Dangerous Clutter: FDA Takes On Errors Caused By Drug Labels, Packaging

Reducing the amount of unnecessary information on drug labels is one of several key ways to stop dangerous medication errors, a panel that is helping FDA develop guidance on the subject agreed.

"We want to start with guidance and move to regulation, but that can take 10 to 15 years," Carol Holquist, director of FDA's Division of Medication Error Prevention and Analysis, said.

One-third of the medication errors reported to the Institute for Safe Medication Practices may be attributable to problems with container or carton labeling, Kellie Taylor, the division's associate director, said as the panel gathered June 24 to discuss the future guidance on naming, labeling and packaging practices to minimize such mistakes.

"From users, the biggest thing we hear is that there is too much information on drug labels," panel member Julie Aker, president and CEO of Concentrics Research, said.

"Removing label clutter" could help, Susan Proulx, president of Med-ERRS, said during a public comment period. "There should be a hierarchy of information." The consultancy is a wholly owned, for-profit subsidiary of the non-profit ISMP.

A similar suggestion came from Gerald McEvoy of the United States Pharmacopeia, who called for "developing a patient-centered prescription drug label [that] should contain only the most important information for safe and effective use. Less critical information should not supersede critical information."

Cleaning Up Packaging

Not only are drug labels packed with irrelevant information that may cause hurried health care providers to overlook critical facts about the drug's identity and proper dose, panel members said; essential facts may also be half-hidden in small print or formatted awkwardly, potentially leading to disastrous outcomes.

In a real case involving a diabetic who needed a given dose of insulin, "the concentration was buried halfway down the label in 7-point font," E. Robert Feroli, medication safety officer with The Johns Hopkins Hospital, recalled. "The nurse accidentally gave the patient the entire vial; fortunately, the error was caught quickly. But a clear articulation of what's in there and a standard format would have prevented this particular error and many others we see."

Other, perhaps less obvious problems Feroli said he has seen include truncated drug names, partial listing of ingredients and "wrap-around" text where essential information is broken up by the end of a line of print. This may cause essential information to be missed if the user stops reading at the end of the line, he said, citing as an example a pain drug label that warns, "Not for intrathecal use" (i.e., not to be injected directly into the spinal cord), where the words "not for" come at the end of a line and it's possible for a health care provider to miss the words "intrathecal use" entirely.

The sheer range of hidden traps in drug label design is daunting. Problems arising from color coding, typography and dangerously confusing abbreviations and dose designations have all led to medication errors, ISMP President Michael Cohen said.

"Inadequate differentiation between different drugs or strengths, confusing statements, missing or excessive information, distracting images, small fonts or illegible information" also can lead to medication errors, Taylor said.

Problems From Modifiers, Packaging

Yet another major text-based problem is caused by inconsistent use of modifiers, such as XR and ER both being used to stand for extended release. "The most common error is the risk of the modifier being omitted during prescribing or overlooked in dispensing or administration, leading to confusion with the currently marketed root name product," Taylor said. For example, earlier this year FDA asked Novartis to rebrand a line extension of the OTC antacid Maalox called Maalox Total Relief , a stomach-ache/diarrhea remedy (¹ (Also see "Medication Errors: FDA Renews Focus On Drug Packaging As Part Of Prevention Campaign" - Pink Sheet, 12 Apr, 2010.)).

At least one aspect of modifier abuse is easy to correct - a ban on the use of "single-letter modifiers," David Lewis, global head of pharmacovigilance systems and safety data management at Novartis, suggested. He cited a UK company that wanted to use "N" for new and was rejected. "What a crazy world that they'd even consider it," he said.

In seeking to cut down on medication errors, FDA and drug manufacturers also have to consider aspects of the packaging and carton design that go beyond the wording and formatting of informational text. ISMP's Cohen cited such problem areas as amber packaging for light-sensitive drugs that makes it difficult to read the label; shrink wrap with printing on it that "obliterates the readability of the label"; branded packaging methods that "means nothing to providers"; embossed labels; two-in-one packaging that can lead to double dosing; difficult to understand icons; and bar codes that can't be read as intended by scanners.

Not only do the bar codes have to be printed so they can be read, they should also be more informative, Cohen suggested. "It's time to extend the bar code to include the expiration date and lot number," he said.

One known way of detecting many of these problems is called Failure Mode and Effects Analysis, Proulx said. She called it "the basic methodology used to evaluate container labels and carton labeling."

Jerry Philips, president and CEO of the Drug Safety Institute, said this method "has a strong track record for safety in device design and aerospace."

Branding Versus Safety?

While no drug manufacturer intends it, basic elements of branding undertaken for marketing reasons can multiply the confusion on drug labels and packaging still further.

