Pill Pushing©

Prescription drug disasters of the 20th century - (6/1/2018)

By Dr. Ron Gasbarro

Society at the time

The year is 1938. In 1938, the New England Hurricane (also referred to as the Great New England Hurricane, Long Island Express, and Yankee Clipper) was one of the deadliest and most destructive tropical cyclones to strike Long Island, New York, and New England. A Category 5 hurricane on the Saffir-Simpson Hurricane Scale, the storm killed 682 people, damaged or destroyed more than 57,000 homes, and caused property losses estimated at $4.7 billion (in 2016 dollars). DuMont, an electronics company, introduced television sets in the US, receiving both pictures and sound. The cost was $650 for a 10 by 8-in. screen ($650 in 1938 dollars equals $11,365 in 2018; to compare, the average cost of a new house in the US was approximately $3,900 in 1938). In the World Series, the New York Yankees defeated the Chicago Cubs, 4–0. Action Comics introduced a new character: Superman. 

In 1938, prominent American lawyer and civil libertarian Clarence Darrow died at age 80. Darrow defended wealthy college students Richard Loeb and Nathan Leopold in the murder of 14-year old Bobby Franks as well as teacher John T. Scopes in the Scope “Monkey” Trial. Also, in 1938, Harvey Firestone died at age 65. Firestone was the founder of the Firestone Tire and Rubber Company, one of the first global makers of automobile tires. 

Who was born in 1938? 
Oliver Reed – British actor (“Women in Love”)
Rudolf Nureyev – Russian dancer and choreographer
Ron Ely – American actor (“Tarzan”)
Natalie Wood – American actress (“Splendor in the Grass” “West Side Story”)
Kenny Rogers – American signer (“Ruby, Don’t Take Your Love to Town” “The Gambler”)
Ted Turner – Founder of CNN, the first 24-hour cable news channel
Connie Francis – American signer (“Where the Boys Are”)

Elixir sulfanilamide was an improperly prepared sulfanilamide medicine that caused mass poisoning in the United States in 1937. It caused the deaths of more than 100 people, including children. The public outcry caused by this incident and other similar poisoning disasters led to the passing of the 1938 Federal Food, Drug, and Cosmetic Act.

The sulfanilamide disaster

In the autumn of 1937, more than 100 Americans—many of whom were children—died from kidney failure after consuming Elixir Sulfanilamide, a raspberry-flavored antibiotic syrup manufactured by The S. E. Massengill Company of Bristol, Tennessee. The new, difficult-to-dissolve antibiotic, sulfanilamide, was mixed with the solvent diethylene glycol, a known toxin and essentially an antifreeze, by the company’s uninformed head chemist, Harold Cole Watkins. The company tested the elixir only for its appearance and palatability before its nationwide distribution. 

At the time, animal testing was not required by law, and the Massengill Co. performed none; there were no regulations requiring premarket safety testing of new drugs. The company started selling and distributing the medication in September 1937. By October 11, the American Medical Association received a report of several deaths caused by the medication. The Food and Drug Administration (FDA) was notified, and an extensive search was conducted to recover the distributed medicine. The Massengill Co. absolved itself from any responsibility. However, chemist Harold Cole Watkins was held legally accountable and committed suicide while awaiting trial. Modern antibiotics have supplanted sulfanilamide on the battlefield; however, sulfanilamide remains in use for treatment of vaginal yeast infections.

The tragedy was seminal in changing drug safety laws. In 1938, The United States Federal Food, Drug, and Cosmetic Act (abbreviated as FFDCA, FDCA, or FD&C), gave authority to the FDA to oversee the safety of food, drugs, and cosmetics, which required preclinical safety studies. 

Other drug safety laws 

The FDA was founded in 1906. A major argument behind its creation was to regulate the sale of dangerous products. One, in particular, was opium-laced "soothing syrups" that had been on the market for more than a century. They were promoted for everything from teething to colic, and even for behavioral issues. If you were a poor woman and needed to leave your child in the care of her 6-year-old sister so you could go to work in a city factory, the opium would keep the baby calm. Yet, many babies were poisoned and died.

Another law came after the thalidomide disaster of the early 1960’s, which took place predominantly in Europe. Widely prescribed to pregnant women in other countries because of its anti-nausea properties, the drug caused hideous bone and limb deformities in their babies. Few American women took the drug because a physician at the FDA refused to approve it, despite enormous pressure from her superiors. Nevertheless, some American women did obtain it. Incredibly, until the 1962 law enacted in the wake of thalidomide was passed, a drug company could test a drug without going to the FDA for permission.

In brief, the 1906 law said you had to have accurate labeling; anything could be in a drug so long as you labeled it accurately. The 1938 law stipulated that the drug also had to be safe, and the 1962 legislation said that a product also needed to be efficacious, meaning that it did what its manufacturer claimed, based on rigorous testing.

