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Health Letter | Public Citizen Report Highlights Crucial Generic Drug Labeling Concerns

Public Citizen Report Highlights Crucial Generic Drug Labeling Concerns

Health Letter article, October 2013

The majority of prescriptions filled in the U.S. today are filled with generic drugs, making medication more affordable for patients. To ensure patient health, it is imperative that the labels for generic drugs include the most up-to-date safety information.

On June 20, Public Citizen issued a detailed report documenting that too often, a serious safety hazard is not identified until years after a prescription drug enters the market and that many drugs today are marketed only in generic form. These facts, combined with the Food and Drug Administration’s (FDA’s) regulations restricting the ability of generic drug manufacturers to update the labels of their products, create a gap with respect to the labeling of generic drugs that threatens patient health and safety.

About generic drugs

In 1984, the U.S. Congress passed a law, commonly referred to as the Hatch-Waxman Amendments, designed to promote the expansion of the generic drug market. Since the law passed, generic drug sales have grown dramatically, fundamentally reshaping the pharmaceutical market. The increased availability of generic drugs has made many prescription drugs more affordable for patients. In 2011, nearly 80 percent of prescriptions filled in the U.S. were filled with generic drugs.

Although generics now dominate the market for prescription drugs, current FDA regulations do not permit a generic drug manufacturer to alter its product’s labeling, except to mimic a change made by the brand-name equivalent or ordered by the FDA. This restriction creates a safety gap for patients because generic manufacturers with a large stake ? perhaps the largest stake ? in the product have no responsibility for the adequacy of its labeling. This gap becomes even more troubling after the brand-name manufacturer stops selling the drug, as often happens within a few years after generics enter the market.

Also, in light of the generic manufacturer’s lack of responsibility for product labeling, a patient injured because a generic manufacturer failed to warn of a serious risk ? or provided unclear or misleading instructions for safe use ? is unable to seek compensation from the manufacturer because of recent federal and U.S. Supreme Court decisions. This release from liability diminishes the incentive for generic drug companies to be vigilant about product hazards and eliminates the incentive to request labeling changes in response to new evidence.

Labeling changes

When the FDA approves a drug for marketing, it approves the drug’s labeling as well. Even after approval, however, FDA regulations require drug labeling to include up-to-date information about hazards associated with a particular drug. Brand-name manufacturers may seek approval for revised labeling in one of two ways.

Under a procedure known as “changes-being-effected,” a brand-name drug manufacturer may make certain changes to a product’s labeling, including changes to strengthen warnings or contraindications and to clarify instructions for use, without first obtaining FDA approval for the changes. In this circumstance, the company must simultaneously notify the FDA of the label changes.

Brand-name manufacturers also can inform doctors and other health care professionals about newly discovered safety concerns by sending “Dear Health Care Professional” letters, which are considered part of drug labeling under federal regulations.

These options for labeling revision are not available to generic manufacturers under FDA regulations. Instead, generic drug companies can revise labeling only to mimic a change made by the brand-name manufacturer (which relies on that manufacturer to initiate the change) or as directed by the FDA.

Timing of warnings

Inadequacies in a drug’s labeling, including those related to safety issues, often do not emerge until after the drug has been on the market for a long time. As one study found, “only half of newly discovered serious [adverse drug reactions] are detected and documented in the Physician’s Desk Reference within 7 years after drug approval.”

For especially serious risks, particularly those that may lead to death or serious injury, the FDA may require that the information be presented in a boxed warning at the top of the label. Sometimes called a black box warning, a boxed warning is reserved for the most serious drug contraindications (circumstances in which the drug should not be used) and warnings.

Public Citizen’s report assessed the quantity of new boxed warnings added after the generic equivalent entered the market. (This research was limited to new boxed warnings added from January 2008 through March 2013.)

Public Citizen identified 53 drugs over the period analyzed for which a black box warning calling attention to serious or life-threatening risks was added after a generic version of the drug entered the market ? and the list is likely incomplete. The report provides a list of these 53 drugs, including the generic and original brand names, the year of approval, current availability, and the year a new black box warning was added to the drug label. The data show that new safety issues commonly arise after generics have entered the market and underscore the public health imperative of maintaining an incentive for generic manufacturers to monitor safety concerns.

The following examples illustrate the severe risks set forth in boxed warnings that were added many years after approval of a drug and introduction of a generic equivalent onto the market:

