consumer laws by labeling their products different from the way innovator companies do, they would be violating federal law. Unmoved by this argument, Justice Ruth Bader Ginsburg observed that state laws are not at odds with federal law, they complement it.

Justice Samuel Alito wondered about the financial consequences of requiring generic-drug manufacturers to monitor for adverse events and inform FDA of them. “I don’t know whether this is a good idea or not, but it does seem to me that it may significantly increase the costs for generic drug manufacturers, and therefore counteract one of the objectives of the statute, which was to provide generic drugs at a low cost,” he said during arguments.

Justice Alito may have a point, but surely we should not overlook another objective of the law, which is to ensure that drugs are safe. The idea that the manufacturer of a generic drug can create and distribute a product without any responsibility for understanding it or ensuring that it does not harm its users is quite hard to swallow, in my opinion.

More than 70% of prescriptions filled in the US are generic drugs. The Court’s decision is expected in June, and it will surely affect a large section of the industry, one way or the other.

If you are sometimes a bit baffled by the instructions accompanying your medicines then you are not alone. Research conducted in the UK by the university of Leeds and Luto Research shows that many commonly-used phrases on medicine labels are easily misunderstood, which is why the latest version of the UK’s British National Formulary (a kind of drugs bible used by doctors, nurses, pharmacists and other health professionals) will feature revised, simplified language and phrases. One of the changes, for instance, will change the phrase “avoid alcoholic drinks” to “do not drink alcohol while taking this medicine — which eliminates any confusion!

The changes are expected to appear on UK medicine bottles and packets within the next 6 months.

But should the pharma industry also be taking action? The research applies to the labels that are applied when medicines are dispensed by pharmacies, but medicines also usually include a leaflet supplied by the manufacturer. Should this language also be simplified into a more easy-to-understand format? I’m sure I’m not the only one who’s been baffled at times when reading a medication leaflet! Pharma companies want their medicines to be as effective and as safe as possible, so it makes sense that they should be encouraging people to take their medicines correctly — and surely one of the best methods is to use simple instructions that leave no room for misunderstanding.

At Pharmaceutical Technology Europe, we’re busy working on our April issue at the moment, but in May we’ll be running a special feature on pharmaceutical packaging where we’ll be interviewing Professor D.K. Raynor from the University of Leeds about the research, and questioning whether pharma should also be getting in on the act. What do you think about this subject? Should pharma’s medicinal information be simplified? We’ll also be looking at other aspects of pharma packaging, including trends and innovations. Tell us what you think by signing up to the PharmTech LinkedIn group.

To avoid liability, Hospira decided to stop manufacturing sodium thiopental, an anesthetic used to administer lethal injections. The company planned to manufacture the drug at its site in Italy until that country’s authorities chose to forbid its export, fearing that it would be used for capital punishment. Hospira was the lone US manufacturer of sodium thiopental.

“Hospira manufactures this product because it improves or saves lives, and the company markets it solely for use as indicated on the product labeling,” said company spokesperson Dan Rosenberg in September 2010, referring to sodium thiopental. “The drug is not indicated for capital punishment, and Hospira does not support its use in this procedure.”

Hospira’s decision worsens the shortage of the drug, and foreign supplies are dwindling. Countries such as Germany and the United Kingdom are refusing to export it to the US.

Oklahoma uses pentobarbital, another anesthetic, in place of sodium thiopental. The state administers the anesthetic as part of the traditional three-drug lethal injection procedure. But critics say that pentobarbital’s effectiveness in preventing pain is unproven.

Ohio plans to administer pentobarbital alone to execute inmates, and defense attorney David Stebbins is concerned about this plan. “We just don’t have any information on that, and I’m not sure anybody does since it’s never been used that way,” he told the Associated Press.

So here we have a state administering a substitute drug in a use for which it is not indicated, seemingly without FDA oversight. If the agency’s mandate is to ensure the safety, efficacy, and security of human drugs, should it be regulating the drugs used for lethal injections? On the other hand, why should we be concerned with the health, safety, or comfort of someone whom we have deemed unworthy of life?

The search for new suppliers of, and alternatives to, sodium thiopental emphasizes the inherent contradictions of capital punishment. The events also reveal an oddity in the way that we regulate drugs.

Gladys Mensing sued PLIVA (Zagreb, Croatia), alleging that metoclopramide, which she took to treat diabetic gastroparesis, gave her tardive dyskinesia, a neurological movement disorder. As required by federal rules, the labels for generic metoclopramide matched those of the innovators, which did not warn about tardive dyskinesia while Mensing was taking the medicine. The US Food and Drug Administration ordered such warnings to be added in February 2009.

A federal judge threw out Mensing’s lawsuit, saying that it was preempted by federal regulations requiring the labels to match. The Eighth US Circuit Court of Appeals overturned this decision, however. “The generic defendants were not compelled to market metoclopramide,” the appeals court said, according to the Associated Press. “If they realized their label was insufficient but did not believe they could even propose a label change, they could have simply stopped selling the product. Instead, they are alleged to have placed a drug with inadequate labeling on the market and profited from its sale.”

It would seem unfair to punish PLIVA after it had marketed its product according to federal regulations. But the Eighth Circuit Judge raises a crucial point: ethical considerations should have stopped PLIVA from selling its drug if it knew that the label was insufficient. But how much did PLIVA know about metoclopramide’s potential side effects?

The fact that FDA originally approved the drug without a warning, only to add it later, reminds me of the controversy surrounding GlaxoSmithKline’s (GSK, London) Avandia. During a 10-year period after the drug was approved, more than 47,000 people taking it needlessly suffered a heart attack, stroke, heart failure, or death, according to one study. It would be wrong to blame the unfortunate adverse events entirely on FDA for approving the drug; the agency may not have gotten all of the relevant data. Senate investigators concluded that GSK did not share with regulatory authorities clear indications that Avandia increased heart risks.

The Avandia story illustrates that, despite its best efforts, FDA cannot yet completely protect us against drugs’ harmful side effects. The belated modification of the metoclopramide label indicates to me that the drug entails a significant risk of causing tardive dyskinesia. Given that FDA sometimes fails to mandate that drugs carry adequate warnings, I think that patients who can demonstrate that approved drugs have harmed them should have legal redress. I look forward to seeing how the Supreme Court decides this case.