The diethylstilbestrol debacle

Diethylstilbestrol (DES) is considered one of the worst drug disasters in human history, and, even though the drug is rarely used today in humans, its effects will be felt for generations of people, perhaps indefinitely.

DES is a synthetic nonsteroidal estrogen. DES (in tablets up to 5 mg) was approved by the United States Food and Drug Administration (FDA) on September 19, 1941, for four indications: gonorrheal vaginitis, atrophic vaginitis, menopausal symptoms, and postpartum lactation suppression to prevent breast engorgement [Meyers, 1983]. The gonorrheal vaginitis indication was dropped when the antibiotic penicillin became available. Until 1971, DES was prescribed to pregnant women in the mistaken belief it would reduce the risk of pregnancy complications and losses. Instead, horror for the children born to these women. In 1971, DES was shown to cause clear cell carcinoma, a rare vaginal tumor, in females who had been exposed to this drug in utero. The US FDA subsequently withdrew approval of DES as a treatment for pregnant women. Follow-up studies indicated that DES also has the potential to cause a variety of significant adverse medical complications during the lifetimes of those exposed. These complications may even affect the grandchildren of the women who were once prescribed the drug. The women who took DES during their pregnancies were often taking doses that were up to 50,000 times the estrogen of today’s birth oral contraceptives.

Who are the DES daughters?

DES gained notoriety when it was shown to cause a rare vaginal tumor in girls and young women who had been exposed to this drug before they were born. In 1971, the New England Journal of Medicine published a report showing that 7 of 8 girls and young women (ages 14 to 22) who had been diagnosed with vaginal clear cell adenocarcinoma had been exposed prenatally to DES [Herbst, 1971]. Subsequent studies have shown an approximately 40-fold increased risk of vaginal/cervical clear cell adenocarcinoma in women exposed in utero to DES, known as DES daughters. As a consequence of this evidence, DES is considered an established human carcinogen. DES was one of the first transplacental carcinogens discovered in humans, meaning a toxin could cross the placenta and harm the fetus. It had originally been believed that the placenta protected the developing fetus but it is now known that is not true. DES daughters may also have an increased risk of moderate to severe cervical squamous cell dysplasia and an increased risk of breast cancer [Troisi, 2007]. 

Who are the DES sons?

In the 1970s and early 1980s, studies were performed on prenatally DES-exposed males. The studies revealed an increased risk of testicular cancer, infertility and urogenital abnormalities in development, such as cryptorchidism (absence of one or both testes from the scrotum) and hypospadias (a congenital disorder of the urethra where the urinary opening is not at the usual location on the head of the penis) [Henderson, 1976; Gill, 1979; Palmer, 2009]  
Even DES grandchildren?

Third-generation children (the offspring of DES daughters and sons) have reached the age when relevant health problems, such as reproductive tract problems, can be studied. A study of the health risks for the granddaughters of women prescribed DES while pregnant, or third-generation daughters was published in 2002 [Kaufman, 2002]. The researchers compared findings of pelvic examinations of 28 DES Granddaughters with findings noted in their mothers (DES daughters). Even though abnormalities were present in more than 60% of DES daughters, no abnormalities were found in the DES granddaughters. However, this study was too small to lead to a definite link with mouse studies demonstrating an opposite result. One study found cervical adenocarcinomas, which are not generally seen in untreated mice, in third generation females similar to those induced by direct prenatal DES exposure (DES daughters) [Walker; 1997]. In the same study, third generation female mice had increases in ovarian, uterine, and mammary tumors with the total number of reproductive tumors being statistically significant from the control mice. DES grandsons are being studied at the Netherlands Cancer Institute. Early research reported that hypospadias, a misplaced opening of the penis, occurred 20 times more frequently among sons of DES daughters [Klip, 2002]. 
The legacy of the adverse effects that stem from DES administration to pregnant women in the 1940s to 1970s has not completely formed. The male and female offspring of those women have reported significant fertility, cancer, and birth-related outcomes, but the cancer outcomes are not completely understood, with few exceptions (cervical adenocarcinomas and breast cancer in women over 40 yrs old). As the male and female offspring of those women age, the overall effect of DES on reproductive cancers will be better understood. Further research is warranted to identify the mechanisms of action on the target tissues, so that future pharmaceutical/environmental estrogen mimics will avoid these pathways, leading to healthier future generations.

The fen-phen fiasco

Everyone searches for the ideal pill that will help one lose weight. The ideal drug would be one that would shed the pounds without exercising or dieting. And it would have no side effects. Fenfluramine was first introduced to the market in the 1970s but was unpopular because it only temporarily reduced weight and only by several pounds. The psychostimulant phentermine, introduced in 1959, had a pharmacologic profile similar to amphetamine. It was used medically as an appetite suppressant for short-term use, as an adjunct to exercise and reducing calorie intake.

