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4 posts from September 2011


The TYLENOL Follies

By Dr. Daniel A. Hussar who is the Remington Professor of Pharmacy at University of the Sciences' Philadelphia College of Pharmacy. He serves as the author and editor of The Pharmacist Activist newsletter (http://www.pharmacistactivist.com) from which this editorial was taken.

Which of the following is the recommended maximum amount of acetaminophen that may be taken (in divided doses) by an adult during a 24-hour period?

a. 4,000 mg
b. 3,000 mg
c. 3,250 mg
d. 3,900 mg
e. It depends on the particular formulation
f. It depends on the company making the formulations
g. All of the above

And the answer is "g" - all of the above.
We will come back to this question later after considering some background information.

Acetaminophen is the most widely used medication in the United States. It is supplied as a single active ingredient in numerous products, and with one or more other active ingredients in hundreds of combination products. When used in the recommended dosage, it is one of the safest medications available. Because of its safety, as well as its effectiveness, I consider it to be the OTC analgesic of first choice for most situations associated with mild to moderate pain.

Very serious, and sometimes fatal, problems may result when acetaminophen is used in amounts that exceed the recommended maximum dosage. Acetaminophen overdosage is the most frequent cause of liver failure in the United States and approximately 100 people die each year from accidental overdoses (as distinct from intentional overdoses [i.e., suicide attempts]). Many of the accidental overdoses result from the concurrent use of two or more acetaminophen-containing products, and most of the deaths have involved the use of prescription combination products such as Percocet (acetaminophen and oxycodone) and Vicodin (acetaminophen and hydrocodone).

On June 29 and 30, 2009, 37 health professionals who serve on three FDA advisory committees were convened by the FDA for the purpose of recommending ways through which acetaminophen overdosages could be reduced. The most important of these recommendations are considered in my editorial in the

July 2009 issue of The Pharmacist Activist.

Recent actions
In early 2011 the FDA notified health professionals that it has asked manufacturers to limit the amount of acetaminophen in prescription drug products (primarily combinations of acetaminophen and opioids [e.g., Percocet, Vicodin]) to 325 mg per tablet, capsule, or other dosage unit, as a step to reduce the risk of severe liver injury. This action is planned to be implemented over a three year period, and does not apply to OTC products. In the FDA communication, health professionals are reminded to advise patients not to exceed the acetaminophen maximum total daily dose, identified as 4 grams/day.

In May it was announced that the companies that make single-ingredient liquid acetaminophen pediatric products would now provide them in only one standard concentration (160 mg/5 mL) to help prevent dosing errors. The more concentrated solutions of acetaminophen intended for administration as drops will no longer be supplied. I agree with this action although I sympathize with the parents having the challenge of administering a larger amount of liquid to a young child.

The recalls
Over the last two years, Johnson & Johnson/McNeil Consumer have had to initiate recalls of dozens of lots of Tylenol and other OTC and prescription products for a variety of reasons primarily related to manufacturing, production, and storage issues. For a company that has enjoyed such an exceptional reputation for decades, due in large part to the confidence of consumers and health professionals in the quality of its products, the continuing series of recalls has been nothing short of shocking. Explanations have been incomplete and unconvincing, but that is another story.

One consequence of the recalls has been that some Tylenol and other OTC products have not been available for many months. When consumers can't find the products they are looking for, with whom do they speak? Although some may contact the company, the vast majority present their questions to pharmacists who then commit the time to explain why the product they are looking for is not available and to recommend another product. I hesitate to even estimate the number of discussions (and the amount of valuable time committed) that pharmacists have had with consumers resulting from the recalls of just the Tylenol products and/or dosage issues relevant to these products. I was interested in the comments of an executive with McNeil Consumer that the company had received more than 73,000 phone calls in 2008 and 2009 about infants' and children's Tylenol products. Based on this number of calls received by the company during a two year period, I have to think that the discussions between consumers and pharmacists regarding Tylenol products number in the many millions.

In my opinion, Johnson & Johnson/McNeil Consumer should be greatly indebted to the nation's pharmacists for the amount and value of time they have devoted to providing responses to questions about recalls and dosage issues regarding Tylenol products (and its other recalled products). However, I am not aware of any acknowledgement or expression of appreciation from the company or its executives for the service and time committed by pharmacists in explaining/clarifying problems the company caused.

Even more confusion ahead
As Johnson & Johnson/McNeil Consumer begins to bring recalled products back to the market, it is making changes in the dosage recommendations for some Tylenol products. In late July, it announced "plans for new dosing instructions lowering the maximum daily dose for single-ingredient Extra Strength Tylenol products sold in the U.S. from 8 pills per day (4,000 mg) to 6 pills per day (3,000 mg). The dosage is designed to help encourage appropriate acetaminophen use and reduce the risk of accidental overdose." These new dosing instructions will appear on packages of this product this fall.

