Excedrin Brands Recalled Due to Faulty Packaging

By Pat Anson, PNN Editor

One of world’s most widely used over-the-counter pain relievers has turned into a real headache for GlaxoSmithKline (GSK).

The British pharmaceutical giant has recalled over 433,000 bottles of Excedrin because of holes found in bottles of five Excedrin brands: Excedrin Migraine Caplets, Excedrin Migraine Geltabs, Excedrin Extra Strength Caplets, Excedrin PM Headache Caplets and Excedrin Tension Headache Caplets.

There have been no reports of any injuries as a result of the faulty bottles, but GSK recalled them because of the risk of Excedrin tablets falling out and being swallowed by young children. Under U.S. federal law, the tablets must be sold in child resistant packaging.

“While the likelihood there are bottles on the market with holes is low, we are asking anyone who has purchased large-sized Excedrin (50 count and above) to check their Excedrin products and if there is a visible issue, contact GSK Consumer Relations at 1-800-468-7746 for a full refund. If your Excedrin bottle is not damaged, the product is safe to use as directed on the label,” GSK said in a statement.

GsK IMAGE

“We take product safety very seriously at GSK and while we have not received any complaints or safety concerns to date on this potential problem, we are still letting consumers know so they can check their Excedrin bottles themselves. We sincerely apologize for any inconvenience, and please be assured we are working closely with the bottle manufacturer to fix this problem as quickly as we can.”

The bottles were sold at pharmacies, stores and online from March 2018 through September 2020. There was no explanation given for what caused the holes or why it took so long for GSK to recognize there was a problem and order a recall.

In January, GSK temporarily halted production of Excedrin Extra Strength and Excedrin Migraine due to “inconsistencies” in their ingredients. That led to spot shortages of the pain relievers.

In 2012, an Excedrin manufacturing plant in Nebraska was shut down for several months after Excedrin bottles were found to contain broken and stray tablets for other medications. At the time, the Excedrin brand was owned by Novartis.

An FDA investigation found that Novartis failed to adequately investigate hundreds of consumer complaints of foreign products found in over-the-counter drugs produced at the Nebraska plant. GSK now holds majority ownership of Excedrin through a joint venture with Novartis.

A recent study found GSK to be the most heavily fined drug company in the United States.  GSK paid nearly $9.8 billion to settle 27 cases brought against it for bribery, corruption, improper marketing, pricing violations and selling adulterated drugs.

GlaxoSmithKline Most Heavily Fined Drug Company

By Pat Anson, PNN Editor

The pharmaceutical industry has long been criticized for engaging in illegal or unethical activities, such as fraud, kickbacks and price gouging. A new study published in JAMA shines a light on the scale of the problem, finding that Big Pharma paid over $30 billion in financial penalties for illegal activities in the United States.

Researchers looked at state and federal settlements from 2003 to 2016 and found that almost every large pharmaceutical company had paid a fine for illegal activity. The biggest transgressor was GlaxoSmithKline (GSK), which paid nearly $9.8 billion to settle 27 cases brought against it for bribery, corruption, improper marketing, pricing violations and selling adulterated drugs. In one settlement alone, GSK was fined $3 billion for encouraging doctors to prescribe its antidepressants to children.  

The fines paid by GSK were over three times higher than the amounts paid by Pfizer ($2.9 billion) and Johnson & Johnson ($2.6 billion) during the study period. Researchers say only four of the 26 drug companies they analyzed were not assessed a penalty.

TOP 10 MOST HEAVILY FINED DRUG COMPANIES

1. GlaxoSmithKline $9.8 billion

2. Pfizer $2.9 billion

3. Johnson & Johnson $2.6 billion

4. Abbott Laboratories $2.5 billion

5. Merck $2.1 billion

6. Eli Lilly $1.8 billion

7. Schering-Plough $1.6 billion

8. Wyeth $1.6 billion

9. Bristol Myers Squibb $1.4 billion

10. Novartis $1.2 billion

“Among the large pharmaceutical companies included in this study, 85% had evidence of financial penalties for illegal activities. Given the scope and nature of the illegal activities involving financial penalties, physicians and regulators should exhibit vigilance over the activities of large pharmaceutical firms,” wrote lead author Denis Arnold, PhD, a professor of business ethics at Belk College of Business, University of North Caroline at Charlotte.

“Four firms were not found to have penalties for illegal activities during the sample period. This may indicate an ability for illegal activity to be undetected, although these firms may instead have effective ethics and compliance programs.”

Because the study period ended in 2016, it did not include any recent settlements with drug companies involving opioid litigation. Nor did it cover fines paid outside the U.S., such as the $490 million fine that GSK paid for bribing Chinese doctors to prescribe its medications.