In the mid-1990s, the drugs were combined into a new formulation known as fen-phen and quickly gained attention as an easy way to help people lose weight. Even though the FDA never approved fen-phen for safe use, manufacturers quickly produced the drug to meet the rising demand from patients around the country.

In 1997, two separate studies appeared in the New England Journal of Medicine linking fen-phen to several serious conditions, including heart disease, cardiac valvular disease, primary pulmonary hypertension (PPH), and cardiac fibrosis [Connolly, 1997; Graham, 1997]. These studies demonstrated that an abnormal number of people using fen-phen showed signs of these conditions. Symptoms were seen in approximately 30% of the surveyed patients, which was an extraordinarily high number given the patients’ relatively young ages. After these initial studies were published, many more users of the product came forward with complaints of harmful side effects. 

In response to the new findings, the FDA asked the manufacturers of fenfluramine to stop distributing the drugs. Acknowledging the extremely dangerous side effects, Dr. Michael A. Friedman, the Lead Deputy Commissioner of the FDA, issued a statement of warning: “These findings call for prompt action. The data we have obtained indicate that fenfluramine…present an unacceptable risk at this time to patients who take them.” 

While the FDA did not go as far as rebuking the use of phentermine as well, the agency did recommend a stiff black box warning about the risk for cardiac valvular disease that comes with using phentermine, and fenfluramine. These drugs, the agency insists, should be used only as a short-term solution for patients with “significant obesity.” 

Phen-fen deaths and serious adverse effects have resulted in thousands of lawsuits. A 1996 study found that PPH (primary pulmonary hypertension) normally occurs in 1 out of 50,000 people, but was observed in 1 out of 20,000 phen-fen users, greatly increasing the odds of suffering phen-fen deaths  [Abenhaim, 1996]. In addition to the potentially fatal conditions of PPH associated with phen-fen, it was later realized that phen-fen deaths and adverse effects were occurring because of heart valve disease.

Heart valve side effects are very serious and can require replacing the valve. However, there is no cure for PPH and deaths were soon reported [Rubin, 1997]. Due to the inability to adequately diagnose phen-fen adverse effects such as PPH, phen-fen deaths occurred. The lawsuits that quickly followed the phen-fen recall were numerous and the company had high financial losses.

American Lawyer reported that more than 50,000 fen-phen victims have filed suits against fen-phen’s maker Wyeth, and legal expenses combined with awards may have exceeded $21 billion. Lengthy time in the marketplace combined with the severity of both the public reaction and the significant awards granted to its victims make its impact unprecedented.

In 2012, phentermine was combined with topiramate, a drug used for psychiatric conditions such as bipolar disorder, to form Qsymia®, a product indicated for weight loss. Qsymia also carries a warning that it can increase heart rate and should not be used by people who have heart disease or have suffered a stroke. Due to the heart concern, Vivus, the manufacturer of Qsymia, is required to conduct a study to determine whether the drug poses a risk of major cardiovascular problems, including heart attack and stroke. Also, pregnant women should not take Qsymia because it increases the risk of their children being born with a cleft lip or palate. Since the formulation only takes off less than 4 pounds in one year, the risks may outweigh the benefits. Exercise and dieting are looking better all the time.  

The Seldane catastrophe

Seldane® (terfenadine) was brought to the US market in 1985 as the first nonsedating antihistamine for the treatment of allergic rhinitis. In June 1990, evidence of serious ventricular arrhythmias among those taking Seldane prompted the FDA to issue a report on the risk factors associated with concomitant use of the drug with macrolide antibiotics (azithromycin, clarithromycin) and the antifungal ketoconazole [Thompson, 1996]. Two months later, the FDA required the manufacturer, Hoechst Marion Roussel (now Aventis), to send a letter to all physicians, alerting them to the problem. In July 1992, the existing precautions were elevated to a black box warning. The issue attracted mass media attention in reports that people with liver disease or who took ketoconazole, an antifungal agent, or a macrolide antibiotic, could suffer cardiac arrhythmia if they also took Seldane.

In January 1997, the same month when the FDA had earlier approved a generic version of Seldane made by IVAX Corporation of Miami, the FDA recommended terfenadine-containing drugs be removed from the market and physicians consider alternative medications for their patients. In late 1997, Seldane and Seldane-D, terfenadine combined with the decongestant pseudoephedrine, were removed from the US market. The recall is notable mostly for its scale; more than 100 million patients worldwide used terfenadine as of 1990. Following Seldane’s recall, Hoechst was able to mitigate its damages to some degree by introducing Allegra (fexofenadine), a drug structurally similar to Seldane but without the side effects seen with Seldane.

Ron Gasbarro, PharmD, is a registered pharmacist, medical writer, and principal at Rx-Press.com. Read more at www.rx-press.com 


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