Who Is Addressing the Availability, Safety & Efficacy of our Medications?

I watched all three presidential debates this summer with health care being a time-consuming topic for all. Universal health care and Medicare-for-All, with or without an option for private insurance, were debated and discussed at length.

At the same time NBC Nightly News presented a story documenting that all our antibiotics come from production in China. With globalization policies, which promote moving production to lower cost overseas factories, there is no longer any production of antibiotics in the USA. A former member of the Joint Chief of Staffs, citing the current trade conflicts and China’s aggressive military stance in the Pacific, considers this a security issue. I have heard not one question or comment on this topic in the debates?

This week, once again, the blood pressure medicines losartan and valsartan were recalled because they contained potential carcinogens. These generics were produced in India, Asia and Israel. These same drugs have been recalled multiple times in the last few years for similar problems.

Due to reduction in funding for FDA inspections, many of these foreign plants have not been inspected for years. We can add recalls of generics to drug shortages. We suffered a shortage of intravenous fluids for hydration because the primary production site in Puerto Rico was destroyed in a hurricane. We had shortages of morphine and its derivatives for treatment of orthopedic trauma and post-surgical pain. They substituted foreign-produced short acting fentanyl. I saw pediatric ER physicians unable to administer the most effective treatments for sickle cell crisis in children because it required the use of a narcotic drip to offset the dramatic pain the treatments induce as they stop the crisis.

Then there are the psychiatric patients on antidepressant generics who are paying hundreds of dollars per month for products that wear off in 16 hours rather than 24 as the brand product did. Their symptoms creep back in allowing them to tell time based on the reduced efficacy of these products. By law, generics are required to provide 80% of the “bioavailability” of the brand product but what does that mean and who is testing?

This all began when the Reagan Administration closed the FDA research lab. Prior to that, all new products were sent to that lab for approval prior to being released in America. On their watch, a pharmaceutical product never had to be recalled. Big Pharma complained they took too long as did some consumer groups. This resulted in the defunding and closing of the lab. Products are now outsourced to private reference labs and their reports are sent to the FDA for review. The frequent drug recalls contrast to the success of promoting safety when the FDA did it themselves.

Isn’t it time for the health care debate, especially the presidential debates, to discuss the safety, efficacy, supply and cost of pharmaceutical products? I am all for bringing production home to the USA, restoring the FDA funding for the reopening of their lab as an impartial test site and putting the cost of repeatedly testing the generics for efficacy even after approval and release on the backs of Big Pharma. Let’s see these topics introduced to the health care debate too.

Generics and Therapeutic Substitution – Safety and Efficacy?

Excuse me for being a “doubting Thomas,” but when I saw articles in JAMA Internal Medicine and commentaries supporting use of generics instead of brand name drugs I asked myself “Where is the proof of equivalent results and safety?”.  Generic substitution implies that the original product is no longer patented and exclusive and another firm is now producing an identical chemical version which produces the same beneficial effects on the patient.  Therapeutic substitution means your pharmaceutical insurance company or pharmacy changes the drug you are prescribed to one in the same drug class. Think of drinking Coca Cola and having the supermarket substitute a comparable brand instead.

The reason for this is simply to spend less money. Many pharmaceutical insurance companies realize if they put an obstacle in your path of obtaining your medication you likely will pay for it independently saving them money.  The authors of the JAMA articles estimate between 2010 and 2012 therapeutic substitution would have saved $73 billion. The out-of-pocket savings to the patient would have amounted to $25 billion.

I’m for saving money and spending less with certain guidelines. However; I want to know that a generic medicine is produced in a factory inspected by the Food and Drug Administration (FDA) at least as frequently as the drugs produced in North American factories. I like to know where the drug was made including country of origin, city, location and the plant’s track record for health and safety. I also want to know the generic medication produces the same drug levels and positive effects as the brand name medication and is made with no more contaminants than the original branded product.

I need reassurance that my patient isn’t receiving a counterfeit product with stolen original labeling, which has been a scam fooling pharmacists and Customs agents for years.   I would additionally like to know that the generic product, or therapeutically substituted product, works as well as the original. We know for example that Levothyroxine generics and substitutions are problematic.  We additionally know that the beta blocker carvidilol (Coreg) has certain unique properties that other beta blockers do not provide making therapeutic substitution for less expensive medications in the beta blocker class problematic.

Once this information is available it should be distributed in package inserts, online and taught in pharmaceutical, nursing and medical school courses as well as CME courses for health care professionals.

