Drug Injury Watch

Extent Of Digitek Recall Remains A Mystery Ten Days Later; Patients Are Left In The Dark

Heart Medication Sold By Mylan Was Made In Actavis Plant That Received FDA Letter About Manufacturing Problems Over A Year Ago

(Posted by Tom Lamb at DrugInjuryWatch.com)

News about the April 2008 Digitek recall came first in the form of a brief company press release dated April 25, which was followed by an FDA MedWatch Safety Alert posted April 28 on the agency's web site.

As of May 5, ten days later, there had been little additional information from Actavis Totowa, the drug manufacturer, and none from the FDA, about the possible extent of the Digitek recall. 

Meanwhile, patients are being contacted by their pharmacists who, admittedly, know nothing more about the situation than what was set forth in the April 25 half-page press release about this "Class 1 nationwide recall of Digitek (digoxin pills, USP, all strengths)".

Understandably, patients are asking how far back in time they have been getting and taking Digitek pills that may have contained double the intended dose of active ingredient.

The latest news about the extent of the Digitek recall comes from a May 6, 2008 article, "Double-strength digoxin recalled in US", by Phil Taylor, which is posted online at In-PharmaTechnologist.com ("Breaking News on Pharmaceutical Technology"), of London, UK.

Because we do not want to misconstrue in any manner the intriguing information developed by Mr. Taylor in his May 6 article, we provide this extended excerpt:

A spokesperson for the company told in-PharmaTechnologist.com that the investigation into the problem was still ongoing, but at the moment there was no further information on what caused it and how many tablets were involved.

This is not the first time that there have been manufacturing problems at the Actavis Totowa facility in New Jersey, which was acquired as part of the takeover of Amide Pharmaceuticals by Actavis in May 2005, although the spokesperson said these earlier issues were entirely unrelated to the current incident.

Just over a year ago Actavis Totowa was sent a warning letter by the FDA after an agency inspection revealed that drugs products manufactured in the facility were 'adulterated'.

The quality control unit at the site came under criticism from the agency, which said it failed to reliably establish the identity, strength, quality and purity of drug products manufactured and released onto the market. The FDA inspectors also noticed a general lack of investigation of out-of-specification test results, as well as a lack of sufficient documentation of the results.

It is understood, however, that all these 'Form 483' issues have since been resolved to the agency's satisfaction.

Hopefully Actavis and/or the FDA will be making an official announcement, soon, about how far back in time the Digitek pills sold under the "Bertek" and "UDL" labels may have been double-strength tablets.  Until then, many patients and their families are left wondering if possibly related symptoms were caused by the use of these double-strength Digitek tablets.

FDA Says It Doesn't Know How Long Defective Digitek / Digoxin Pills Were Sold

Actavis Says They Have Received 11 Complaints About Digitek Side Effects That Date Back To 2006

(Posted by Tom Lamb at DrugInjuryWatch.com)

The facts surrounding a late April 2008 recall of Digitek (digoxin) pills that may have twice the usual active ingredient are becoming less clear as we learn more in the days following the FDA's April 28 announcement.

In a May 1, 2008 Newsday.com article, "Pharmacists will call you: Digitek recalled", by reporter Kathleen Kerr, we learn that the defective Digitek tablets may have been sold for more than a year:

"We had some concerns about the process," [Actavis Totowa spokesman John] LaRocca said. He said the company knew of no deaths linked to Digitek use but Actavis and the FDA had received 11 complaints about side effects since 2006.

As reported previously, this improperly manufactured generic digoxin medication could lead to digitalis toxicity; patients with renal insufficiency are especially at risk.

According to Californian staff writer Emily Hagedorn, in her May 1, 2008 article "Recall of heart drug worries Bakersfield family", the FDA is still trying to get a handle on the magnitude and ramifications of this Digitek recall:

Considering it was voluntarily recalled Friday afternoon, it’s too soon to tell how many people have suffered adverse reactions, said Sandy Walsh, spokeswoman for the Food and Drug Administration. She didn’t know how long the defective pills were sold....  The FDA has inspected the manufacturer’s facility since the error was discovered, she said....  While Actavis has 50 percent of the digoxin market, the FDA does not foresee a shortage from other manufacturers, Walsh said.

