Anyone that watches television, surfs the web, or flips through magazines and journals is very familiar with advertising for pharmaceuticals picturing attractive, healthy and active people. Prescriptions and over the counter medications are safely used by millions of consumers for various ailments, diseases and medical conditions everyday. While many great things have been accomplished by the development of so many medications and the marketing to millions of consumers, there are also serious side effects or other undesired results. In some cases, the U.S. Food and Drug Administration or manufacturer may recall or withdraw a specific batch or completely remove a medication from the market.

What is a drug recall?

Recalls are, with a few exceptions, voluntary on the part of the manufacturer. However, once the FDA requests a manufacturer recall a product, the pressure to do so is substantial. The negative publicity from not recalling would significantly damage a reputation, and the FDA could take the manufacturer to court where criminal penalties could be imposed. The FDA can also require recalls in certain instances with infant formulas, biological products, and devices that pose a serious health hazard. Manufacturers may of course recall drugs on their own and do so from time to time for any number of reasons.

Recall classifications

There are three drug recall classifications.

Class I

• Reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death.
• An example would include the diet aid Fen-Phen (fenfluramine/phentermine) which caused irreparable heart valve damage and pulmonary hypertension.

Class II

• Use of, or exposure to, a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.
• An example would include a medication that is under-strength but that is not used to treat life-threatening situations.

Class III

• Use of, or exposure to, a violative product that is not likely to cause adverse health consequences.
• Examples might be a container defect (plastic material delaminating or a lid that does not seal), off-taste or incorrect color, and simple text errors such as the incorrect expiration date on the manufacturer's bottle.

How drug recalls work

When an FDA-regulated product is either defective or potentially harmful, recalling that product, removing it from the market or correcting the problem is the most effective means for protecting the public. This is a multi-step process.

Step 1: Reports of adverse effects

FDA first hears about a problem product in several ways:

• A company discovers a problem and contacts the FDA.
• The FDA inspects a manufacturing facility and determines the potential for a recall.
• The FDA receives reports of health problems through various reporting systems.
• The Centers for Disease Control and Prevention (CDC) contacts the FDA.

After receiving enough reports of adverse effects or misbranding it decides the product is a threat to the public health and it contacts the manufacturer to recommend a recall.

Step 2: Manufacturer agrees to recall

Provided the manufacturer agrees to a recall, they must establis a recall strategy with the FDA that addresses the depth of the recall, the extent of the public warnings, and a means for checking the effectiveness of the recall. The depth of the recall is identified by wholesale, retail, or consumer levels.

Step 3: Customers contacted

Once the strategy is finalized the manufacturer contacts it customers (pharmacies, wholesalers, etc.) with the following information:

• the product name, size, lot number, code or serial number, and any other important identifying information,
• reasons for the recall and the hazard involved, and
• instructions on what to do with the, beginning with ceasing distribution.

Step 4: Recall listed publicly

FDA recalls are listed in the FDA's weekly enforcement report ( http://www.fda.gov/Safety/Recalls/EnforcementReports/default.htm ), see recent recalls at http://www.fda.gov/Safety/Recalls/default.htm , and you can receive email alerts at https://public.govdelivery.com/accounts/USFDA/subscriber/new?topic_id=USFDA_48 . Many subscription services, such as Medscape and Drug Facts and Comparisons eAnswers, also include drug recall information.

Step 5: Effectiveness checks

FDA evaluates whether all reasonable efforts have been made to remove or correct a product. A recall is considered complete after all of the company’s corrective actions are reviewed by FDA and deemed appropriate. After a recall is completed, FDA makes sure that the product is destroyed or suitably reconditioned, and investigates why the product was defective in the first place.

10 worst drug recalls in the United States

To emphasize the importance of drug recalls let's look at what are commonly considered the 10 worst drug recalls in U.S. history.

Fen-Phen (fenfluramine and phentermine)

• Manufacturer: Wyeth-Ayerst Laboratories (formerly American Home Products)
• Recall date: 1997 (after 24 years on the market)
• Financial damage: Over $21 billion (awards to victims are close to $14 billion), making it one of the most costly products liability cases in history.

Fen-Phen’s was a ver popular anorectant. It is estimated that as many as 6.5 million people took it to help fight obesity. After consumers began experiencing rare heart valve deffects and pulmonary hypertension problems, the FDA set the recall in motion. American Lawyer reported that more than 50,000 Fen-Phen victims have filed suits against Fen-Phen’s maker Wyeth, and legal expenses combined with awards are believed to have exceeded $21 billion. Its 24 years in the marketplace combined with the severity of both the public reaction and the significant awards granted to its victims make its impact unprecedented.

