By T.Christian Miller and Jeff Gerth, ProPublica
Design & Development: By Krista Kjellman Schmidt, Lena Groeger, Al Shaw
OPELOUSAS, La. — On a chilly Friday night in January 2003, Christina Hutto took her 5-month-old daughter to Opelousas General Hospital, a brown building squatting near the center of this small Louisiana town.
A chubby girl with bright blue eyes and blond hair, Brianna had suffered from a cold and fever for several days. A nurse suggested Tylenol. He scribbled the dose on a piece of paper: one teaspoon every four hours.
Within days, Brianna was lying comatose in a pediatric intensive care unit — her life threatened not by a deadly virus or rare disease, but by an accidental overdose of one of the nation’s most popular over-the-counter pain relievers. Her liver had been destroyed by a toxic byproduct of the medicine that was supposed to help her.
The Huttos were blindsided. Like many Americans, Christina and Eric Hutto had trusted Tylenol, a brand synonymous with safety. Tylenol, as the advertisements proclaimed, was the No. 1 doctor-recommended brand of pain reliever; the one hospitals used most; the one used by moms decade after decade.
Yet Tylenol’s pediatric products had the potential for lethal confusion — and this was no secret to federal regulators or McNeil Consumer Healthcare, the division of Johnson & Johnson that manufactures the drug.
For at least 15 years, until 2011, McNeil continued selling two versions of Tylenol for young children, despite knowing that parents and even medical professionals mixed them up, sometimes with serious consequences. And the Food and Drug Administration failed to intervene.
The two types of pediatric Tylenol had a counterintuitive difference. Drop for drop, the strength of Infants’ Tylenol far exceeded that of Children’s Tylenol.
In addition, the active ingredient in Tylenol, acetaminophen, has what the FDA deems a narrow margin of safety. The drug is generally safe at recommended doses, but the difference between the dose that helps and the dose that can cause serious harm is one of the smallest for any over-the-counter drug.
By confusing the pediatric products and administering too much of the infants’ version, parents could inadvertently overdose their children. Other manufacturers also made two children’s products with different concentrations of acetaminophen.
Between 2000 and 2009, the FDA received reports of 20 children dying from acetaminophen toxicity – a figure the agency said likely “significantly underestimates” the problem. Three deaths were tied directly to mix-ups involving the two pediatric medicines. Such errors may have caused some of the other deaths, but the agency has acknowledged that its data lacks sufficient detail to determine the precise cause.
Similar gaps exist in data for non-fatal liver injuries. The FDA has estimated it may capture less than 1 percent of such cases. Still, one small study found that confusion between the two pediatric products was the most common reason for overdoses among kids with acetaminophen-related liver damage. A study conducted by McNeil found that about one child a year on average was hospitalized because of mix-ups involving its drugs.
Such tragic accidents are among the reasons that between 2001 and 2010, there were about twice as many deaths annually associated with acetaminophen than with all other over-the-counter pain relievers combined, according to data from the American Association of Poison Control Centers. On average, more than 150 Americans die accidentally each year from acetaminophen poisoning, most of them adults, Centers for Disease Control and Prevention data shows. Tens of thousands more are hospitalized for overdoses.
Over a span of decades, federal regulators have been slow to protect consumers in the face of the drug’s rising toll, and McNeil has argued against warning labels, dosing restrictions and other protective measures that would have affected its flagship brand.
The company and the FDA said they have done what they can to reduce overdoses through labeling changes, public education efforts and other measures.
McNeil pressed the FDA for years to allow it to add dosing instructions for children under 2 to its pediatric products; the government-approved label said only to ask a doctor how much to give kids of that age. The company presented mountains of data and made repeated public pleas in arguing for the change.
For more than a decade, the FDA deliberated on the company’s petition but never took action. The issue “requires careful consideration of myriad inter-related factors,” the agency said in a statement, including that “limited safety and efficacy data” existed for acetaminophen in children under two. Today, the agency said, it is continuing an effort to write “user-friendly” instructions for pediatric acetaminophen.