The announcement also notes that the company "will also be lowering the maximum daily dose for Regular Strength Tylenol and other adult acetaminophen-containing products beginning in 2012." It is my understanding that the maximum daily dose that will be recommended for Regular Strength Tylenol will be 3,250 mg (10 tablets each containing 325 mg), and that the maximum daily dose for Extended-release Tylenol will remain at 3,900 mg (6 caplets each containing 650 mg). As a consequence, there will be Tylenol products for adult use that have maximum daily doses of 3,000 mg, 3,250 mg, and 3,900 mg. How do these changes reconcile with the request from the FDA earlier this year that health professionals advise patients to not exceed the maximum daily dose of 4,000 mg?

The dosage changes being implemented give every appearance of being some sort of marketing strategy rather than a plan to enable optimum pain relief and safety. If anything, the title of this editorial, The Tylenol Follies, is too weak of a description for this plan. If it is really important that the maximum daily dose of Extra Strength Tylenol be reduced to 3,000 mg, why should the maximum dose of Extended-release Tylenol not also be reduced in a similar manner?

Johnson & Johnson/McNeil Consumer has acted unilaterally in changing the dosage of certain Tylenol formulations. The FDA has not required these changes to be made. There is no reason to think that the other companies that make acetaminophen-containing products will decide that it is wise for them to change to the same multiple maximum doses being implemented for Tylenol products. Although the Johnson & Johnson/McNeil Consumer announcement notes that it "...is working closely with other manufacturers of acetaminophen products to help ensure consistency in dosing instructions," what incentive is there for other companies to do that? Indeed, the company that markets the new formulation of acetaminophen that is administered intravenously has specifically confirmed that the approved dosage recommendations remain at 4,000 mg/day for adults. The FDA should require Johnson & Johnson/McNeil Consumer to rescind its plans to change the dosage of Tylenol products until dosage regimens that provide the best balance of efficacy and safety considerations can be identified and adopted by all companies that supply acetaminophen-containing products.

The Johnson & Johnson Credo
Johnson & Johnson has what I consider to be an exceptional Credo (that may be accessed on its website), but it has one very important omission in the first sentence (noted below):

"We believe our first responsibility is to the doctors, nurses, and patients, to mothers and fathers and all others who use our products and services."

The omission to which I refer is that pharmacists should be specifically identified as individuals to whom Johnson & Johnson has a responsibility. I have written to the current CEO and the previous CEO of Johnson & Johnson to specifically request this change. I received courteous responses from both individuals with the basic message (with my paraphrasing) that the company loves pharmacists but rarely changes its Credo.

Johnson & Johnson must no longer ignore the expertise, services, and time of pharmacists that have been of great value in the past success of its products and company. It should change the Credo now to include pharmacists. Our professional associations should take action to obtain this long-overdue recognition.


Start’Em Young–Nurturing the Next Generation of Scientist

Grade school children are natural scientists.  Early in their education, everything they do is an experiment, both new and wonderful.  Can we nurture that sense of wonder and excitement so as adults they become the next generation of innovators who sustain our nation’s leadership in the sciences and technology? 

For many of our nation’s students, the study of the sciences and healthcare are drudgery.  Consequently, nearly half (49 percent) of U.S. high school students will not consider a career in the sciences or healthcare.  They feel they are not sufficiently prepared or encouraged, and some are convinced the sciences are just too tough for them.  We know this from a 2011 survey of high school students Harris Interactive conducted for the University of the Sciences in Philadelphia (USciences), which showed an 8.9 percent increase in students not considering future careers in the healthcare and sciences from the 2010 survey Alarmingly, the lack of interest among younger teens (aged 13-15) also grew and stands near 60 percent.

The most recent Trends in International Mathematics and Science Study (2007) has U.S. students scoring around the global average.  While showing improvement over prior TIMSS results, we can and must do better if our nation is to maintain its ability to compete in a global economy.  Tellingly, TIMSS shows students’ scores tend to go down as they progress in their school careers, another indicator that even when we hook students on the sciences early, we must find ways to make the sciences ever more engaging as students progress through their primary and secondary school years.

To break through the stereotypes and make sure our nation continues to play a leading role globally in scientific endeavors, and to ensure we have the healthcare providers our aging population will require, we need to fundamentally change our approach to science education.