“This has been a deeply disappointing matter for GSK," chief executive Sir Andrew Witty said in a formal apology to the Chinese government in 2014.

Not much has changed at GSK over the years. This year the company agreed to pay $4.5 million in fines in Australia for marketing and price violations involving the pain relief gel Voltaren.  The British pharmaceutical giant was also recently fined $2.8 million by Romania for failing to supply the country with asthma medication.

Drug company executives rarely serve prison time for illegal activities and the large fines do not appear to be much of a deterrent against unethical behavior. The nearly $9.8 billion paid by GSK amounts to less than 2 percent of its total revenues during the study period. On average, GSK’s illegal activities went on for over seven years before the company stopped them, according to the JAMA study.

GSK did not respond to a request for comment for this story.    

Fraud Alert for Speaker Programs

In recent years, federal watchdogs have become increasingly concerned about the use of speaker fees, free meals, entertainment and other kickbacks paid by healthcare companies to promote their drugs and medical devices. In the last three years, companies paid nearly $2 billion to healthcare providers for speaker-related services.

In a special fraud alert released this week, the Office of Inspector General (OIG) for the Department of Health and Human Services warned against the practice, saying high-priced speaker programs “may be subject to increased scrutiny.” The OIG cited cases where speaker programs were held at wineries, stadiums and restaurants where expensive meals and alcohol were served at no charge to attendees.

“OIG is skeptical about the educational value of such programs. Our investigations have revealed that, often, HCPs (healthcare providers) receive generous compensation to speak at programs offered under circumstances that are not conducive to learning or to speak to audience members who have no legitimate reason to attend,” the report warns.

“Furthermore, studies have shown that HCPs who receive remuneration from a company are more likely to prescribe or order that company’s products. This remuneration to HCPs may skew their clinical decision making in favor of their own and the company’s financial interests, rather than the patient’s best interests.”

Production of Two Excedrin Brands Halted

By Pat Anson, PNN Editor

Spot shortages of Excedrin are being reported after a pharmaceutical company halted production of two leading brands of the pain reliever due to “inconsistencies” in their ingredients.

GlaxoSmithKline (GSK) says consumers are not at risk, but as a precaution it has indefinitely suspended all production and distribution of Excedrin Extra Strength and Excedrin Migraine.

“Through routine quality control and assurance measures, we discovered inconsistencies in how we transfer and weigh ingredients for Excedrin Extra Strength Caplets and Geltabs and Excedrin Migraine Caplets and Geltabs,” GlaxoSmithKline said in a statement.

“Based on the available data, GSK believes that the product does not pose a safety risk to consumers. However, as a precautionary measure, GSK Consumer Healthcare has voluntarily implemented a discontinuation of production and distribution.”

Some drug stores in upstate New York have already run out of Excedrin Extra Strength and Excedrin Migraine. GSK said other Excedrin products are still available and urged consumers to ask their pharmacist for advice on alternative pain relievers.

“We are working hard to resolve the issue as quickly as possible, but at this point in time cannot confirm a definite date as to when supply will resume,” the company said.

In 2012, an Excedrin manufacturing plant in Lincoln, Nebraska was shut down for several months after Excedrin bottles were found to contain broken tablets and stray tablets for other medications. That led to a recall and shortages of Excedrin products around the world.

At the time, the Excedrin brand was owned by Novartis. An FDA investigation found that Novartis failed to adequately investigate hundreds of consumer complaints of foreign products found in over-the-counter drugs produced at the Nebraska plant. Novartis spent millions of dollars re-tooling the plant and shifted some production to third-party manufacturers.

GSK now holds majority ownership of Excedrin through a joint venture with Novartis. GSK did not say where the new production problems originated.

Can Kratom Be Patented?

By Jane Babin, Guest Columnist

Discussions surrounding kratom are heating up following the Food and Drug Administration’s public health advisory, and questions have appeared about whether kratom and its constituents are patented or could be. 

The short answer is no.

Patents are important tools for protecting investment in innovation.  Without patent protection, far fewer new drugs would be developed.  An alternative is to keep details of an invention secret to ensure that no one will be able to copy it.  However, this approach isn’t possible in the pharmaceutical industry, where regulations require extensive public disclosure. 

To encourage inventors to share details about their inventions, the U.S. grants a patent right to prevent other people from making the same invention for a limited time, in exchange for publicly disclosing the details about the invention.  The public can read patents and apply their disclosures to other situations, which immediately advances science and technology.  After a patent expires, the invention itself can be made by anyone.

Patents Granted for a Limited Time

U.S. Patents 3,256,149 (“Compositions Compromising an Alkaloid of Mitragyna Speciosa and Methods of Using Same”) and 3,324,111 (“Speciofoline, an Alkaloid from Mitragyna Speciosa”), were both granted to Smith Kline & French Laboratories.