All along, there was another option. At any time, the FDA could have pushed McNeil and other manufacturers to switch to a single pediatric concentration. Or McNeil could have done so voluntarily, ensuring that no one could mix up the dose. Neither did.
Having two products allowed the company to sell to different consumers — parents of babies and toddlers on the one hand, and older children on the other.
Under oath in a lawsuit brought by the Huttos, McNeil’s former medical director, Anthony Temple, was asked how often mixing up the two pediatric products had led to liver injury. Over a 30-year period, he said, “There are maybe a couple of dozen, maybe a little more, where incidents of significant liver injury has occurred, and there’s probably a handful of those cases that were fatal.”
“And for 25 years you’ve elected to continue to offer Infants’ Tylenol in the concentrated form that has led to the death of babies, correct?” he was asked.
“Yes, we’ve continued to do it,” Temple testified.
The company viewed moving to a single concentration as “a second-best option,” Temple said in an interview.
“It’s easy looking back to say maybe we should have made a fix,” he said. But he explained that McNeil believed for years that the FDA was going to add dosing instructions. During that period, he said, the benefit to children warranted keeping the two versions on the market.
PeterMax Miller, a pharmaceutical marketing ethicist at the University of Colorado in Denver and a former executive at a Johnson & Johnson competitor, said he saw the math — and the morality — differently. First, do no harm.
Asked if just one infant death should trigger a drug maker to pull a product, he replied that it would be “more than a trigger, that is a huge cannon.”
“One death is too many,” he added. “I would not have had any hesitation at all about yanking it off the shelf overnight. Everywhere. And Johnson & Johnson knows how to do that.”
Two years ago, as federal regulators were considering pulling the product, and as lawmakers in Louisiana were weighing their own solution to the problem, McNeil and other companies voluntarily withdrew the stronger formulation of their infant drugs from U.S. store shelves.
That came too late for the Huttos.
Both Infants’ and Children’s Tylenol were on the shelves when Christina and her mother walked into the local Walmart after leaving the hospital in early 2003. They purchased what they had previously given Brianna — a bottle of the more concentrated Infant’s Tylenol.
They drove to their home in Krotz Springs, a tiny community of trailers and small tin-roofed houses nestled against a levee on the dark brown Atchafalaya River. It was here that Eric Hutto had fallen in love with Christina after they met at the “kissing log” — a creosote-covered post over a ditch that was a make-out spot in town.
They were young when they got married, only 17. With Christina pregnant, the couple worked hard to make their home safe for Brianna. Before her birth, they tore up the old carpet in their trailer to put in new, allergen-free carpet. They did the same thing in the kitchen, replacing the worn, old flooring with new linoleum. They furnished a nursery for her.
A construction worker who loved hunting and fishing, Eric doted on his young daughter. He held her to him swaddled in a blanket, fed her, watched television with her. Christina loved her baby more than she could have believed — “like the sun had just opened a door in our lives,” she would say.
Over the weekend, the Huttos remembered, they dutifully began giving Brianna the dosage recommended by the nurse at the hospital. They used a small plastic cup with teaspoon indicators to measure the syrup. They used the dropper that came with the package to administer it. They made sure they were giving her the medicine at the right time intervals — no sooner than every four hours.
By Sunday morning, Brianna seemed worse. She was restless and vomiting. By that evening, she was listless. She wasn’t even responding to the sound of Christina’s voice. “Sunday, there was no crying. There was no movement. She just became a vegetable,” Christina said.
Christina had to go to her job at a truck stop, so Eric and his father, Jimmy, the local fire chief, decided to take Brianna back to Opelousas General.
As the evening wore on, things went from bad to worse. Brianna wasn’t responding to stimuli. She was dehydrated. The doctors were having trouble getting an IV into her. Her veins kept collapsing. Christina rushed to the hospital. She and Eric spent a sleepless night at the hospital with Brianna.
At the morning shift, Brianna’s regular pediatrician came into the hospital. Christina remembers that she saw Brianna and immediately screamed: “Why wasn’t I called? This baby is in bad shape!”