Parents and educators can, and should, do more to help young people develop a greater appreciation for opportunities in the sciences and in healthcare.  By learning to deal with their own prejudices or inadequacies today’s adults can be more supportive in nurturing the scientists of tomorrow.  Teachers, especially grade school teachers, can create a new science paradigm for their students: making science fun.  The idea is exciting, it’s creative and it’s very, very doable … if teachers and parents will approach the challenge with an open mind and a positive attitude. 

One approach to making the study of the sciences fun has its roots in show business.  Jeffrey Vinokur, then a college junior, used his interest in the sciences to create an act he took all the way to Las Vegas, competing in the television show “America’s Got Talent.”  Jeffrey made it to the top 100 finalists out of 70,000 acts that started the competition.  Since then, he has taken his act, “So You Think You Can Do Science,” on the road to elementary, middle and high schools.  We need more Jeffreys.

Our nation will fare much better in the long run, if we encourage schoolchildren to participate in and perform interesting, challenging scientific experiments, to see firsthand, and by their own hand, how things work and interact with their environment.  Once they have grasped their ABCs and 123s, students are ripe for science as play, exploring and understanding the world around them, allowing their minds to expand with new ideas, making them comfortable with the idea they can do it.

President Obama’s “Educate to Innovate” campaign is designed to improve the participation and performance of America’s students in science, technology, engineering, and mathematics.  This STEM-focused campaign includes efforts from the federal government and from leading companies, foundations, non-profits, and science and engineering societies encouraging young people across the nation to excel in the sciences.

Beyond sustaining the nation’s global leadership role, careers in the sciences can be financially rewarding.  For example, USciences is tied for 11th on a national list based on highest earning graduates.  USciences graduates are earning a median salary of $113,000 at mid-career, according to PayScale.com’s 2010-11 College Salary Report.

Funding and focus are important.  But the real solution is to get parents and teachers to start ’em young — fourth grade’s not too soon.  Make it fun.  Build on kids’ natural curiosity.  Encourage them to ask questions, rather then just rote respond to them.  Too many students are turned off by an Archie Bunker “Stifle yourself!” approach to education.  Take a page out of Jeffrey’s book and make science the highlight of the school day today and the pathway to stupendous accomplishments tomorrow.

Russell J. DiGate is provost at University of the Sciences. He can be reached at r.digate@usciences.edu.


DRUG SHORTAGES - Pharmaceutical Companies Have Caused This Problem and it is Their Responsibility to Resolve it!

By Dr. Daniel A. Hussar who is the Remington Professor of Pharmacy at University of the Sciences' Philadelphia College of Pharmacy. He serves as the author and editor of The Pharmacist Activist newsletter (http://www.pharmacistactivist.com) from which this editorial was taken.

There have been numerous concerns voiced about the high cost of prescription medications to which the pharmaceutical companies have responded that this level of revenue is necessary to support their extensive research programs that will result in the development of new life-saving drugs. The companies have had their way and, unless there are strong competitive restraints, have been able to set the prices for their medications at whatever level they choose or, as some would suggest, whatever the market will bear. A recent example is ipilimumab (Yervoy), an important new drug for the treatment of metastatic melanoma, for which the cost of a four-dose treatment regimen is approximately $120,000. And it is not just these intravenously-administered monoclonal antibodies for which the cost is high. For example, the cost of the important orally-administered antibiotic linezolid (Zyvox) is more than $100 for each tablet.

Although the high cost of medications is a continuing concern, it is mentioned here primarily for context in considering what I would suggest is a related issue - drug shortages - including situations in which certain life-saving medications are not available on a timely basis at any cost.

Shortages of drugs used to be isolated experiences. However, in 2011 alone, more than 200 drugs have been in short supply and some of these situations have reached crisis proportions. There have been serious shortages of medications used in surgery (e.g., propofol), critical care situations (e.g., furosemide, norepinephrine, labetalol), and the treatment of certain cancers (e.g., cytarabine). Patients with a diagnosis of cancer have a huge challenge in coping with the implications of their illness. They should not have to experience the additional uncertainties and anxiety as to whether the medications they need will be available, or the fear prompted by a call from the oncologist to cancel an appointment because the dose of the medication to be administered is not available. The American Society of Health-System Pharmacists is providing important leadership in increasing the awareness and urging action with respect to the shortages and the extremely important risks presented, and the Food and Drug Administration is doing much more to identify situations in which drug shortages exist or can be anticipated. However, progress has been slow and the need for action is urgent.

Consequences of Drug Shortages

Some of the medications for which there are shortages are life-saving drugs and patients may be endangered when they are not available on a timely basis. This is clearly the consequence that requires the highest priority attention.