There is an abnormally perverse concern that if a pharmaceutical representative takes a health care provider out for a meal and a drink while explaining their product, we will prescribe it even if it is more expensive or doesn’t work as well.  I doubt sincerely that most physicians would do that but do believe if the cost is comparable, or less, and the efficacy is as good, they might choose the product as a viable alternative.

Viagra, Cialis and Levitra Use and Malignant Melanoma

Risk v1Jiali Han, Ph.D of the Indiana University School of Public Health in Indianapolis reported in JAMA that use of Viagra or sildenafil was associated with an 84% greater risk of malignant melanoma. Their preliminary data obtained from the Health Professionals Follow-up Study (HPFS) looked at 51,529 men aged 40 – 75 years old and all health professionals. Beginning in 1986 these individuals filled out a detailed health questionnaire every other year. The researchers reached their conclusions after reviewing the 2,000 HPFS survey and excluding all participants with a history of melanoma, squamous cell cancer or basal cell skin cancer prior to calendar year 2000. They were left with 25,848 men who had a mean baseline age of 64.8 years. 5.3 % of these men (1370) reported use of sildenafil (Viagra). From 2000 until 2010 142 melanomas were reported in that group.

The authors theorize that Viagra and the other drugs promote tumor growth by inadvertently inhibiting our immune system’s ability to suppress tumor growth messages at the genetic and molecular level. They emphasize that this is a preliminary study that does not prove cause and effect but does generate enough concern to warrant the creation of a study to answer the question” Our data provide epidemiological evidence on possible skin adverse effects of PDE5A inhibitors and support continued investigation of this relationship.” There was no mention of frequency of use or dosage and development of melanoma.

The authors were clear that if the relationship does in fact hold true, it extends to all the drugs in this class. Considering the billions of dollars in pharmaceutical profit involved it is hard to imagine that the question will not be addressed in a well-planned and funded study.

Pradaxa: More Concerns. More Myocardial Infarctions?

Pradaxa is part of a new group of anticoagulants (thrombin X inhibitors) that eventually will allow anticoagulation by the pill route without requiring patients to alter their food and medication intake and avoid foods and medications that interfere with the anticoagulant as patients must do with Warfarin. Pradaxa additionally eliminates the need to take blood tests (INR/ PT) to monitor the dosage as one has to do with Warfarin (Coumadin).

There is a large commercial advertising campaign underway on TV and print media to encourage patients with atrial fibrillation to ask their doctors to switch them from Coumadin to Pradaxa (Dabigatrin).  The campaign bases its claims on the RE-LY trial of 18,000 patients at 80 medical centers throughout the world who took the 150 mg dosage and had significantly fewer strokes than patients taking Warfarin.  The original study was criticized because many of the patients in the Warfarin (Coumadin) group were not on enough Warfarin or at a therapeutic PT/INR to prevent embolic strokes so the comparison with Pradaxa may not be valid. Another criticism involved the fact that Pradaxa can cause major bleeding and there is no antidote to stop the bleeding. Patients on Pradaxa who are bleeding are advised to undergo hemodialysis to remove the drug from their system because there are no medications or treatments available to stop Pradaxa related bleeding.

One wonders how the Food and Drug Administration approved this product for general use under these circumstances without conducting further testing?  The issue becomes even more confusing with the addition of data presented by Ken Uchino, MD, and Adrian Hernandez MD, PhD of the Cleveland Clinic in the online version of the Archives of Internal Medicine. They claim that by reviewing the RE-LY data there is a 38% relative increase in the risk of a myocardial infarction (MI) or heart attack in the Pradaxa group. In an accompanying editorial in the same journal, clinicians at the Hadassah- Hebrew University Medical Center in Jerusalem wrote, “The robust finding that Dabigatran is associated with increased rates of MI (heart attack) is alarming and emphasizes the need for continued critical appraisal of new drugs after phase III trials.”

In my practice I generally will not switch to a new or controversial medication until it has been on the US market for at least one year. I make exceptions for orphan drugs, products to treat incurable diseases with no other choices available. The 12 months gives the medical and scientific community a chance to see how the medication performs and what unexpected adverse effects may be associated with it.

Thrombin X inhibitors are the wave of the future. With no way to stop the bleeding, and data on their safety and efficacy still accumulating, they are just not ready for prime time yet.