The doctor was confused. She suspected Brianna had ingested poison, but didn’t know what. She asked Eric if the family had lead or other dangerous substances in the house. Finally, she ordered up tests to check for liver damage and the levels of acetaminophen, the active ingredient in Tylenol, in Brianna’s blood.
The results showed Brianna’s liver enzymes were nearly 200 times higher than normal. And the amount of acetaminophen in her blood indicated that she had taken far more than the recommended dose.
Time was now of the essence. McNeil had helped to fund the development of an antidote to acetaminophen poisoning that is remarkably effective if administered within the first eight hours. Then its efficacy declines. Brianna had passed the window. Her liver was failing fast. But there was still a chance.
A medical helicopter whisked Brianna to New Orleans Children’s Hospital, where she could receive more specialized care.
There was no room on the helicopter for the Huttos. So Christina, Eric and Jimmy piled into Jimmy’s pickup, and started driving down Interstate 10, past swamp and cypress forest, toward New Orleans.
The two-hour drive was agony. Christina sobbed the entire way. Eric was bewildered. Three days ago, he had a child with a fever. Now she was being airlifted for a liver transplant.
“It was a long, long ride,” Eric said. “It was like it was just a tunnel we was riding through that never was going to end.”
It would take several years to sort out what happened. Opelousas General, as it turned out, did not use Infants’ Tylenol — precisely because hospital administrators wanted to avoid the risk of overdosing by confusing two different formulations. Nurses were used to giving dosage instructions based on the less-potent form, Children’s Tylenol.
So when she first got to the hospital on that January night, Christina said, she told the intake nurse that she had been giving Brianna Infants’ Tylenol. She said she pulled the bottle out of the diaper bag to show the nurse.
After Brianna was examined, a nurse in the emergency room handed Christina and her mother a form, which recommended ¾ of a teaspoon of Tylenol. Christina’s mother questioned the dose because she thought it was too high. When the form came back, the nurse had increased the dosage to 1 teaspoon.
However, nowhere on the form that the nurse gave Christina did it say the teaspoon dose was for Children’s Tylenol. And when Christina bought Infant’s Tylenol, as she had before, there was no way for her to double-check the nurse’s instructions, because there was no dosing information for a child under 2.
It was hardly a new problem.
McNeil built its business partly on providing relief to sick children. When it began selling Tylenol in 1955, one of its first products was a liquid form for children. In 1957, McNeil introduced a second pediatric medicine: Infant’s Tylenol. Originally prescription drugs, they became available as over-the-counter products by 1959.
The infant’s formula, meant for kids under 3, contained more than three times as much acetaminophen as the same volume of the children’s version, meant for those up to 12. Though it might seem counterintuitive to make a stronger Tylenol for younger kids, there were practical reasons to design the products this way.
The more concentrated infant’s formulation meant that parents had to force fewer drops down the throats of fussy babies to deliver the same amount of medicine. Having two concentrations “was considered a rational strategy to facilitate dosing for infants and children at the time it became available,” the FDA said in a statement.
Some experts believe that isn’t persuasive. “Babies drink 4 to 8 ounces of formula at a time. They can take a teaspoon of liquid,” said James Heubi, a pediatric gastroenterologist at Cincinnati Children’s Hospital Medical Center who has testified in court against McNeil. “There’s absolutely no reason to have two different concentrations on the market.”
Having two products is a common sales strategy, helping to reach different demographics. Johnson & Johnson does not release revenue information for Tylenol products, so it isn’t publicly known how much the two pediatric formulations generated. Industry-wide, infants’ strength products accounted for 12 percent of sales of over-the-counter acetaminophen in 2009 and children’s strength products accounted for about 16 percent, according to an FDA study.
McNeil did not directly answer why it continued to keep two concentrations on the market. The company said that the “standard of care” in the U.S. included providing more concentrated products to infants to facilitate giving the medicine to babies.
“Sales were not an issue” in deciding whether to keep the two concentrations on drugstore shelves, said Temple, the company’s retired medical director.
Understanding of acetaminophen’s potential to harm children began emerging decades ago.
