On March 4, 2021, I received a large packet of information from the company that publishes the Physicians’ Desk Reference (PDR). On the front of the envelope a large thick red box surrounded the large red words, “IMPORTANT DRUG WARNING.” This largeness and redness was presumably designed to ensure that doctors would actually open the letter in order to find out what newfound serious risks have been identified for one of the drugs they have been prescribing.

The letter announced that a new “black box warning” has been issued by the Food and Drug Administration (FDA) for the Pfizer drug Xeljanz (tofacitinib). A black box warning is the FDA’s most serious warning for drugs and medical devices. These warnings are issued to alert the public and healthcare professionals about serious side effects such as cardiovascular events, cancer, or death.

Xeljanz was approved by the FDA in 2012 as a treatment for rheumatoid arthritis, and its approved indications have expanded since then to include psoriatic arthritis, ulcerative colitis, and juvenile idiopathic arthritis. The drug costs patients about $5,000 per month, and total sales of Xeljanz in the year 2019 were $2.24 billion. Pfizer spent $161 million in one recent year to advertise Xeljanz. In 2019 the FDA issued a black box warning that the use of Xeljanz was associated with an increased risk of blood clots and death. Now we find out that the drug also increases the risk of serious heart-related events and cancer.

So, here we have a situation where, from 2013 to 2018, Xeljanz was prescribed for more than 140,000 patients with rheumatoid arthritis, and neither the doctors nor the patients knew how dangerous the drug is. This situation frequently occurs because the studies upon which FDA approvals are based are typically not large enough to identify all safety issues. It is only during “post-marketing surveillance,” a program in which drug companies are required to submit reports of adverse events to the FDA, that the full scope of a drug’s dangers becomes apparent.

The belated discovery of drug side effects is by no means rare. A 2017 study in the Journal of the American Medical Association examined post-marketing “safety events” among the 222 drugs the FDA had approved from 2001 to 2010. During a median follow-up period of 11.7 years, new safety events were identified for 32% of those drugs, including 61 new black box warnings and 59 “safety communications.” Three of the drugs were removed from the market. The median time from FDA approval to the first post-marketing safety event was 4.2 years, but in a few cases the first safety event was not discovered until the drug had been on the market for more than 10 years. Drugs that received fast-track FDA approval were 2.2 times more likely to have a post-marketing safety event, compared with drugs that did not receive accelerated approval.1

Black box warnings for prescription drugs – whether they were created at the time of drug approval or later during post-marketing surveillance – are not uncommon. According to one report, more than 600 medications have black box warnings, and 40% of people are taking at least one drug that has such a warning attached to it. Some of the well-known drugs that carry black box warnings are listed below.

Humira (adalimumab): Humira is approved for the treatment of ulcerative colitis, Crohn’s disease, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, and a few other conditions. The black box warning mentions an increased risk of serious infections leading to hospitalization or death, including tuberculosis, bacterial sepsis, invasive fungal infections, and infections due to other opportunistic organisms. It also mentions an increased risk of cancers, particularly lymphoma.

Latuda (lurasidone): This drug is used to treat bipolar disorder and schizophrenia. It carries a black box warning about an increased risk of death in elderly patients with dementia-related psychosis.

Abilify (aripiprazole): This drug is approved for the treatment of major depression, bipolar disorder, and autism spectrum disorders. Like Latuda, it increases the risk of death in elderly patients with dementia-related psychosis. Among children, adolescents, and adults who are taking antidepressants, adding Abilify increases the risk of suicidal thoughts and behaviors.

Celebrex (celecoxib): This drug is approved to treat various types of arthritis, acute pain, and dysmenorrhea. The black box warning lists an increased risk of serious cardiovascular and gastrointestinal events.

Chantix (varenicline tartrate): This drug is approved to help people to stop smoking. Beginning in 2009, it carried a black box warning about an increased risk of serious neuropsychiatric events such as depression and suicidality. In 2016, an advisory panel voted 10 to 9 to remove that warning, which the FDA did. Considering the closeness of the vote, perhaps the FDA should have retained the warning, but changed the color of the box to gray.

Selective serotonin-reuptake inhibitors (e.g., Prozac [fluoxetine], Zoloft [sertraline], Celexa [citalopram], and Paxil [paroxetine]): One or more drugs in this class are approved to treat major depression, obsessive-compulsive disorder, bulimia, post-traumatic stress disorder, premenstrual dysphoric disorder, panic disorder, and social anxiety disorder. All drugs in this class carry a black box warning regarding an increased risk of suicidal thoughts and behaviors.

Pradaxa (dabigatran etexilate mesylate): This commonly prescribed anticoagulant is approved for the prevention of strokes in patients with atrial fibrillation, deep vein thrombosis, and pulmonary embolism. The black box warning indicates that premature discontinuation of the drug may increase the risk of thrombotic events, such as stroke or myocardial infarction.

Uloric (febuxostat): This drug was approved in 2009 to lower uric acid levels in patients with gout. In 2019 a black box warning was added regarding an increased risk of cardiovascular death, when compared with allopurinol (a drug that has a similar mechanism of action).

These are but a few of the more than 600 medications that have black box warnings. Moreover, the PDR lists countless other drug side effects which, while clinically significant, do not rise close enough to the level of death or mayhem to warrant them being placed inside a black box.

There are three main points to take from this article. First, many of the drugs used in modern medicine are dangerous. Second, in some cases these dangers may not be identified until the drug has been on the market for many years. And third, natural approaches such as dietary and lifestyle changes and nutritional supplements can be used safely and successfully for many patients who suffer from the various conditions for which dangerous medications are being prescribed. While these “alternative” treatments are well known to most readers of the Townsend Letter, there continues to be resistance in mainstream medicine to the natural approach. This resistance will change only after our colleagues in mainstream medicine begin thinking outside the box, or, should I say, outside the black box.