New drug candidates undergo immense testing and review before being approved for use in patients. On average, it takes less than $1 billion to over 2 billion dollars in research and development costs and 10 to 15 years to bring a single drug to market. Despite this, continued safety monitoring of medicines after regulatory approval can reveal severe safety issues in some patients, leading the FDA to withdraw a drug from the market or issue a black box warning for a drug with potentially severe side effects.

What is a black box warning?

‍Black box warnings refer to prominent warnings on medication containers and in the literature that describe severe side effects and safety hazards of a drug when a drug should not be used, as well as steps that should be taken if they occur. Black box warnings are the highest classification issued for medications by the FDA and are designed to warn consumers and prescribers about potential drug safety issues. The FDA first implemented black box warnings in 1979. Since then, over 400 medications have acquired a black box warning.

A black box warning means that a particular drug, or often an entire class of drugs, has been shown to cause specific problems or severe adverse reactions, including death or serious injury, in humans or some animal studies. Notably, black box warnings can change over time: a single medication can have warnings added, removed, or updated based on new clinical and experimental evidence. The FDA will issue black box warnings any time research provides reasonable evidence of an association between a severe safety risk and a particular drug, regardless of whether studies can support the drug is causing the specific safety risk or problem.

Several safety checks have been implemented to ensure prescribers fully consider the potential risks of a medication for a particular patient and its potential benefits. If a black box warning applies to a specific patient, prescribers should explain the possible risks and benefits of using a particular drug to the patient. Pharmacists and medication literature also explain potential severe side effects to patients when filling prescriptions. Medication-prescribing software systems are also programmed with safety checks to ensure that prescribers and pharmacists know possible side effects and medication interactions that can occur in some patients.

How does the FDA issue black box warnings?

‍The safety monitoring of medications doesn’t end after regulatory approval. The FDA and other regulatory agencies continually assess the safety of drugs through postmarket surveillance. This includes monitoring any adverse events reported by consumers or clinicians, additional clinical studies, and animal effects for a particular drug.

Suppose the FDA identifies a severe concern with the safety of a drug or drug class. In that case, the agency may require a drug manufacturer to include a prominently displayed black box warning, restrict medication use, or even remove the drug from the market. While removing a drug from the market is relatively uncommon, one study determined that 8.2% of drugs approved over a 25-year period acquired black box warnings issued by the FDA.

The most frequent black box warnings associated with medications include:

- Identification of and avoidance in high-risk patient populations
- Special dosage considerations and drug interactions
- Requirements for special training or settings for drug administration

A typical example of high-risk patient population identification and avoidance is the black box warning for contraceptive pills in women who smoke. Studies indicate a higher incidence of heart attack, stroke, blood clots, and high blood pressure in women who smoke and use oral contraceptive pills, compromising the safety of the medication in this patient population.

How can pharmacogenomics help?

‍Hepatotoxicity, or damage to the liver caused by medication, is the most common reason the FDA withdraws drugs from the market or issues black box warnings.4 Importantly, hepatotoxicity doesn’t always occur in every person with specific drugs, and the field of pharmacogenomics (PGx) is beginning to explain why.

The active chemical compounds in drugs are broken down, or metabolized, by the body in the liver by enzymes that are coded by specific genes. Critically, genes can have changes in their sequence or “spelling” that affect how well their enzymes can break down chemical compounds. If a patient harbors a particular gene variant that compromises their ability to break down a medication, for example, that medication could damage the patient’s liver or other organs or affect how the medication functions in the body. Patients can also harbor more than one copy of a gene responsible for medication metabolism.

The effect a particular medication has on a patient depends on a variety of proteins and enzymes, including those responsible for medication metabolism. Active drug ingredients must also be transported appropriately in the body to have a therapeutic effect. An entire field of genetics, pharmacogenomics (PGx), is dedicated specifically to understanding how genes, gene modifications, and specific medications affect the body and drug transport and metabolism.

The pharmacogenomics field is uniquely positioned to enhance the safety and effectiveness of drugs for every individual based on the specific gene variants each person harbors. Depending on the genes responsible for the effect of a particular drug in the body, safe, customized drug dosages, and combinations can be prescribed to optimize both therapy effectiveness and overall safety.

For example, lapatinib is a drug used in some patients with advanced breast cancer. Patients with specific variants, or alleles, in the HLA-DRB1 or HLA-DQA1 genes, may cause the patient’s immune system to become sensitive to lapatinib, causing hepatotoxicity. 71% of patients in a research study that developed elevated liver alanine aminotransferase (ALT) enzymes while taking lapatinib harbored the HLA-DQA1*02:01 allele, a particular gene variant or “misspelling” of the HLA-DQA1 gene. PGx sequencing these genes before lapatinib treatment can help clinicians make a more informed decision regarding the costs and benefits of therapy and potential alternatives for patients with these gene variants.

Critically, 91.4% of the US Population carries at least one actionable pharmacogenomic variant, and almost 90% of patients older than 70 will be exposed to at least one drug with pharmacogenomic guidance. These statistics will increase as pharmacogenomics, clinical researchers, and the FDA uncover additional gene-drug interactions. Thankfully, the field of PGx is at the cusp of a personalized medicine revolution that will redefine the standards of medication safety and efficacy to optimize drug therapy for all.

The Kadance Precision Health Management program is designed to help you understand how your genetics influence medication interactions. This article is the first of a three-part series outlining how PGx currently optimizes medication therapy for patients. You can access part two of this series here and part three here.

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