Going back to the Newsday.com May 1 article, we get some pharmacy perspective on the Digitek recall:

Joel Bassuk, pharmacist at Raindew Pharmacy in Manhasset, said he received the recall notice yesterday....  "They said to immediately examine your inventory and discontinue all lots," Bassuk said....  CVS spokesman Mike DeAngelis said the chain had removed all Digitek from its stores. "We went back to see which patients had prescriptions over the past 12 months and contacted them," DeAngelis said.

As always, we welcome information about emerging drug safety issues:  [email protected].  This situation, in particular, calls for such assistance from anyone who may know more about the extent of this apparent manufacturing problem whereby some digoxin pills may be too potent.  At this juncture, at least, it seems we are not getting much in terms of "specifics" from Actavis, the drug manufacturer, nor the FDA about this Digitek recall.

Digitek Digoxin Recall: Tablets May Be Double The Normal Dose

So-called "Digitalis Toxicity" Is Possible, Especially In Patients With Renal Failure

(Posted by Tom Lamb at DrugInjuryWatch.com)

In an April 28, 2008 MedWatch Safety Alert about Digitek (digoxin tablets), the FDA informed doctors and patients that this prescription medication is the subject of a nationwide Class I recall because of the possibility that some tablets were manufactured such that they contain twice the approved level of active ingredient.

In more detail, according to this Digitek MedWatch Safety Alert:

• The products are distributed by Mylan Pharmaceuticals Inc., under a “Bertek” label and by UDL Laboratories, Inc. under a “UDL” label.
• The existence of double strength tablets poses a risk of digitalis toxicity in patents with renal failure.
• Digitalis toxicity can cause nausea, vomiting, dizziness, low blood pressure, cardiac instability and bradycardia.

This April 28 MedWatch Safety Alert came several days after a press release about this Digitek manufacturing problem was issued by Actavis Totowa LLC (formerly known as Amide Pharmaceutical Inc).  Therein, the manufacturer said it is recalling all strengths of Digitek because it may have accidentally released pills that are double the normal thickness, carrying twice the normal dose.

Digoxin is used in the treatment of arrhythmias and heart failure.

Patients taking Digitek tablets should contact their doctor if they have any concerns or questions.

P.S.  According to a brief newspaper article dated April 25, 2008, "Digitek heart drug recall":

[Actavis Totowa LLC spokesman] John LaRocca said 11 people have reported getting sick after taking the drug, but the Morristown, N.J., company is not aware of any deaths.

We will keep you informed about the number of patients injured by Digitek (digoxin) tablets that were defective, i.e., manufactured with a double-dose, as well as anything that we learn about the dates when these recalled Digitek tablets were being dispensed at pharmacies across the country. 

My law firm has been contacted already by several people who have had family members hospitalized with serious side effects apparently caused by the defective Digitek tablets.  We are in the process of investigating possible Digitek cases where the patient was hospitalized or that involve a death that may be related to the person's use of Digitek tablets.  (5/1/08)

Trasylol Sales In U.S. And Canada Suspended Temporarily By Bayer In Early November 2007

Market Withdrawal Or Recall Of Trasylol Seems Possible As Bayer Waits For Final Data From Halted BART Study

(Posted by Tom Lamb at DrugInjuryWatch.com)

On November 5, 2007 the FDA announced and Health Canada announced that sales of Bayer AG' s anti-bleeding drug Trasylol (aprotinin) would be suspended temporarily in the U.S. and Canada while investigations continued about whether Trayslol is linked to a higher risk of death than competing heart surgery drugs.

