White pills in a green bottle
22 April 2015

Should Zofran’s Warning Label Be Changed?

In a series of recent lawsuits, US families have claimed that the popular anti-nausea drug Zofran has the potential to cause birth defects. Zofran is not approved for use as a morning sickness treatment, but physicians have increasingly used the drug “off label” to alleviate the symptoms of nausea and vomiting that commonly accompany early pregnancy.

While the practice of off-label prescription is not regulated by the US Food & Drug Administration, pharmaceutical companies are barred by US law from promoting their drugs for unapproved purposes.

At least five legal claims now accuse Zofran’s manufacturer of doing just that: marketing Zofran as a “safe and effective” treatment for morning sickness, without any clinical evidence to support that assertion. In making these allegations, plaintiffs echo the US Department of Justice. 2012 saw the federal government file a litany of civil and criminal charges against the pharmaceutical manufacturer, including allegations that the company had unlawfully promoted Zofran to physicians as a morning sickness treatment.

Was Zofran’s Manufacturer Aware Of Its Alleged Potential To Cause Birth Defects? White pills in a green bottle

But the newly-filed complaints make a more troubling claim. Beyond marketing Zofran as a safe medication for pregnant women to take, plaintiffs allege that the company had knowledge of evidence to the contrary.

They cite a series of studies in pregnant animals allegedly conducted in the 1980s, which reportedly revealed evidence of Zofran’s toxicity and fetal malformations. They also claim that the drug’s manufacturer began receiving reports of birth defects, with suspected links to maternal ingestion of Zofran, as early as 1992.

Complaints claim that the company has received at least 200 such reports to date, and then go on to argue that these reports provided the drug’s manufacturer with sufficient evidence of Zofran’s potential to cause fetal harm. Thus, they allege that the drug’s manufacturer should have revised Zofran’s warning label.

Why Are Drug Warning Labels Changed?

According to federal regulations, a drug’s label “must describe clinically significant adverse reactions (including any that are potentially fatal [or] serious even if infrequent).” In the fields of public health, “clinical significance” relates to the practical, everyday consequences of a treatment option. A drug’s potential to cause birth defects would certainly fall under this category.

Furthermore, the law mandates that a medication’s “labeling must be revised to include a warning about a clinically significant hazard as soon as there is reasonable evidence of a causal association with a drug; a causal relationship need not have been definitely established.”

Who Is Responsible For Revising A Drug’s Warning Label?

The FDA reserves the right to take “appropriate action,” including changing a drug’s warning label, when evidence of a new risk becomes apparent.

In a Guidance called “Classifying Significant Postmarketing Drug Safety Issues,” the FDA states that it “monitors and reviews safety information about a drug throughout the product’s lifecycle[, including] monitoring safety reports after the drug is marketed.” By reviewing reports of adverse drug reactions and epidemiological studies, the FDA’s Center for Drug Evaluation and Research may “learn of new, more serious, or more frequent adverse drug reactions” and can take “appropriate action when the risks indicate a need to provide additional safety information to the public.”

But drug manufacturers routinely receive adverse event reports directly from patients and physicians, and many of these reports only come to the FDA’s attention after a manufacturer submits them itself.

Plaintiffs note that under federal law, pharmaceutical companies are “free to add or strengthen — without prior approval from the FDA — a contraindication, warning precaution, or adverse reaction.” By this logic, plaintiffs claim that Zofran’s manufacturer not only had the “ability” to add warnings, but also had an “obligation” to do so. The law’s explicit call for urgency, the fact that alterations must be made “as soon as” reasonable evidence of harm arises, could be interpreted to imply that pharmaceutical manufacturers are obligated in this way.

Do Those Responsibilities Cover Off-Label Use?

Yes.

These requirements are not limited to adverse events that occur when the drug is prescribed for its approved indications. The law continues by clearly stating that “a specific warning relating to a use not provided for under the [label’s] ‘Indications and Usage’ section may be required by FDA […] if the drug is commonly prescribed for a disease or condition and such usage is associated with a clinically significant risk or hazard.”