Diethylstilbestrol (a.k.a., DES)

• Manufacturer: Multiple manufacturers (DES was never patented as it was created with British public funds)
• Recall date: 1975 (after 37 years on the market)
• Financial damage: Unknown quantity of financial reparations in the billions, but difficult to fully quantify since each manufacturer paid out legal damages correlated with its respective market share (a new way of awarding damages in these cases).

DES was prescribed for more than thirty years to prevent miscarriages and other complications during pregnancy. It was not until 1971 before it was connected to a rare tumor that kept appearing in the daughters of women who had taken it. The FDA only banned DES prescriptions to women because no such problems have been found in men. In fact, it can still be prescribed to men to treat estrogen deficiency. Litigation over DES led to a landmark products liability award that heavily influenced how both the courts and the FDA approach oversight of drugs with multiple manufacturers.

Baycol (cerivastatin)

• Manufacturer: Bayer A.G.
• Recall date: 2001 (after four years on the market)
• Financial damage: $1.2 billion

Baycol (cerivastatin) is a synthetic member of the class of statins, used to lower cholesterol and prevent cardiovascular disease. It was withdrawn from the market in 2001 because of the high rate of serious side-effects.

Cerivastatin was marketed by the pharmaceutical company Bayer A.G. in the late 1990s as a new synthetic statin, to compete with Pfizer's highly successful Lipitor (atorvastatin).

During post-marketing surveillance, 52 deaths were reported in patients using cerivastatin, mainly from rhabdomyolysis and its resultant renal failure. Risks were higher in patients using fibrates (mainly gemfibrozil) and in patients using the high (0.8 mg/day) dose of cerivastatin. Another 385 nonfatal cases of rhabdomyolysis were reported. This put the risk of this (rare) complication at 5-10 times that of the other statins.

Vioxx (rofecoxib)

• Manufacturer: Merck
• Recall date: 2004 (after five years on the market)
• Financial damage: nearly $6 billion in litigation-related expenses alone

Rofecoxib is a NSAID developed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea. Rofecoxib was approved as safe and effective by the FDA on May 20, 1999 and was subsequently marketed under the brand name Vioxx.

Rofecoxib gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time.

During the post-marketing phase the VIGOR and the APPROVe study both showed dramatic increases in myocardial infarctions. There is even evidence that the authors of an article for NEJM that promoted Vioxx had seen the disturbing results of VIGOR and withheld this information in the article. In addition to its own studies, on September 23, 2004 Merck received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users.

FDA analysts estimated that Vioxx caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market.

Merck publicly announced its voluntary withdrawal of the drug from the market worldwide on September 30, 2004.

Bextra (valdecoxib)

• Manufacturer: G. D. Searle & Company (a subsidiary of Pfizer)
• Recall date: 2005 (after four years on the market)
• Financial damage: over $2 billion

Valdecoxib is a non-steroidal anti-inflammatory drug (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, and painful menstruation and menstrual symptoms. It is a cyclooxygenase-2 selective inhibitor.

Valdecoxib was manufactured and marketed under the brand name Bextra by G. D. Searle & Company. It was approved by the United States Food and Drug Administration on November 20, 2001, and was available by prescription in tablet form until 2005, when it was removed from the market due to concerns about possible increased risk of heart attack and stroke.

Rezulin (troglitazone)

• Manufacturer: Parke-Davis (which was purchased by Pfizer)
• Recall date: 2000 (after three years on the market)
• Financial damage: The manufacturer grossed $1.2 billion in sales prior to the recall.

Rezulin (troglitazone) is an anti-diabetic (NIDDM) and antiinflammatory drug, and a member of the drug class of the thiazolidinediones. In the United States, it was introduced and manufactured by Parke-Davis in the late 1990s, but turned out to be associated with an idiosyncratic reaction leading to drug-induced hepatitis. One FDA medical officer evaluating troglitazone, John Gueriguian, did not recommend its approval due to potential high liver toxicity, but a full panel of experts approved it in January 1997. Once the prevalence of adverse liver effects became known, troglitazone was withdrawn from the U.S. market in 2000.

Able Laboratories generic prescription medications

• Manufacturer: Able Laboratories
• Recall date: 2005
• Financial damage: Able Laboratories had $103 million in annual sales before recall.

On May 27, 2005 the Food and Drug Administration notified consumers and healthcare professionals of a nationwide recall of all manufactured drugs (mostly generic prescription drugs, including drugs containing acetaminophen) from Able Laboratories of Cranbury, NJ, because of serious concerns that they were not produced according to quality assurance standards. Able Laboratories subsequently ceased all production.

Inconsistencies in manufacturing by Able Laboratories resulted in both subpotent and superpotent medications.

Seldane (terfenadine)

• Manufacturer: Hoechst Marion Roussel (now Sanofi-Aventis)
• Recall date: 1997 (after 13 years on the market)
• Financial damage: Seldane was a big moneymaker for Hoechst Marion Roussel for such a long period (the year before it was pulled it sold $440 million worth of Terfenadine worldwide). In addition to its legal expenses, the loss of market share alone to drugs such as Claritin (loratadine) was steep.