As we had reported previously, the FDA has been reviewing the safety of Trasylol since early 2006:

In mid-February 2006 the FDA issued a Public Health Advisory informing doctors and patients that the agency was evaluating the safety of Bayer AG's heart surgery drug Trasylol (aprotinin injection) after new studies had linked it to higher risks of kidney problems, heart attacks, and strokes.  At the end of February 2006, a "Dear Doctor" letter from Bayer regarding Trasylol was posted on Health Canada's MedEffect web site.

Later, in September 2006, an FDA advisory panel reviewed data from medical journals that suggested that Trasylol might increase the chance of kidney damage, heart attacks, and strokes.

A second Trayslol advisory panel meeting was scheduled for September 2007.  Two days before, FDA staff released 235 pages of briefing documents they had prepared for that Trasylol advisory panel meeting which seemingly foreshadowed this most recent development in the Trasylol saga.

From a September 10, 2007 Reuters article, "Bayer's Trasylol may boost death risk: FDA staff", by reporter Kim Dixon:

FDA staff, in briefing documents ahead of Wednesday's advisory panel, said the totality of three recent studies support the risk of renal failure and dysfunction, and noted a "mortality disadvantage detected" in the Bayer study.

A Bayer spokeswoman said the company looks forward to discussing the drug's merits at the advisory panel meeting....

"There is still no new clinical data, so the question is whether (Bayer's) observational study is enough of an alarm," said Ira Loss, an analyst at the investor research firm Washington Analysis.

"My assumption is this drug is being put into the dead-end of drug land," he added.

While the September 2007 Trasylol advisory panel decided this heart surgery drug should remain on the market despite its increased renal and cardiovascular risks, it urged Bayer to conduct a randomly controlled clinical trial on Trayslol.

Bad news for Bayer, however, soon followed when a Canadian study -- the BART study, an independent randomized, controlled trial that was being conducted in high-risk cardiac surgery patients -- was suddenly stopped in mid-October 2007 due to emerging serious safety concerns regarding Trayslol.

On October 25, 2007 the FDA posted on its web site an "Early Communication about an Ongoing Safety Review Aprotinin Injection (marketed as Trasylol)" which said, in part, stated that the 30-day mortality risk in the Trasylol group of the BART trial was nearing statistical significance, compared with other treatments Trasylol was being tested against.

A November 5, 2007 Reuters article about the suspension of Trayslol sales brings us up-to-date with this information:

• On [November 5, 2007] Bayer said it had been informed that BART trial data were now being collected from centers throughout Canada and final data analysis would emerge in around eight weeks.
• "Once the complete BART dataset is available, Bayer will work with health authorities to evaluate whether these data have any impact on the positive benefit-risk assessment for Trasylol," Bayer said [November 5, 2007].
• "Bayer believes that the totality of the available data continue to support a favorable risk-benefit profile for Trasylol when used according to labeling," the company said.

We will wait to see whether or not the final analysis of this BART study data and any other relevant information leads to Bayer withdrawing Trasylol from the market altogether in the months to come.  Of course, it is possible that based on their findings the FDA or Health Canada may make that choice for the drug company.

Medtronic Sprint Fidelis Wire Leads Fracturing In Defibrillators May Have Caused Five Deaths

Events Leading Up To October 2007 FDA Recall Include A Little Noticed March 2007 "Dear Doctor" Letter And July 2007 Medical Journal Article About Model 6949

(Posted by Tom Lamb at DrugInjuryWatch.com)

An October 16, 2007 article in The Wall Street Journal about the Fidelis Sprint leads recall presented the current situation:

In announcing the recall early yesterday, Medtronic said that its Sprint Fidelis leads have broken at a rate apparently higher than that of competing leads, including another from Medtronic....

When the lead fractures, it can have serious consequences: Some patients can receive unnecessary and massive shocks, sometimes compared to the jolt of sticking a fork in a light socket. Other patients don't get the shock when they do need it to save their lives after cardiac arrest. Overall, five patients so far have died in cases Medtronic says may be related to the flaw.