Color, which many manufacturers use to distinguish their products, falls squarely into that category. "The indiscriminate use of color is confusing and really poor. Appropriate use of color is really powerful," Lewis said.

"Judicious use of color is really the key," Allison Yale Strochlic, a specialist in managing human factors for Wiklund Research and Design, agreed. "It seems to me that it would be simple to have text that is legible on a background, to have a reasonable amount of contrast. But we've come into contact with a lot of labels that have white on a light gray background or white on a light blue background, or companies that want to use certain color coding for certain candidate products."

Wiklund performs reviews and analyses of drug label designs, she added. "What we do ... is to basically run a color contrast analysis and see what the contrast is between the text and the background. It's not something that's particularly difficult to do. ... But it's something manufacturers can do before even moving forward with the design. Contrast is not the only thing that feeds into legibility, but it's certainly one of the critical factors."

Seeing Red On Packaging

Medication errors can arise when the same manufacturer uses similar colors for different dosage strengths of the same drug. For example, Baxter's midazolam 10 mg/2 mL and 2 mg/2 mL dosages have similar reddish-orange labels, a slide shown by Miriam Klein, assistant director of pharmacy medication safety at Kings County Hospital Center, Brooklyn, N.Y., said. Even "colored caps on the container" can be confusing, she said.

Not that the problem is limited to Baxter. Generic drug manufacturer Roxane Laboratories uses brown on most of its drug labels, but distinguishes the highest strengths with red. "If that's something that moving forward is not recommended, we would certainly like to hear feedback on that," Marissa Craddock, a regulatory affairs/labeling specialist for the company, said.

"A lot of the types of errors that we see, especially with the Roxane product line, are really attributed to that brown ... that's used across all the products," Holquist responded. "It's really great that you differentiate strength, but it's really hard to tell what product's in there."

On the other hand, proper use of color helps distinguish different doses of dimorphine in the UK, Lewis said. Previously, labels were standardized, with black text on white background and no differently colored emphasis on dosage, "which is a killer. Now we've brought in color on top of the black and white and that has dramatically reduced [errors]. It's not eliminated, but it has been dramatically reduced. ... Uniformity is not always a good thing."

Drug manufacturers also should keep in mind that not all health care providers and patients may be able to distinguish all colors. "About 7 percent of American men have red-green color blindness, so you have to be careful," Bruce Lambert, University of Illinois at Chicago, said.

FDA's nascent guidance should "include that if the manufacturer wants to use color to distinguish A from B," it would need to provide a rationale, Matthew Grissinger, director of error reporting programs at ISMP, said.

"It's important for a company to have its trademark for marketing purposes, but it's the last thing on the mind of the user," Feroli said.

Manufacturers Take Action

Some drug makers have come to understand the need to vary the uniform branded appearance of their products. "Pfizer had one basic look for all its products in the U.S. and around the world. The idea was that from five feet away you should be able identify the strength," Rich Hollander, the company's vice president of packaging services, said. "But as we grew we realized a lot of products look alike, so we built six new layouts based on how the product is likely to be used."

Pfizer's process for developing proprietary drug names is even more elaborate, Thomas Ruth, director of trademark development, said. Just finding a name that is available because it is not in use anywhere in the world takes two-and-a-half to three years. The company may start with 1,000 possible names for a single product, and then, after "a lot of safety screening, whittle that down to 100 names for Legal to check against."

The company also does linguistic and cultural checks to avoid dubbing a drug with an inappropriate name, he said. But despite all that work, "in looking for a global name, many times we will have to juggle at the very end of the process; the European Medicines Agency rejects about 60 percent of names on the first pass, and here it's about one-third."

Still, he added, "we hope final guidance will not be too specific in terms of methodologies" of proprietary name selection.

No matter how much checking is done in this area, it seems to be impossible to guess at and eliminate all the potential ways a provider or a patient might confuse drug brand names, so that occasionally, post-marketing action is necessary.

A recent case in point involved Takeda's heartburn treatment dexlansoprazole, whose brand name, Kapidex, was confused with two unrelated drugs: AstraZeneca's prostate cancer drug Casodex (bicalutamide) and Actavis' opioid analgesic Kadian (morphine extended-release). As a result, Takeda and FDA announced that dexlansoprazole will go by the trade name Dexilant (² (Also see "Name Change For Takeda's Dexilant Shows Challenge Of Pre-Market Screening" - Pink Sheet, 31 May, 2010.)).

Manufacturers should "consider the risk/benefit tradeoff when reaching a decision on a [brand] name," Philips told the panel. It's a calculation that industry and FDA alike must apply to all aspects of drug labeling, package and carton design, and that the agency will have to keep in mind as it develops guidance and regulation.

- Martin Berman-Gorvine (³ [email protected])