Seldane (terfenadine) is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi-Aventis). According to its manufacturer, terfenadine had been used by over 100 million patients worldwide as of 1990. It was superseded by fexofenadine in the 1990s due to the risk of cardiac arrhythmia caused by QT interval prolongation.

Terfenadine is a prodrug, generally completely metabolized to the active form fexofenadine in the liver by the enzyme cytochrome P450 CYP3A4 isoform. Due to its near complete metabolism by the liver immediately after leaving the gut, terfenadine normally is not measurable in the plasma. Terfenadine itself, however, is cardiotoxic at higher doses, while its major active metabolite is not. Toxicity is possible after years of continued use with no previous problems as a result of an interaction with other medications such as erythromycin, or foods such as grapefruit. The addition of, or dosage change in, these CYP3A4 inhibitors makes it harder for the body to metabolize and remove terfenadine. In larger plasma concentrations, it may lead to toxic effects on the heart's rhythm (e.g. ventricular tachycardia and torsades de pointes).

Phenylpropanolamine (a.k.a., PPA)

• Manufacturer: Multiple manufacturers (widely manufactured across the industry)
• Recall date: 2000 (at least 60 years on the market)
• Financial damage: untold millions, if not billions (one manufacture alone settled for $15 million)

Phenylpropanolamine is an ingredient used in prescription and over-the-counter (OTC) drug products as a nasal decongestant to relieve stuffy nose or sinus congestion and in OTC weight control drug products to control appetite.

On May 11, 2000, FDA received results of a study conducted by scientists at Yale University School of Medicine that showed an increased risk of hemorrhagic stroke (bleeding of the brain) in people who were taking phenylpropanolamine. Phenylpropanolamine has been used for many years and a very small number of people taking the drug have had strokes. The Yale study helped show that the number of people having strokes when taking phenylpropanolamine was greater than the number of people having strokes who were not taking phenylpropanolamine. Although the risk of hemorrhagic stroke is very low, FDA has significant concerns because of the seriousness of a stroke and the inability to predict who is at risk. Because of continued reports to the FDA of hemorrhagic stroke associated with phenylpropanolamine and the results of the Yale study, the FDA now feels that the risks of using phenylpropanolamine outweighs the benefits and recommends that consumers no longer use products containing phenylpropanolamine.

Posicor (mibefradil)

• Manufacturer: Roche
• Recall date: 1998 (after one year on the market)
• Financial damage: Analysts had projected $2.9 billion in sales within 4 years.

In only one year on the market, Posicor (mibefradil) was linked to 123 deaths. Considered relatively safe when taken alone, Posicor became potentially deadly when combined with any of 25 different drugs. The large number of deaths are troublesome considering that the drug was prescribed to no more than 200,000 people worldwide in the space of one year, a relatively small number. Posicor is on this list for stimulating debate surrounding policies encouraging the FDA to hasten the approval of certain drugs. It is often cited as a strong example of what can go wrong when drugs are rushed to market.

See also

FDA: Recalls, Market Withdrawals, & Safety Alerts, http://www.fda.gov/Safety/Recalls/default.htm
Food and Drug Administration
Five rights
MedWatch
Medication errors
Vaccine Adverse Event Reporting System
Antidote
Tallman lettering
High-alert medications
Barcoding technologies
Medication safety

References

1. FDA 101: Product Recalls From First Alert to Effectiveness Checks, http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM143332.pdf
2. Wikipedia, Class I recall, https://en.wikipedia.org/wiki/Class_I_recall
3. Drug Recalls.com, America's Top 10 Recalled Drugs, Augst 2, 2011, http://www.drugrecalls.com/component/content/article/35-drugarticles/166-americas-top-10-recalled-drugs.html
4. Seamon MJ (2011). Active Pharmaceutical Ingredients and the Globalization of Pharmaceutical Manufactures: Contributors to US Drug Recalls and Shortages Pharmacy Law Column / Drug Store News Pharmacy Practice , (August), http://www.cedrugstorenews.com/userapp/August%202011%20Law%20Column.cfm
   
5. The Ten Worst Drug Recalls In The History Of The FDA - 24/7 Wall St. http://247wallst.com/2010/12/10/the-ten-worst-drug-recalls-in-the-history-of-the-fda/#ixzz1vtlDR4qu
6. Drugs@FDA, http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
7. Wikipedia, Troglitazone, https://en.wikipedia.org/wiki/Troglitazone
8. FDA, Able Laboratories Products - Recall of all Manufactured Drugs, http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150544.htm
9. Wikipedia, terfenadine, https://en.wikipedia.org/wiki/Terfenadine