So far, 2.3% of the implanted leads have malfunctioned over a 30-month period studied by Medtronic since the device's introduction in the fall of 2004. Most of these thousands of malfunctions are fractures.

While this fracturing or breaking problem with the Sprint Fidelis wire lead was the subject of a little noticed (and hard to find, now) March 2007 "Dear Doctor" letter from Medtronic, this emerging medical device safety issue only began to get some real public notice in July 2007.

First, Dr. Robert G. Hauser and some of his colleagues had a paper published in the July 2007 edition of Heart Rhythm about the Sprint Fidelis model 6949 having a higher than expected lead failure at their facility.  From the Abstract for this paper, "Early failure of a small-diameter high-voltage implantable cardioverter-defibrillator lead":

• OBJECTIVE: The aim of this study was to assess the performance of small-diameter Sprint Fidelis high-voltage ICD leads.
• RESULTS: The survival of 583 Sprint Fidelis 6949 leads implanted at our center between September 2004 and February 2007 was significantly less than 285 Sprint Quattro Secure model 6947 leads implanted by us between November 2001 and February 2007 (P = .005). Six patients presented with Sprint Fidelis lead failure 4-23 months after implant. Five of the six patients experienced multiple inappropriate shocks associated with pace-sense conductor and coil fractures; the sixth patient had a fixation mechanism failure. The [United States Food and Drug Administration Manufacturers and User Facility Device Experience (MAUDE) database] search rendered reports for 679 Sprint Fidelis leads. The most frequent complaints or observations were inappropriate shocks (33%), high impedance (33%), and fracture (35%). Of 125 leads analyzed by the manufacturer, 62 involved fracture of the pace-sense conductor or coil and the high-voltage (defibrillation) conductor.

Then, seemingly prompted by this medical journal article by Dr. Hauser, reporter Janet Moore of the Star-Tribune newspaper in Minnesota -- where Medtronic Inc. is headquartered -- picked up the Sprint Fidelis story in a July 30, 2007 article, "Medtronic device under scrutiny":

In late March [2007], Medtronic Inc. sent a letter to doctors advising them that the wire leads in a line of widely used heart defibrillators could tear at a "higher than expected" rate.

The "Dear Doctor" letter assured physicians that the performance of the Sprint Fidelis line of leads is consistent with similar products, and it offered suggestions about how to best implant it.

Four months later, several physicians in the Twin Cities have stopped using the leads, and Medtronic is investigating a patient's death in which a model of the Sprint Fidelis lead is "in question."

And it was Janet Moore at the Star-Tribune who apparently first reported on the Sprint Fidelis recall in her October 14, 2007 article, "Medtronic stops selling heart device":

Medtronic Inc. said today it has stopped selling a popular wire lead used with heart defibrillators because the lead may tear inside the body.

About 235,000 patients worldwide may be affected by the [Minnesota]-based company's action. Patients who believe they may have the device implanted in their chest should contact their doctor, but Medtronic does not recommend replacing it.

The Food and Drug Administration (FDA) said it has classified Medtronic's action as a recall, which means Medtronic must stop selling the devices.

For those interested in learning more about what is known at present about the problems associated with Sprint Fidelis leads, we provide these resources:

October 15, 2007 Statement from FDA

October 15, 2007 Consumer Q&As from FDA

October 15, 2007 "Dear Doctor" Letter from Medtronic

October 15, 2007 News Release from Medtronic

We will continue to monitor and report what is learned about the relatively high rate of breaks or fractures in Sprint Fidelis leads used with defibrillators -- even though it is a bit off-topic for us -- because of its importance and because it seems to be closely / coincidentally related to our October 15, 2007 post: "How Should Drug Companies And Their Ad Agencies Respond To Safety Signals?"