By the late 1960s, science showed that, at certain doses, acetaminophen could damage or even destroy the liver. Some research found that children were less vulnerable than adults to the drug’s toxic effects, but in a 1975 article, Barry Rumack, a toxicologist whose work McNeil later funded, noted the death in 1970 of a 3-year-old in England from acetaminophen poisoning. (The drug is known there and in many other countries as paracetamol.)
For many years, the chief concern was “unsupervised ingestion” – children getting into medicine bottles and taking too much acetaminophen. Such accidents are the reason for the majority of emergency room visits by kids suffering from potential overdose, studies show.
In those cases, parents often rush their child to the doctor, increasing the chance the antidote will be administered in time for it to work. But when parents or healthcare providers mixed up the two concentrations of pediatric Tylenol, they often wouldn’t realize anything was wrong for days, until symptoms became severe and the antidote was less likely to be effective.
In 1994, parents overdosed a 14-month-old girl by confusing the two Tylenol products. She lived but underwent a liver transplant. In a later statement quoted by newspapers, McNeil called her case a “tragic error and confusion on the part of the parents.”
Two-thirds of parents who brought children under 7 into city emergency rooms did not know the difference between concentrated infant’s drops and other formulations of acetaminophen, a study published in 2000 found.
As McNeil saw it, the problem had always been the label and its lack of instructions for children under 2. The FDA’s rationale was that parents with children that young should speak to a doctor in case the symptoms indicated a more serious condition.
In 1983, McNeil’s Temple tried to address this issue by writing a scientific article that included dosing instructions for children by weight and age. The company began handing out tear sheets with the information to doctors to pass on to parents. The tear sheets also functioned as a marketing tool for Tylenol, according to court records, offering discounts for the medicine.
Temple, whose research was supported by McNeil, later testified that the company considered the tear sheets an imperfect solution.
Starting in the mid-1980s Temple said, McNeil officials publicly and privately pushed the FDA to act — without success.
As research piled up in the 1990s on pediatric deaths and injuries, the FDA held a series of public meetings at which McNeil and others advocated for adding dosing instructions.
Doctors and pharmacists expressed growing concern about the two children’s concentrations. In 1997, Dr. Cheston Berlin, an influential professor of pediatrics at the Penn State University College of Medicine, said pediatricians were “mystified” by the different formulations and urged drug makers to move to a single version.
McNeil didn’t take this step. Nor did the FDA require it.
At the same hearing at which Berlin testified, an FDA advisory committee recommended adding dosing information for children under 2 to acetaminophen labels.
In 1999, the FDA approved such dosing instructions for pediatric medicines containing ibuprofen, another over-the-counter pain reliever, including Motrin, a brand marketed by McNeil.
But for products with acetaminophen, the FDA spurned the advisory committee’s recommendation. The agency insisted that the label should continue to tell parents to ask their pediatricians for the appropriate dose.
McNeil undertook other efforts to combat pediatric overdose. The company designed a special safety cap that made it more difficult to pour out the more concentrated infants’ formula.
The company also filed a formal petition asking the FDA to allow dosing instructions for young kids. It marshaled a growing stack of evidence that dosing confusion persisted even among consumers who sought medical advice.
More than half the calls to McNeil’s consumer hotline concerned parents with children under 2 asking for dosing information, McNeil told the FDA. Moreover, a company analysis showed, most dosing errors occurred when parents had obtained instructions from health professionals.
The FDA still put off action, saying that acetaminophen makers needed to supply even more data showing how the drug affected kids of different weights and ages. Unlike ibuprofen, acetaminophen had been approved under older safety rules which did not require extensive testing. And, the agency said in a statement, “there was not a lot of data on which to base dosing” for children using acetaminophen.
Dr. Charles Ganley, an FDA official who was in charge of regulating over-the-counter drugs, said at a 2002 hearing that the agency was “struggling” with McNeil’s request for dosing instructions. The agency had even written a proposal for instructions, he said, but there were complex issues involved — including the agency’s own burdensome rule-making procedures.
“It’s just not as straightforward as folks think,” he said at the hearing. “But it is a priority to get done.”
Still, more time passed with no decision — and no guidance for parents like the Huttos.