FDA Commissioner Scott Gottlieb has ties to GlaxoSmithKline (the successor to Smith Kline & French) and some have suggested a conflict of interest motivated his warning about kratom.

If there is a conflict, it isn't over these patents, which were issued in the 1960's and have long since expired.  Patents are granted for a limited time.  Currently, patents expire 20 years after filing.  Prior to 1995, a patent term was 17 years from the date of issuance.

Products of Nature are Not Patentable

Prior to their expiration, the two patents gave Smith Kline & French the right to prevent others from making, using, selling, and importing certain alkaloids isolated from kratom, but not the whole plant or leaf. 

Plants themselves and other substances found in nature have never been patentable, unless they are changed substantially by an inventor.  In the 1960s, isolating a substance from a plant was considered a substantial change to the substance. Today it isn’t. 

Courts have held that substances found in nature, even in impure form, cannot be patented whether they are isolated from a natural source or synthesized in a lab.  If a chemical has the same structure as a natural substance, it is not patentable.

Derivatives are Patentable

Derivatives of natural chemicals can be patented, however.  As good as a natural chemical may be, changing it slightly may make it even better -- or worse.  Scientists tweak a compound's structure to alter its properties, repurpose it, investigate interactions with other molecules, and design around compounds that are unpatentable. 

Patents have been granted for derivatives of kratom alkaloids, particularly derivatives of mitragynine and 7-hydroxymitragynine (e.g. U.S. Patent Nos. 8,247,428 & 8,648,090), which potentially may become new drugs that are improved over natural alkaloids. 

Even if they are never commercialized, studying how structural changes affect biological activity can lead scientists to modify other compounds to impart similar properties.  For example, making non-addictive kratom derivatives may show scientists ways opioids could be made non-addictive. 

U.S. patent law recognizes the importance of such inquiry and includes an exception under 35 USC §371(e), allowing scientists to use patented inventions in certain types of research.  Unlike scheduling under the Controlled Substances Act, no permission or pre-approval is needed to take advantage of this exception.

Distinguishing a Patent from a Published Application

Another misconception about patents is that every document that looks like a patent is one.  To obtain a patent, an inventor must first file an application, which doesn't become a patent until the Patent Office is satisfied that it meets all legal requirements. Whether granted or not, the application is usually published, and it looks very much like a granted patent. 

There are two ways to distinguish a U.S. patent from an application:

1. U.S. Patents have the words "US Patent" at the top of the first page, while applications have "US Patent Application Publication."
2. Current patents are identified by a 7 digit number.  Published applications numbers have eleven digits beginning with a 4 digit year. For example, 9,458,426 is a US patent, while 2014/0186948 is a published application.

Foreign countries also issue patents and an inventor must obtain a patent in each country where he or she wants to enforce patent rights.  Thus, there may be multiple patents covering the same invention in different countries.  Each country has its own numbering system and may or may not publish applications prior to granting them.  Instead of immediately filing multiple applications in foreign countries, inventors can initially file a single international application with the World International Patent Organization (WIPO) under the Patent Cooperation Treaty (PCT), which can be used as the first step toward patents in many countries.  

Requirements for a Patent and Examination

Applications don't automatically become patents.  They are first examined to see if a patentable invention that meets certain legal criteria is described and claimed.  In addition to claiming patentable subject matter, an invention must be novel, non-obvious, and the application must disclose sufficient description that someone in the field would be able to make and use the invention. 

Examination involves a dialogue between applicant and a patent examiner, often resulting in changes to the claims (the legally enforceable part of a patent).  Some applications are never granted.

US 2010/0209542 is a kratom-related application that is frequently discussed.  It claims a method for treating withdrawal from an addictive substance using a kratom extract.  When this application was first examined, it was rejected because existing literature described kratom itself as being addictive.  The applicant might have overcome this rejection by arguing that kratom is non-addictive or that other addictive substances are used to treat withdrawal.  However, the inventors faced bigger challenges because they didn't actually treat anyone for withdrawal with a kratom extract and described no studies of their own showing the method actually worked. 

Self-treatment using kratom had been reported, but that didn’t help the application because it meant that the applicant was not the first to "invent" the method and the invention was not novel.  Facing an uphill battle, the application was abandoned and never matured into an enforceable patent.

There may be many obstacles on the path to general acceptance of kratom as a beneficial herbal supplement.  Fortunately, patents are not one of them.

Jane Babin, PhD, is a molecular biologist and a biotechnology patent attorney in southern California. Jane has worked as a consultant for the American Kratom Association, a pro-kratom consumer group.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.