P.S.  Insofar that the March 2007 "Dear Doctor" letter reported the five deaths possibly related to faulty Sprint Fidelis leads one must wonder did the FDA wait to long to issue its October 2007 recall?  (10/18/07)

P.S.   Now U.S. Representative Henry Waxman wants to know what the FDA knew about the Sprint Fidelis defibrillator lead wire fractures and when they knew it.  On October 22, 2007, as Chairman of Committee on Oversight and Government Reform, this California Congressman sent a letter to FDA Commissioner Andrew von Eschenbach requesting the Medtronic information which the FDA had access to before its October 2007 Sprint Fidelis recall.  (10/23/07)

Parkinson's Disease Drug Permax Ordered Off The Market By Health Canada

Permax Was Voluntarily Withdrawn From the U.S. Market Earlier This Year At The Insistence of FDA

(Posted by Tom Lamb at DrugInjuryWatch.com)

As you may recall, the Parkinson disease drug Permax was voluntarily withdrawn from the U.S. market in late March 2007 after studies in the New England Journal of Medicine underscored the increased risk of serious heart valve damage associated with Permax.

In Canada, however, Eli Lilly Canada Inc. had continued to sell Permax (pergolide). 

On August 16, 2007, however, Health Canada announced the sales of Permax must cease in their country as of August 30, 2007

In more detail, from a MedEffect Public Communication about Permax issued on August 16, 2007, we get this information about why Health Canada has taken this action:

• Two studies published in the New England Journal of Medicine (NEJM) in January 2007 showed that patients with Parkinson's disease who were treated with Permax had an increased chance of serious heart valve damage when compared to patients who did not receive the drug. [footnotes omitted] In light of this recent information, Health Canada has determined that there is not enough evidence to support the continued safe use of Permax as currently recommended in the prescribing information.
• Eli Lilly Canada Inc., in co-operation with Health Canada, will stop sales of Permax (pergolide mesylate) in Canada as of August 30, 2007 due to the potential for cardiac valvulopathy, a condition involving inflammation or stiffening of the heart valves. Pharmacies may continue to sell Permax after that date to allow patients sufficient time to consult with their healthcare providers and to transition to an alternative medication.

Eli Lilly Canada Inc. has sent a so-called "Dear Doctor" letter to Canadian healthcare providers about Permax informing them that sales of this Parkinson's disease drug will stop in Canada as of August 30.  This Permax Dear Doctor letter also gives advice for discontinuation and transition to alternative medications for Canadian patients currently taking Permax.

Australian Regulators Request That Novartis Withdraw Their Painkiller Drug Prexige

Prexige Associated With Reports Of Liver Damage, Liver Transplants, And Death

(Posted by Tom Lamb at DrugInjuryWatch.com)

An August 11, 2007 Bloomberg article, "Novartis' Prexige Painkiller Drug Pulled by Australia", let us know about the latest prescription drug recall.

According to this Bloomberg article, eight serious adverse reaction reports about the use of the painkiller Prexige being associated with liver damage have been made to Australia's drugs regulator, the Therapeutic Goods Administration, "including two deaths and two liver transplants".  These adverse reaction reports apparently formed the basis for this Prexige recall in Australia. 

In more detail, from this August 11 article:

"It seems that the longer people are on the medicine, the greater the chance of liver injury," the [Therapeutic Goods Administration (TGA)] said. Prexige, which is used to treat osteoarthritis as well, is also known as lumiracoxib. "The TGA is, therefore, advising people to stop taking the lumiracoxib immediately." ...

John Gilardi, a spokesman for Novartis, declined to comment today on whether the company plans to withdraw Prexige from other markets.

Novartis said most of the cases in Australia were for 200mg doses of Prexige while one was for 400mg, higher than recommended.

"The 100mg dose of Prexige, which is the recommended dose worldwide for treatment of osteoarthritis, has not been associated with an unexpected incidence of liver-related side effects," the company said in a statement.

According to Novartis, more than 7 million prescriptions for Prexige have been written worldwide since this painkiller drug was first approved for use in July 2005. Further, Novartis said that the drug regulators or other health authorities in the 50 countries where Prexige is sold had been notified about the this drug being withdrawn from the market in Australia.

