Zofran: Looking beyond the label
BIRMINGHAM, AL (WBRC) - Over 200 lawsuits allege that pregnant mothers prescribed Zofran, or a generic equivalent, caused them to have babies born with congenital birth defects.
Jon and Clara Rickman, of the Birmingham area, are plaintiffs in one such lawsuit. They say their baby, Nicholas, was born with congenital heart defects after his mother took the generic form of Zofran, called "ondansetron," to alleviate her morning sickness during her first trimester.
At only five days old, Nicholas underwent his first of three heart surgeries.
Nicholas' mother blames herself for taking the drug.
"Every day, you see his scar. And I can't never fix it and I think it's my fault," said Clara.
The Rickmans say if Clara had not taken the generic form of Zofran, Nicholas would not have been born with a heart problem. According to their lawsuit, there is no family history of his conditions and there are no signs of a genetic cause.
The Rickmans are speaking publicly about their lawsuit and Nicholas' health because they believe they can prevent a similar fate for others.
"I don't want other mothers to go through what I've been through. And I don't want them to feel guilty for the rest of their life, like I do," Clara said.
Zofran was FDA-approved in 1991 to prevent post-operative nausea, and to help cancer patients alleviate nausea during chemotherapy treatments. It was not FDA-approved for treatment of morning sickness.
"It's never been tested in pregnant women for safety and for safety in unborn children," said the Rickman's lawyer, Don McKenna, a partner at Hare Wynn in Birmingham.
McKenna says physicians began prescribing Zofran for uses other than what is FDA-approved. This is called an "off-label" prescription, and according to Peter J. Hughes, Pharm. D., such prescriptions are not uncommon.
"The estimates are that as many as one in five prescriptions written and filled in a pharmacy is for an off-label use, so that's 20 percent," said Dr. Hughes.
A professor at Samford University's McWhorter School of Pharmacy, Dr. Hughes is an expert in drug information and off-label use.
"It's nothing to lose sleep over, but I do think it's important for patients to know what they're taking and why they are taking it," he said. "The medication in their medicine cabinets may be used for a purpose that's not associated with original intended use of the drug product."
Dr. Hughes says patients should initiate a conversation with their doctors about prescriptions. He says patients should ask: Why I am receiving this prescription? Is this an off-label prescription? If so, what is the level of evidence supporting the decision to prescribe it to me?
Clara says she was never advised by her OBGYN that Zofran was not tested on pregnant women. Her lawyer believes that is a problem.
"It's being continued to be prescribed today off-label because a doctor can prescribe off-label for any use they believe is necessary," said McKenna. "What we don't believe they've been told by the pharmaceutical company is that this has never been tested for use in pregnant women and safety in their children."
The Rickmans are suing GlaxoSmithKline, manufacturers of Zofran, alleging that the drug company illegally marketed the drug for use in pregnant mothers and withheld information about the drug's safety and effectiveness.
McKenna explained it is illegal for a drug company to market an FDA-approved drug for an off-label use.
"You can only market a drug that has been approved for use by the FDA and they never sought approval for use in pregnant women," he said.
The Department of Justice (DOJ) previously accused GlaxoSmithKline of illegally promoting the off-label use of Zofran for the treatment of morning sickness in pregnant women. The DOJ alleged that GlaxoSmithKline paid kickbacks to doctors to induce them to prescribe Zofran and other drugs. The company settled those claims, without admitting liability, in 2012.
In a statement, a spokesperson for GlaxoSmithKline said, "There have never been any findings that GSK illegally marketed Zofran at any time. In 2012, GSK agreed to include Zofran in a larger settlement with the government in order to avoid the distraction and expense of litigation."
GlaxoSmithKline paid over $3 billion for the total settlement, which included criminal and civil charges. It remains a settlement that the DOJ calls the largest combined federal and state health care fraud recovery in a single global resolution in the history of the United States.
Though the FDA does not regulate the off-label use of prescription drugs, it collects data about adverse events associated with use. The FDA has more than 5,000 adverse events involving Zofran reported by a patient, health care provider, or manufacturer. While reporting of adverse events is optional for consumers and healthcare providers, reports are mandatory for drug manufacturers.
More than 400 adverse events from Zofran are reported for "maternal exposure during pregnancy." More than 300 adverse events are associated with "foetal exposure during pregnancy." There are 170 adverse events reported for "congenital anomaly."
These reports were reviewed and considered by the FDA when it issued a public letter in October 2015 about Zofran. The letter responded to a Citizen's Petition filed with the FDA in January 2013 requesting that the agency reclassify the drug with stronger warnings of potential risks associated with its use by pregnant women.
The Citizen's Petition also wanted OBGYNs to be notified that Zofran may lead to adverse maternal and fetal outcomes.
After reviewing the medical literature studying the off-label use of Zofran, the FDA denied the Citizen's Petition.
A GSK spokesperson pointed to this FDA letter and said, "They found that the evidence did not support a conclusion that there is an increased risk of adverse fetal outcomes or birth defects from exposure to Zofran during pregnancy."
Dr. Hughes has also reviewed the FDA letter. He explained that the denial is based on a review of publicly available published medical studies. It did not include a medical study initiated by the FDA.
According to Dr. Hughes, the letter concludes that current available medical literature is inadequate to support a definitive conclusion on whether there is an increased risk of fetal outcomes when pregnant mothers take Zofran.
"The studies that are published cannot support conclusions on whether there is an increased risk," he said.
The FDA was critical of these studies because, "they were not the highest quality, had low sample sizes, and/or were retrospective studies."
The FDA letter, itself, recognized, "While a potential association between use during pregnancy and cardiovascular malformation warrants continued vigilance, given the limitations…the study does not support a change in the pregnancy risk category at this time for those products."
And with regard to its denial of the request to notify physicians about alleged adverse outcomes, the letter stated, :FDA does not believe that such an unusual notification is warranted in this case."
"Absent a compelling legal or public health concern, FDA generally does not comment on the number or quality of studies regarding the efficacy of a drug product for an unapproved use or provide notification to health care providers regarding its relative efficacy as compared to other drug products for such unapproved use," the letter stated.
The federal judge presiding over the Zofran litigation, including the Rickmans' lawsuit, also reviewed the FDA's response letter. He noted that GSK could be in possession of additional information that the FDA did not consider.
"If – as plaintiffs allege – GSK was in exclusive possession of information not previously submitted to the FDA indicating a need for a new or strengthened warning…that information could not, however, have been submitted by a citizen petition, as no citizen (according to plaintiffs) had access to it," wrote U.S. District Judge F. Dennis Saylor, IV.
The Rickmans' lawyer says the next 12 months, or more, will be spent collecting and reviewing internal company documents from GSK about the development, testing, and marketing of Zofran. It could be three to five years before these cases are ready for a trial.
In the meantime, the Rickmans will raise Nicholas. About one year after his heart surgeries, Clara says baby Nicholas is doing better.
"I want him to know that he's a really strong baby, that he's a fighter, and that he should be proud of about it," said Clara.
"If I could go back," she said with tears streaming down her face, "I would never take anything, if I knew it would hurt him."
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