Price-gouging has been another consequence of the shortages, with the prices requested for some drugs being 50 times their usual costs. An article titled, "Drug Shortages Lead to price gouging," (Liz Szabo in USA Today, August 18, 2011, p. 3D) begins:

"Scalping tickets to a rock concert can get you arrested. But reselling lifesaving medications at a hefty markup is a thriving business."

The antihypertensive drug labetalol is often used in emergency situations and is one of the examples cited. The usual cost is approximately $25 a dose but some hospitals have been asked to pay as much as $1,200.

Shortage situations result in the development of a "gray market" in which drugs may not be available from the manufacturer or usual wholesaler(s), but can be obtained from "nontraditional" suppliers about whom little may be known. Such situations raise questions as to whether the stability and quality of the products have been maintained, and even whether counterfeit supplies of medication have been distributed in these secondary distribution channels. The profession of pharmacy should establish a "registry" of organizations and individuals who are involved as secondary suppliers of medications and/or in the sale of medications at prices that differ significantly from the usual price. This registry could have a Better Business Bureau-like role. Experiences of pharmacists who have purchased medications from these suppliers could be entered in the registry that could be accessed by other pharmacists considering such purchases.

There have been allegations that some of the current shortages may have been anticipated and that "speculators" were able to buy large quantities of these drugs that they were later able to sell at a much higher price. It does not require a leap of imagination to recognize that, for certain drugs, unscrupulous individuals could create a shortage by buying most of the supply at a relatively low price and reselling it at a much higher price when its availability has been artificially limited.

There are even allegations that some pharmaceutical companies may be using concerns about drug shortages as a scare tactic in the marketing strategies for certain of their drugs. This could be done by suggesting to pharmacies that they buy a larger-than-usual amount of a drug so that they would be assured of having an adequate supply in the event of a shortage. A variation of this strategy is to note that there is only a limited supply of an important drug (e.g., an anticancer drug) and, that to guarantee the continued availability of this medication for their patients, physicians should register them in a special program with the company.

Pharmaceutical Companies Must be Accountable

Most of the medications that are currently in short supply are not drugs for which sophisticated technology is required for their production or for which demand has unexpectedly and sharply increased. Various explanations for the shortages have been proposed including increased regulatory requirements and monitoring, less reliable sources of raw materials, and consolidation within the pharmaceutical industry. Some are advocating greater regulatory authority for the FDA and/or legislative action that would help prevent drug shortages. However, there has been too little attention given to the need for the pharmaceutical industry to be more accountable.

Many of the drugs for which shortages are of the greatest concern (i.e., life-saving or life-extending medications) are older drugs for which patents have expired resulting in their availability in less expensive generic formulations. These drugs are no longer highly profitable for the companies that developed and initially marketed them, and there is not an incentive for these companies to be certain that there are adequate supplies of these drugs available. Indeed, in a number of situations, a company that initially developed and marketed a drug that generated billions of dollars in profits during the period in which it had patent protection, discontinues marketing the drug or sells it to another company when generic equivalent products become available.

The pharmaceutical industry takes pride and credit, and rightfully so, for the development of life-saving drugs and many other medications that cure or effectively control numerous medical problems and/or greatly improve the quality of life. These companies justify the high prices for the medications they bring to the market by claiming that this revenue is needed to support the research programs that will result in the development of more life-saving drugs. However, if this pricing strategy of the companies is to be credible, and if the companies are to be recognized for the development of drugs that are of great value for patients, the companies must also accept the responsibility for assuring the availability of these drugs on a timely basis, even after patents have expired and they are available generically.

The pharmaceutical industry, collectively and as individual companies, must resolve the drug shortage problems that currently exist and should develop a system/strategy through which needed medications are available on an uninterrupted basis and shortages are avoided. One approach could be to have the FDA's initial approval of a drug include a commitment from the company to make supplies available on a timely basis unless, at some future time, there is agreement between the company and the FDA that there is no longer a valid need for the drug, or that arrangements deemed acceptable to the FDA are made through which the responsibility for supplying the drug is transferred to another company. In this latter situation, if a company is purchased by another company, the responsibility for maintaining the supplies of the medications would also be assumed by the purchasing company.


George Gamow, pioneer of the Big Bang

On a recent visit to Boulder, Colorado, I had the opportunity to visit the grave of George Gamow, pioneer of the Big Bang.

Born in Odessa in 1904, then part of the Russian empire, Gamow escaped to the west and became professor at George Washington University. There, along with his student Ralph Alpher, he developed the concept of Big Bang nucleosynthesis. He later moved to Boulder where he was Professor of Physics at the University of Colorado. He wrote numerous popular books, and died in 1968.

Here are a few photos of Gamow's grave:

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