For various reasons, Novartis has not yet sought FDA-approval for Prexige in the U.S.  If and when it does so, however, the drug company may have an uphill battle given this action taken by Australia's TGA.

P.S.  Health Canada is currently requesting and reviewing new safety information regarding Prexige as concerns these reports of serious liver adverse events in patients using this Cox-2 inhibitor non-steroidal anti-inflammatory drug (NSAID), it was announced on August 16, 2007.  (8/16/07)

P.S.  In an August 23, 2007 Drug Safety Message from the MHRA entitled "New (interim) restrictions on prescription of lumiracoxib, following concerns over liver safety" we learned that Novartis has sent a "Dear Doctor" letter about Prexige (lumiracoxib) to health professionals in the UK and other European countries in order to inform them of new restrictions on the prescribing of Prexige.  (8/23/07)

Novartis Ordered To Recall Zelnorm From Market In Switzerland

Swiss Pharmaceutical Regulator States That Side Effect Risks Outweigh Benefits

(Posted by Tom Lamb at DrugInjuryWatch.com)

In a brief June 1, 2007 Wall Street Journal (WSJ) article it was reported that Switzerland's pharmaceuticals regulator has ordered Novartis AG to recall Zelnorm from the market because the irritable bowel drug's risk of serious side effects outweighed its therapeutic benefits.  In parts of Europe, including Switzerland, Zelnorm is known as Zelmac.

Zelnorm was pulled from the U.S. market on March 30, 2007 after it was linked to a higher chance of heart attacks and strokes.

According to the June 1 WSJ article, the Swiss regulator, Swissmedic, and Novartis disagreed about the safety profile of Zelnorm:

Swissmedic said a new analysis of data from clinical studies revealed an increased risk of angina, heart attacks and strokes when compared with a placebo. Novartis, based in Switzerland, said it is complying with the order but remains convinced that Zelmac has important benefits for certain patients.

According to a May 31, 2007 Reuters article about this Zelnorm recall in Switzerland, that country had approved the use of Zelmac / Zelnorm in women with irritable bowel syndrome in 2001.

FDA Orchestrates Voluntary Recall of Parkinson's Disease Drug Permax

Action Follows News Of Studies Which Revealed Link To Serious Heart Valve Damage

(Posted by Tom Lamb at DrugInjuryWatch.com)

On March 29, 2007 the FDA announced that Permax as well as two generic pergolide drug products, which had been used to treat Parkinson’s disease, would be voluntarily removed from the U. S. market because Permax (pergolide) had been linked to serious heart valve damage.

From the FDA News item entitled "FDA Announces Voluntary Withdrawal of Pergolide Products":

The products being withdrawn are Permax, the trade name for pergolide marketed by Valeant Pharmaceuticals, and two generic versions of pergolide manufactured by Par and Teva. Pergolide is in a class of medications called dopamine agonists and is used with levodopa and carbidopa to manage the symptoms (tremors and slowness of movement) of Parkinson’s disease.

In 2006, an estimated 12,000 patients received prescriptions for pergolide from retail pharmacies in the United States. Patients taking pergolide should contact their doctors to discuss alternate treatments. Patients should not stop taking the medication, as stopping pergolide abruptly can be dangerous.

This move by the FDA follows two studies published in the New England Journal of Medicine (NEJM) as well as a more recent article published in the Archives of Neurology which seemed to confirm several previous studies that had associated Permax (pergolide) with an increased risk of developing regurgitation -- or backflow of blood -- of the mitral, tricuspid, and aortic valves of the heart. Generally, valvular regurgitation is a condition in which the heart valves do not close tightly which, in turn, allows blood to flow backward across the valves; common symptoms include shortness of breath, fatigue, and heart palpitations.