Smoking Increases the Risk of Breast Cancer, Lung Cancer and Colon Cancer in Women

The Surgeon General of the United States issued another report on the dangers of smoking and its addictive potential last year.  At the time of release I was quite skeptical about the cost of the report and the need to remind Americans again that smoking is dangerous for you.  Then along comes a detailed review of the National Surgical Adjuvant Breast and Bowel Project. According to Stephanie Land, PhD, of the University of Pittsburgh, long-time smokers had a 59% increase in the risk of invasive breast cancer compared with nonsmokers.  The study looked at the links between four types of malignancy: breast, lung, colon, and endometrial cancer with smoking, alcohol use and leisure time activity.  The findings suggested that:

1.       Women who had smoked between 15 and 35 years had a 35% increase in the risk of breast cancer compared to non smokers. In that same group, if a woman smoked more than a pack a day she had a five – fold higher risk than non smokers.

2.       Women who had smoked 35 years or more had a 59% increase in the risk of breast cancer. These long-term smokers had a 30 times higher risk of lung cancer than non smokers.

3.       The risk of colon cancer among long–term smokers was five times higher than among non smokers.  A drink of alcohol a day reduced the risk of colon cancer by 65% compared to non drinkers.

4.       Inactive women had a 72% increased risk of uterine endometrial cancer compared to active participants in the study.

The study of almost 14,000 women highlighted the benefits of improving life style choices.  While researchers search for drugs and medication to prevent these life threatening illnesses, the study pointed out the benefits of altering the life style choices of women to prevent the development of cancer.

It is clear that smoking prevention and smoking cessation programs can do far more to prevent these cancers than pharmaceuticals. With cutbacks on funding for public health and the elimination of most health and hygiene classes in middle schools and high schools due to financial constraints, I wonder if we are being penny wise and pound foolish.

Coumadin versus Pradaxa

Coumadin (Warfarin) is a blood anticoagulant which prevents clotting by inhibiting Vitamin K dependent clotting factors.  It is taken orally and becomes effective after several days of administration when the Vitamin K dependent clotting factors have been depleted.  It is inexpensive and has been used for years to prevent clots from forming in patients with the irregular heart rhythm known as atrial fibrillation.  These clots can form in the chambers of the heart and break off and travel to the brain causing embolic strokes.

Coumadin is additionally used to prevent recurrent blood clots in patients who have had phlebitis (or inflammation of a blood vessel) and in certain postoperative conditions such as joint replacements. Physicians monitor your ability to clot by drawing blood for a test called “the prothrombin time or INR (International Normalized Ratio).  The blood can be drawn from a vein and sent to a lab or performed by a finger stick method in a doctor’s office.  Based on the blood test result we adjust your medication dose up or down. Coumadin’s effect on blood clotting can be easily affected by certain foods rich in Vitamin K (green leafy vegetables in particular) and by medicines which either enhance or limit Coumadin’s effect on clotting.

The major complication of Coumadin is excessive bleeding. We stop the bleeding by administering Vitamin K and infusing blood products intravenously containing active blood clotting factors.

Pradaxa and the new wave of direct thrombin inhibitors that are now being released are designed to do the same job as Coumadin without requiring monitoring by blood test of your ability to clot. This new class of medications should have many fewer interactions with food and other prescription and over the counter medicines. Its two major drawbacks are bleeding and expense.  The drug was tested extensively in Europe and proved to be safe but it has been on the US market for less than six months. While Coumadin costs pennies per tablet, Pradaxa costs about $300 per month. It requires taking a pill twice per day.

It is clear that thrombin inhibitors like Pradaxa will one day replace Coumadin. For now I prefer to have other physicians’ patients use it and compile a safety record before I try it on my patients. We know the pros and cons of Coumadin.  Let Pradaxa survive the test of use on the US market, and time, and show a clear cut safety advantage before giving it to our patients locally.

Prescription Refills For My Patients

My office staff is instructed to automatically fulfill any refill request for active patients seen within the last six months requesting non-narcotic prescriptions. If your medication bottle says that you no longer have any refills, we ask that you call the office and request a refill rather than calling the pharmacy.

If you have been calling your pharmacy first when you are out of refills, we have most likely not received a message from them.  Pharmacies typically communicate with us electronically and if the transmission does not go through they just keep resending it without recognizing that the message is not going through.

In this scenario, patients have been told by the pharmacy that we have not responded to their request for a refill. We can not respond if we don’t know about it. Please, if you are out of refills please call us first and we will call the pharmacy and renew the medication.  If your prescription bottle shows that you have remaining refills then it is quicker to call the pharmacy directly and give the prescription number.