In a complaint filed in the US District Court of Montana, under case number 1:15-cv-00026-SPW-CSO, plaintiffs claim that Zofran’s manufacturer “knew well from its off-label promotion and payments to doctors, and its conspicuous increase in revenue from Zofran, and its market analyses of prescription data, that physicians were prescribing Zofran off-label to treat morning sickness in pregnant women.”

In the wake of the federal government’s case, Zofran’s manufacturer maintains that it never promoted the drug for unapproved use. This is a question of fact, and one that will be decided by the courts in time.

Did Zofran’s Manufacturer Receive “Reasonable Evidence” Of Harm?

Another question that will be decided in the filed court cases involves whether or not Zofran’s manufacturer in fact received numerous reports of birth defects, as plaintiffs allege, and if so, whether those reports constitute “reasonable evidence of an association between” Zofran and major congenital abnormalities.

Plaintiffs cite multiple epidemiological studies intended to investigate Zofran’s effects on fetal development. At least four of these studies have found a significant increase in birth defects among babies exposed to Zofran during early pregnancy.

In conjunction with the alleged birth defect reports, plaintiffs argue that these studies provided Zofran’s manufacturer with substantial evidence of the drug’s potential risks, enough to warrant an alteration of the drug’s warning label. The complaints claim that the company “failed” in its obligation to warn the public of a serious health risk.

What Labeling Changes Do Plaintiffs Demand?

Plaintiffs demand that Zofran’s manufacturer alter numerous sections of the drug’s warning label. One such change would involve stating that “there is a lack of evidence that Zofran is safe for the treatment of morning sickness in pregnant women,” under the label’s “Indications and Usage” section.

This demand is bolstered by a statute of federal law, 21 C.F.R. § 201.57(2)(E)(ii), which states that “if there is a common belief that the drug may be effective for a certain use or if there is a common use of the drug for a condition, but the preponderance of evidence related to the use or condition shows […] that the therapeutic benefits of the product do not generally outweigh its risks, FDA may require that [the label] state that there is a lack of evidence that the drug is effective or safe for that use or condition.”

Pregnancy Categories

But the complaints also claim that Zofran’s manufacturer “had the ability, and indeed was required, to update Zofran’s label to reflect at best a Pregnancy Category D designation.”

Federal law states that “if there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks[,] the labeling must state: ‘Pregnancy Category D.’ “

By contrast, Zofran is currently designated as Pregnancy Category B, which indicates that “animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.” Plaintiffs claim that the alleged birth defect reports and four epidemiological studies are sufficient to demonstrate “risk to the fetus,” and thus Zofran should be downgraded to Category D.

Has The FDA Changed Pregnancy Categories Before?

In early 2011, the FDA announced that Topamax, an anti-epileptic drug, was being reclassified as a Pregnancy Category D medication. Topamax was previously designated as Category C.

According to the FDA’s Drug Safety Communication on March 4, 2011, the alteration was made after data from the North American Antiepileptic Drug Pregnancy Register (NAADPR) showed an increased risk of oral clefts among infants born to mothers who had taken Topamax during early pregnancy. Like all pregnancy registries, the NAADPR collects adverse event reports with suspected links to prescription drugs. These reports are generally submitted by pregnant women and their health care providers.

Since 2011, the NAADPR has continued its analysis of oral cleft defects associated with Topamax. As of October 2004, the database includes 425 pregnancies exposed to Topamax or its active ingredient. In babies exposed to Topamax, the risk of developing an oral cleft is 1.2%, compared to only 0.39% among non-exposed infants.

By contrast, the studies that have sought to determine Zofran’s potential effects on fetal development have actually included more exposed pregnancies than the study that spurred Topamax’s label change. For example, researchers in Denmark investigated the drug’s effects by looking at the pregnancy outcomes of almost 1,400 women who had been exposed to Zofran’s active ingredient. Likewise, a team in Sweden studied Zofran’s potential risks in 1,349 women.