FDA Reaffirms Plavix Black Box Label Decision

The US Food and Drug Administration (FDA) is standing by its original decision to update the Plavix label with pharmacogenetic information. A meta-analysis published last year in the Journal of the American Medical Association led by Michael Holmes of the University College of London, raised questions about whether the label changes were premature.

The FDA black box warnings are the strongest type of printed warnings put on prescription drugs. Many pharmaceutical companies and physicians believe black box warnings stigmatize a drug and lead to a decline in prescription rates. However, to date, there is no evidence of a meaningful relationship between the warning labels and any changes in demand.

The CYP2C19 enzyme converts Plavix into its active form. Pharmacogenetic testing identifies the amount of the enzyme a person creates and assigns a value ranging from poor to rapidmetabolizers. The FDA updated the label to inform doctors that poormetabolizers experienced a diminished response to the drug. In 2010, the FDA added the black box warning to highlight that poor metabolizers exhibited a higher cardiovascular risk following acute coronary syndrome or percutaneous coronary intervention (PCI) than normal metabolizers. Both warnings emphasized that pharmacogenetic tests could help guide therapeutic strategies, with the black box advising doctors to "consider alternative treatment strategies" in poor metabolizers.

Holmes et al noted “evidence of small-study bias” in the data collected by the original meta-analysis, and restricted their analysis to only four studies with 200 or more events. These four studies, plus six randomized trials, failed to identify any significant associations between CYP2C19 genotypes and Plavix efficacy in terms of cardiovascular events and bleeding.

According to Lawrence Lesko, former director of the Office of Clinical Pharmacology at FDA's Center for Drug Evaluation and Research, emerging data has shown that the FDA was right in updating the Plavix label. He noted that two other meta-analyses, published before the Holmes et al study, found that poor metabolizers were at heightened risk for cardiac events. Jessica Mega, a cardiologist at Brigham and Women’s Hospital authored a meta-analysis two years ago reporting Plavix-treated patients who were poor to intermediate metabolizers had a “significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis.”

Scripps Health Chief Academic Officer, Eric Topol, has repeatedly argued that CYP2C19 pharmacogenetic testing is most useful in patients who have undergone PCI and are at risk of stent thrombosis. Many agree that these studies have been positive and that the resulting dialogue continues to be extremely valuable to doctors and patients. Ultimately, conversations like the Plavix/FDA debate continue to underpin the value of pharmacogenetic testing in treatment strategies.  

Did You Know?

More than 50% of the most commonly prescribed drugs are processed by enzymes whose levels vary due to genetic factors. This genetic variability is a leading cause of adverse reactions.

There are over 2 million severe adverse drug reactions every year.

Every day more than 5,000 Americans have  an adverse drug reaction serious enough to require hospitalization.

In 2001, the direct healthcare costs associated with adverse drug reactions were estimated at $177 billion.

Personalized Prescribing in Action: Case Study

You don’t need genetic information to benefit from YouScript™!

A 62-year-old male doctor whose health conditions, at the time, included hyperlipidemia, erectile dysfunction, dental carries, and insomnia. His daily medications consisted of aspirin, Lipitor, Viagra (as needed), and chlorhexidine mouth rinse, also valerian root, melatonin, and Benadryl for sleep. Along with coffee and energy drinks, the subject had been taking over-the-counter medications including: fish oil, coenzyme Q10, Niacin 1000mg, L-carnitine, Voltaren gel (purchased from Mexico) and IBU 400-600 mg daily as needed for need pain. He had no known drug allergies.

His ophthalmologist instructed him to start taking the over-the-counter herbal medications Wobenzyme, red yeast rice, curcumin powder, and grape seed as supplements.

Soon after adding the supplements to his daily regimen, the doctor began to experience muscle aches, pains, and flu-like symptoms.

Unfortunately, the ophthalmologist had advised the doctor to take substances that interacted with the prescribed medications he was taking. The interactions were severe and based on the report may have been early signs of rhabdomyolysis.