  • Promethazine hydrochloride, originally marketed under the brand name Phenergan, was approved by the FDA in tablet form in 1951, in injectable form in 1956 and in suppository form in 1960. It is approved for several uses, including treatment of motion sickness, nausea and some allergy symptoms. In 2000, the warning in the drug’s label was strengthened to recommend against use in children younger than 2 years old, and in 2004, the FDA required a boxed warning instructing against such use. The boxed warning was added after the brand-name manufacturer reported cases of respiratory depression, including fatalities, in children under 2. Phenergan was later discontinued, but generic versions are still available. In 2009, the FDA required an additional boxed warning for injectable promethazine hydrochloride due to the risk of gangrene if the drug is injected into an artery.
  • Metoclopramide hydrochloride, sold under the brand name Reglan and other names, was approved to treat gastrointestinal issues in three dosage forms: an injectable formulation approved in 1979, a tablet approved in 1980 and an oral solution approved in 1983. The drug received its first black box warning in 2009, 30 years after its first approval, when doctors discovered that its use could cause tardive dyskinesia in certain patients. Tardive dyskinesia is a serious, often irreversible movement disorder that causes involuntary, repetitive movements of the extremities, as well as lip smacking, grimacing, tongue protrusion and other uncontrollable facial movements. When the FDA announced the warning in 2009, the agency estimated that more than 2 million Americans were taking these products.
  • Haloperidol is an antipsychotic drug approved by the FDA in 1967 as brand name Haldol. In 2007, the FDA announced that the drug company had updated the warning label due to reports of sudden death and heart-related side effects. In 2008, the FDA required manufacturers of haloperidol and many other antipsychotic drugs to add black box warnings following the release of several studies suggesting that the use of these types of drugs to treat elderly patients with dementia increased the risk of death among these patients.

Lack of alternatives

Competition from generics frequently leads a brand-name manufacturer to cease production of the brand-name drug. For those drugs, patients and physicians cannot rely on the brand-name manufacturer to monitor reports of adverse effects and update the labeling. In such situations, the limitation on generic drug companies’ ability to update labeling to provide the most current warning information takes on added significance, particularly when the drug is known to pose serious risks.

The market withdrawals of Accutane and Serzone illustrate the point:

  • Isotretinoin, originally marketed under the brand name Accutane, is used to treat a severe form of acne. It first received FDA approval in 1982. Accutane was linked to several severe side effects, including birth defects when taken by pregnant women, damage to the liver and other internal organs, and depression. In 2009, after nearly 30 years on the market, the brand-name manufacturer discontinued manufacturing and distributing Accutane, citing the cost of personal-injury lawsuits and the effect of generics on its market share. Generic versions of isotretinoin remain available.
  • Nefazodone hydrochloride, an antidepressant approved in 1994 as brand-name Serzone, was removed from the market by the brand-name manufacturer in 2004. Although the drug had been withdrawn from the market in Canada for safety reasons and is associated with liver failure, the company purported to stop selling it in the U.S. due to economic considerations. Nefazodone hydrochloride remains on the market in the U.S. in generic form.

Using a publicly available FDA database, Public Citizen compiled a list of 434 approved prescription drug formulations for which the brand-name manufacturer has discontinued sales but a generic equivalent remains on the market. The complete list is provided in Public Citizen’s report, available at www.citizen.org/hrg2138.

Public Citizen Petition

In August 2011, Public Citizen submitted a citizen petition to the FDA to request that the agency amend its regulations to allow generic drug manufacturers to take advantage of the same procedures for updating labeling that are currently available to brand-name manufacturers. The petition was intended to help address the existing regulatory gap that threatens patient health and safety.

Allowing generic drug manufacturers to provide updated safety information would have two benefits. First, in light of the large market share of generic drugs, it would help to ensure that drug labeling provides adequate warnings to patients based on information that comes to light after the drug is approved for marketing.

Second, because the U.S. Supreme Court held in PLIVA, Inc. v. Mensing in 2011 that a patient harmed by a generic drug that had inadequate labeling cannot sue the manufacturer for compensation for her injuries, revised regulations would correct the illogical disparity between the rights of patients injured by generic drugs and the rights of those injured by brand-name drugs.

The FDA has not responded substantively to the petition, although it recently signaled its intention to issue a proposed rule that may implement this change.


The data presented in Public Citizen’s report demonstrate that new serious risks to patients are sometimes identified years after a drug enters the market, making a drug’s longevity no guarantee of safety. In addition, hundreds of generic drugs are sold without a currently marketed brand-name equivalent. These facts make generic drug manufacturers’ inability to update the labeling of their products under current regulations a threat to the safety of prescription drugs, and, accordingly, a source of unnecessary risks to patients.

Under the laws of many states, the brand-name company cannot be held liable for harm caused by inadequate labeling in cases where the injured patient took a generic form of the drug. When more than 75 percent of all prescriptions are filled by generic versions, this legal reality further diminishes the brand-name manufacturer’s incentive to be vigilant and to take the time and expense to submit an application to the FDA to update a drug label.

These developments, among others cited in Public Citizen’s report, collectively give rise to a safety problem: As generic market share increases, the brand-name manufacturer loses incentive to invest resources in post-approval safety monitoring, while generic manufacturers face no concomitant increase in incentive and have no authority to update labeling. Given that the FDA cannot monitor all post-approval data by itself, drug safety is threatened when the regulatory and legal incentives designed to motivate manufacturer diligence weaken with shifting control of market share.

Regulatory revisions are needed to bring post-market regulation in line with the realities of the pharmaceutical market and to help ensure that drug labeling provides adequate warnings to patients based on information that comes to light after the drug is approved for marketing.