drug monograph

What is missing in your prescription?

Did you fill a prescription recently? If you did, you certainly received a 3-4 page printout called a drug monograph. This is a legal document that designed to explain:

  • the possible harms that could be caused by the drug (dizziness, nausea, etc.)
  • how it should be taken (i.e. take three times a day with food),
  • what avoid (i.e. do not drink alcohol, avoid milk and dairy products)

In theory this should be a very useful and important document; yet why do so many people give up after a few failed attempts read it? The problem is three fold –the legality, design, prescription issues.
Legality: a drug monograph is the outcome of a very lengthy legal process of review by regulatory agencies such as FDA, EMA or Health Canada that summarizes the results of clinical trials that demonstrated drug’s utility for a particular indication, what side effects were observed in the trial and how the drug should be administered. The company manufacturing the medication provides a monograph that could be used as a shield against possible liabilities, such as failure to disclose the risk of adverse side effects, while trying to make it palatable for physicians. The regulatory agencies use the drug label as a way to communicate with physicians who have to be aware of drug’s limitations. Sometimes the agencies slap what is called a “black box” – a specially highlighted warning about potentially dangerous side effects. The result of this “tug or war” is an incomprehensible mess and an almost useless document.

Design: language is the biggest “utility barrier”. Lawyers and scientists who do not care much about the readability and accessibility of the information tend to write the monographs. The limitation of space and conflicting desires to pack in an excess of legal information causes the font size to be decreased to an illegible size if the length suppressed to 4-5 pages as full text frequently exceeds 40 pages. Health Canada recognized the need for more “consumer-friendly” drug monographs.

The FDA has not standardized the “Table of Contents”; this varies from one medication to another. The inconsistency of terminology causes a difficult understanding for a layperson.
Only a few companies include graphical summaries of drug clinical trials showing the clinical impact of the specified medication, and even when they implement graphs, they are not optimized for the miniscule amount of space and monochrome printing, and the quoted publications are inaccessible most of the time.

Finally, the documents are printed on paper that is typically lost the next day, minimizing the utility of the drug monograph as a reference tool. Recently agencies stated to use enhanced PDFs that allow skipping to relevant sections, but the design and content are disastrous.

Prescription: Most importantly, though, the drug monographs do not help physicians decide how to use these medications in the most effective and safe way. Frequently, on the drug monographs frequently there are no clear guidelines on which patients should be getting the medications in the first place, though this is clearly stated on the initial drug approval documents. So which patients will get the medication is totally up to the physician, but this decision is swayed by legions of pharma sales reps. Secondly the “standard” dosage guidelines include calculations or formula based on patient’s weight, gender or age, and sometimes mention ethnic variability in drug response. However, the latter is worded in vague and unclear terms:

“The pharmacokinetics of perphenazine covary with the hydroxylation of debrisoquine which is
mediated by cytochrome P450 2D6 (CYP 2D6) and thus is subject to genetic polymorphism, i.e., 7%-10% of Caucasians and a low percentage of Asians have little or no activity and are called “poor metabolizers”. Poor metabolizers of CYP 2D6 will metabolize perphenazine more slowly and will experience higher concentrations compared with normal or “extensive” metabolizers.”

So how are physicians expected to find who is in the “7%-10% of Caucasians and a low percentage of Asians” and how to dose the medication? Presumably physicians need to refer to genetic testing to find out, but this is not explicitly stated, but even if the genetic testing is done how physicians need to adjust the dosage? Such absence of clear guidelines leaves too much guess work, so naturally physicians choose to ignore this section as pharmacogenetic testing is not a routine clinical practice.

In theory, over 100 medications have FDA mandated labels that link drug response to specific genetic variations, yet none of the medications stated how the results of genetic testing should be used in clinical practice. It is up to a physician to scan the literature for clinical guidelines and best practices, and in chronic shortage of time it is not feasible in real life. So the FDA has very good intentions to improve the safety of medications by providing drug-gene interaction alerts, but without specific recommendations the effort is largely fruitless.

So in the end another questions came to my mind: who is responsible to ensure that the medication is given at the correct dose to right patient, and at the right time? “Of course, it is the physician’s responsibly!” – you might say, but is it pharmacist who filled your prescription and ensured right dosage? Or is it the nurse who actually gave you the pill? With such distributed responsibility and lack of clear recommendations you better act on your own behalf, and educate yourself carefully before swallowing that pill because it might cure or kill you, depending on the dosage, your genes and what you ate in the morning….