Had either the doctor or the ophthalmologist utilized YouScript™ prior to initiating the OTC herbals, they would have seen the following interactions:

·         Red yeast rice contains the compound lovastatin which is in the same class of drugs as Lipitor. The subject was already on high dose Lipitor. This combination alone could have resulted in the adverse reactions described. This combination is not advised.

·         Levels of lovastatin may be increased up to 150% by grape seed due to 3A4 inhibition. Levels of Lipitor might also be increased but to a lesser extent. This interaction could also help explain the adverse reaction the patient had.

·         Clinical studies show that co-administration of niacin and lovastatin has been found to increase the risk of rhabdomyolysis. The lovastatin product insert recommends no more than 20 mg daily when niacin levels exceed 1 gram per day – however, since the patient was taking lovastatin in a non-standardized form, it is unknown how much he was truly receiving.

Once the doctor stopped taking the drugs and herbal preparations recommended by his ophthalmologist, the problems resolved.

You don’t need a patient’s genetic information to benefit from YouScript™. It is a powerful algorithm-based program that can help patients and practitioners predict clinically significant drug interactions before they happen. YouScript™ predictions are based on clinical studies and the most up to date expert opinions in the field.

Identifying Twins: DNA Straight Talk

Some may not see the value in knowing the difference between identical and fraternal twins, but to the parents of twins, it can matter a great deal. It’s a part of their children’s identity.

Unfortunately, according to a new study, a fair number of parents were misinformed due to a common misconception that twins who gestate in separate placentas are fraternal. Actually, 25-30 percent of identical twins have separate placentas and amniotic sacs.

A 2004 survey among members of the American College of Obstetricians and Gynecologists found that 81 percent of doctors were under this misconception. This new study, published in the journal BJOG this past February, showed 14.7 percent of  the 1,302 parents of same-sex twins were misinformed that their twins were either identical or fraternal.

The type of twins was confirmed through DNA testing, which may be a lesson learned for the future. With the availability, accuracy, and simplicity of DNA testing, the “rule of thumb” no longer need apply.

“I think there are a lot of parents who just want to know. A lot of parents finding out later on felt they just didn’t know their own children.” -Abi Fisher,an author of the study

New Look, New Brand, and New Pharmacists

After more than a decade, the medical and insurance communities are beginning to embrace DNA-based analysis as a powerful tool in selecting and optimizing pharmaceutical treatments. Genelex has been a consistent front-runner in these technologies.

GeneMedRx and our drug sensitivity tests are combining under our new YouScript™ brand. Over the next few months, you’ll notice changes in our informational materials and a major upgrade to our services.

Tyler Mamiya & Paul Verbeurgt  

For those who haven’t taken advantage of GeneMedRx, our new YouScript™ Personalized Prescribing System is a comprehensive, long-term solution for safer, more targeted prescribing. Most patients taking a series of drugs have genetic variations that affect their ability to process those drugs – to either eliminate or activate them. This includes most classes of routinely prescribed drugs, over-the-counter medicines, many herbal preparations, and some dietary supplements and foods. Cytochrome P450 testing detects those genetic variations.

Now, whenever a major or significant drug-drug or drug-gene interaction risk is noted, YouScript™ will generate a medication advisory report including potential alternative drug or dosing recommendations based on the patient’s DNA test results and overall medication regimen.

To bring more clarity to the prescribing process, we have a new team of clinical pharmacists: Paul Verbeurgt and Tyler Mamiya. They are busy analyzing patient medication regimens, DNA test results, and recommending specific actions to help improve prescribing outcomes. They are available to help prescribers, patients, and other pharmacists understand specific cases and to guide users in getting the most out of the YouScript™

system.

We’re celebrating the evolution of our state-of-the-art personalized prescribing services. We encourage you to join in the excitement, and the opportunity to improve patient care, by taking advantage of our new services today!