As one may recall, the two NEJM studies also discussed the association of another drug, Dostinex (cabergoline), with these heart valve side effects.  In a March 30, 2007 Wall Street Journal (WSJ) article, however, Dr. Robert Temple, director of the FDA's Offices of Drug Evaluation, said his agency is "not particularly worried" about Dostinex:

The two studies, published in January in the New England Journal of Medicine, also tied another Parkinson's drug, Pfizer Inc.'s Dostinex, or cabergoline, to heart-valve problems. In the U.S., FDA officials said, cabergoline is sold for a hormone condition, not for Parkinson's, and is recommended at far lower doses than the ones tied to the heart problems. Dr. Temple said the agency was "not particularly worried" about the drug.

Also from this March 30 WSJ article, it seems as if Eli Lilly & Co. disputes this FDA action concerning pergolide products, including Permax:

Eli Lilly & Co., which began marketing pergolide in the U.S. in 1989 and still sells it overseas, said it has no plans to pull it from foreign markets. The drug is "still an important treatment option for Parkinson's disease in Europe and around the globe," a spokesman for the Indianapolis company said. Eli Lilly believes "the risk-benefit profile of pergolide is still favorable" for certain patients when they follow the safety recommendations, he said.

In connection with this recall, the FDA has released a Public Health Advisory about Permax (pergolide) intended to provide information and recommendations to doctors, pharmacists, and patients in the wake of Permax being withdrawn from the market.

Constipation Medication Zelnorm Linked To Apparent Increased Risk Of Heart Attacks And Strokes

Novartis Suspends Sales After FDA Determines That Risks Of Serious Side Effects Outweigh Benefits Of Zelnorm

(Posted by Tom Lamb at DrugInjuryWatch.com)

On March 30, 2007 the FDA announced that Novartis Pharmaceuticals Corporation had suspended the marketing and sales of Zelnorm (tegaserod), a widely prescribed medication for irritable bowel syndrome (IBS) and constipation, due to an apparent increased risk of heart attacks and strokes in patients using Zelnorm.

According to a March 30, 2007 FDA News release entitled "FDA Announces Discontinued Marketing of GI Drug, Zelnorm, for Safety Reasons":

Zelnorm was approved for short-term treatment of women with irritable bowel syndrome whose primary symptom is constipation and for men and women younger than 65 with chronic constipation.

An analysis of 29 placebo-controlled clinical trials comprising over 18,000 patients conducted by Novartis found 0.1% of patients taking Zelnorm showed evidence of a serious cardiovascular event, compared with 0.01% taking a placebo. The FDA concluded that, for most patients, the benefits of Zelnorm no longer outweigh the risks. The agency is working with the manufacturer to keep the drug available for those who have no other treatment options.

A time line of the events leading up to Novartis' withdrawal of Zelnorm from the U.S. market is outlined in a March 31, 2007 New York Times article by Gardiner Harris:

The worries about Zelnorm began with a routine safety review last year by drug officials in Switzerland. To prepare, Novartis scientists gathered data from all 29 of their Zelnorm studies and looked for patterns. By January, they had found the difference in heart problems.

Thirteen cases of heart problems in more than 11,000 patients is about what one might find in a normal population, said Dr. Stephen Cunningham, head of clinical development and medical affairs in the United States at Novartis.

The company reported its finding to the drug agency on Feb. 22. The agency mobilized a team of reviewers.

The team met with Novartis officials on March 15 to ask questions. On Thursday, the F.D.A. notified the company that it had decided that Zelnorm should be withdrawn. On Friday the company complied.

Zelnorm was approved by the FDA in July 2002 for short-term treatment of women with irritable bowel syndrome whose primary symptom is constipation and approved in August 2004 for men and women younger than 65 with chronic constipation.

As for how often Zelnorm was prescribed in the U.S., according to a March 30, 2007 Reuters article:

Zelnorm was Novartis's 12th-biggest selling drug in 2006, with global turnover growing 30 percent to $561 million, of which $488 million was generated in the United States.

About 500,000 U.S. patients are taking Zelnorm, Novartis spokeswoman Anna Frable said.

The FDA has released a Public Health Advisory about Zelnorm intended to give doctors and patients further information about why Zelnorm was taken off the market.