The Brief Life and Sudden Death of Duract
In July 1997, bromfenac sodium, under the brand name Duract, was approved by the U.S. Food and Drug Administration (FDA) for the short-term management of acute pain. This was a competitive market, with many other NSAIDs already available, but bromfenac was designed as a potent analgesic. Despite its approval, initial clinical trials had already hinted at potential liver enzyme elevations, which led the FDA to restrict its use to a maximum of 10 days. The product labeling reflected this strict time limit, and it was never approved for chronic conditions like arthritis.
Post-Marketing Surveillance Reveals Fatal Flaws
Following its market introduction, a critical gap emerged between the drug’s labeling and its real-world usage. Patients and prescribers, perhaps accustomed to the longer-term use of other NSAIDs, did not universally adhere to the 10-day limit. This non-compliance quickly led to a surge of adverse event reports, highlighting a rare but severe risk of hepatotoxicity that was not fully apparent during clinical trials. The FDA and the manufacturer, Wyeth-Ayerst, received multiple reports of severe liver damage, including cases of fulminant hepatic failure.
Recognizing the danger, the FDA and Wyeth-Ayerst took action in February 1998 by strengthening the product's warning labels, including a black box warning to re-emphasize the strict 10-day usage limit. A “Dear Doctor” letter was also issued to alert healthcare providers. However, these measures proved insufficient. Despite the heightened warnings, reports of severe injuries and death continued.
The Final Decision: Market Withdrawal
Within just a few months of the strengthened warnings, twelve cases of severe liver complications, resulting in four deaths and eight liver transplants, were reported. The vast majority of these cases were in patients who had used the medication for longer than the specified 10 days. Faced with this mounting evidence and the continued risk of serious harm, the manufacturer concluded that further attempts to restrict the potent analgesic's use to just 10 days were not feasible or effective.
On June 22, 1998, Wyeth-Ayerst voluntarily withdrew Duract from the market. The FDA concurred, noting that considering the availability of safer alternative therapies, the withdrawal was a prudent course of action. This decision cemented the principle that if a drug's potential for off-label abuse and severe adverse effects cannot be reliably managed with cautionary labeling, withdrawal may be the necessary step to protect public health.
The Ophthalmic Bromfenac Exception
The story of bromfenac's withdrawal only applies to its oral formulation. Bromfenac is, in fact, still very much in use today, but as an ophthalmic solution (eye drops). These eye drops are used to treat inflammation and pain following cataract surgery. The reason for the stark difference in safety profile between the two formulations lies in the route of administration.
Unlike an oral medication that is absorbed systemically and processed by the liver, the ophthalmic solution is applied topically to the eye. Systemic absorption of the drug is minimal, keeping blood plasma concentrations extremely low and thus avoiding the hepatic toxicity risk associated with the oral version. This is a crucial distinction that allows the ophthalmic preparation to remain a safe and effective treatment option for its intended purpose.
Comparing Systemic vs. Ophthalmic Bromfenac
| Feature | Systemic Bromfenac (Duract) | Ophthalmic Bromfenac (Prolensa, Bromday) |
|---|---|---|
| Formulation | Oral capsules | Ophthalmic solution (eye drops) |
| Indication | Short-term management of acute pain | Postoperative inflammation and pain after cataract surgery |
| Market Status | Withdrawn in 1998 due to safety concerns | Currently marketed and approved for ocular use |
| Key Safety Concern | Severe hepatotoxicity (liver failure) from prolonged use | Very low risk of systemic toxicity; rare ocular adverse events (corneal issues) |
| Route of Administration | Systemic absorption through the gastrointestinal tract | Local application to the eye, with minimal systemic absorption |
| Duration of Use | Initially limited to 10 days, but restriction was ineffective | Typically used for a limited period before and after surgery |
Lessons Learned from the Bromfenac Experience
The withdrawal of oral bromfenac serves as a powerful case study in pharmacovigilance—the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem. It demonstrated several key lessons:
- The Limitations of Labeling: Even with clear, prominent warnings, patients and prescribers may not always follow them, especially when alternative uses seem plausible based on a drug's class (e.g., long-term NSAID use).
- Importance of Post-Marketing Surveillance: Rare but serious adverse effects may not appear in pre-approval clinical trials due to the limited number of subjects. Real-world monitoring through pharmacovigilance is essential for detecting these risks.
- The Risk-Benefit Equation: The decision to withdraw a drug is often based on weighing its benefit against its risks. Given the existence of many safer NSAID alternatives for acute pain, the potential for severe, life-threatening liver toxicity with oral bromfenac was deemed unacceptable.
- Formulation Matters: The route of administration can dramatically alter a drug's safety profile. This is evident in the contrast between the withdrawn oral formulation and the safe, enduring ophthalmic version of bromfenac.
Conclusion
The oral formulation of bromfenac, Duract, was a short-lived analgesic that was removed from the market in 1998 because of severe liver toxicity associated with use beyond the recommended 10-day period. Despite warnings and a black box label, a handful of deaths and liver transplant cases occurred, prompting the manufacturer to voluntarily withdraw the drug. This action highlighted the critical role of pharmacovigilance and demonstrated that a drug's safety profile can vary dramatically depending on its formulation and usage. The continued success of ophthalmic bromfenac for treating eye inflammation serves as a positive example of how the same active ingredient can be safely used when risks related to systemic exposure are mitigated. For more details on the Duract withdrawal, you can find archival information from the FDA.
