Evelyn Pringle January 29, 2007
On December 5, 2006, five women with ages ranging from 53 to 71, who took the appetite suppressants drugs known as fen-phen in 1996 and 1997, filed lawsuits against Wyeth Pharmaceuticals after being diagnosed with a life-threatening lung disorder.
These lawsuits demonstrate that the harm caused by fen-phen can surface many years after a person stops taking the drugs. For instance, plaintiff, Renee Tedesco, 53, of New Jersey, took fen-phen 10 years ago but was not diagnosed with primary pulmonary hypertension (PPH), until April 2006. She has undergone a double lung transplant to save her life.
In addition, studies released in November 2001, indicate that PPH in fen-phen users may be 7 times higher than originally predicted in 1997.
Fen-phen refers to a combination of the drug phentermine and the diet drugs Redux (dexfenfluramine) or Pondimin (fenfluramine). According to the FDA, these drugs were approved as appetite suppressants to be used separately in the treatment of obesity for short periods of time.
The fen-phen combination was never FDA approved for any indication so all prescriptions were written for off-label uses. Drug companies are prohibited from promoting drugs for off-label use but doctors may prescribe a drug that has been approved for one indication for any condition they deem appropriate. In recent years numerous drug makers have come under fire for illegally promoting their drugs for off-label uses.
Prescriptions written off-label for fen-phen were massive. Patients were able to get fen-phen over the internet, and Jenny Craig and Nutri-System set up weight loss programs where doctors would prescribe the drugs to patients.
Doctors prescribed fen-phen without doing a thorough examination, and in many cases without any exam at all. Most doctors prescribing the drugs had little or no training in obesity, according to One Half-Phen In the Morning/One Fen Before Dinner: A Proposal For FDA Regulation of Off-Label Uses of Drugs, by Maime Wilsker (1998).
One Illinois patient said that she obtained fen-phen from a weight-loss clinic without ever seeing a doctor and that a nurse gave her the prescriptions.
An estimated 6 million people have taken fen-phen and more than 18 million prescriptions were written for the combination in 1996 alone. From 1992 to 1997, new prescriptions for fen-phen increased by 442% for phentermine and 6390% for fenfluramine, according to a report in the March 24, 1997, Archives of Internal Medicine.
However, the run-away-train prescribing about came to a screeching halt on July 8, 1997, when the FDA issued a Public Health Advisory to 700,000 health care professionals and institutions warning that researchers at the Mayo Clinic had reported 24 cases of heart valve disease in previously healthy women who took fen-phen on average for 12 months.
Of the 24 women identified who had valve disease, eight also had moderate or severe pulmonary hypertension, which had not been previously identified.
The Advisory also noted that the agency had received additional reports of the same nature, and advised health care professionals to report any similar cases to the FDA through MedWatch. Subsequently, the FDA received 66 more reports of valve disease.
The lesions that formed on the heart valves of fen-phen users cause blood to flow backwards instead of forwards, which is called regurgitation. The Mayo Clinic study was reported in the August 28, 1997, New England Journal of Medicine and concluded by stating: "significant de-novo left-sided regurgitant valvular heart disease in a population less than 50 years old is rare. Thus, the association of valvular regurgitation with fenfluramine-phentermine is not likely due to chance."
The researchers said that fen-phen users "should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease."
Cardiologist, Dr Heidi Connolly led the study and was interviewed on PBS on August 27, 1997. At that time, she reported that five of the women in the study had required open heart surgery to repair or replace damaged heart valves.
Pulmonologist, Dr Lewis Rubin was also interviewed on the PBS program as part a member of the research team that linked PPH to fen-phen. Dr Rubin's research found that people who took fen-phen for 3 months had a 9-fold increased risk for PPH, and 6-month users had a 23-fold increased risk of developing PPH.
After the Mayo Clinic report was published, the FDA conducted a study in five areas of the country, including Florida, Minnesota, Wisconsin, Indiana, and Pennsylvania and found a 32.8% presence of lesions causing valvular regurgitation, significantly higher than would be expected amongst the general population.
In addition to the FDA data supporting the link, Dr Mehmood Kahn performed a study in Minneapolis shortly after the July, 1997 announcement about valvular disease and found that approximately 25% of the 226 fen-phen users in his study had aortal regurgitation of mild or greater severity, compared with 1% in the 81 patients who did not take the drugs.
On August 27, 1997, acting FDA Commissioner, Dr Michael Friedman was interviewed on PBS and basically blamed the problems on the off-label prescribing explaining that "when these drugs are used in accordance with the labeled instructions, the number of side effects from pulmonary hypertension or from the valve abnormality are extremely rare."
"When these medications are used outside of those labeled indications," he advised, "at a higher dosage, for a longer period of time, or in combination with one another, then these side effects are seen more frequently."
"But we've had very few, if any, valve abnormalities in patients who have used the products in an appropriately-labeled fashion," Dr Friedman said in the interview.
He explained that the label indication "says to use these medications only for a short period of time, some few weeks, and in conjunction with dietary restrictions."
On September 15, 1997, the FDA called for the removal Pondimin and Redux from the market, based on findings from patients evaluated with echocardiograms to test heart valve functioning. "These findings," the FDA stated, "indicate that approximately 30 percent of patients who were evaluated had abnormal echocardiograms, even though they had no symptoms."
The injuries resulting from the fen-phen debacle are reportedly one of the largest number of adverse drug reactions that the FDA has ever dealt with.
Since American Home Products Corporation, which became Wyeth in 2002, withdrew the drugs from the market, a massive number of lawsuits have been filed against the company alleging injuries of valvular heart disease and PPH caused by the drugs.
Heart valve damage is an extremely serious medical condition that is life-threatening. Experts note that there are no medications that can reverse valve damage and valve replacement surgery is often the only option available.
In a healthy heart the valves fit tightly when closed, preventing blood from flowing backwards. But in the hearts of the patients studied at the Mayo Clinic, a waxy substance prevented the valves from closing completely.
Valvular insufficiency occurs when the valves do not close properly, which forces the heart to work harder to circulate the blood and can lead to serious problems such as heart attack or heart failure, according to WebMD.
Valve replacement requires open heart surgery, according to the Texas Heart Institute. The 2 kinds of valves used are mechanical valves made of metal or plastic, and biological valves made from animal tissue or human tissue from a donated heart.
Mechanical valves are stronger but because blood tends to stick to them and create blood clots, patients need to take blood-thinning drugs for the rest of their lives. And because these drugs increase the risk of bleeding, patients must wear a medical alert bracelet so that medical professionals will know they are taking a blood-thinning drug.
Patients with biological valves usually do not have to take blood-thinning medications but because the valves are not as strong as mechanical valves, they may need to be replaced every 10 years.
PPH is also an extremely serious condition that may require a heart-lung transplant. In its simplest form, PPH means high blood pressure in the lungs and the constriction of the vessels makes it harder for the heart to pump blood through the lungs. According to the FDA, PPH "results in death in about 40% of affected individuals within 4 years."
On November 22, 1999, the Philadelphia Inquirer interviewed a woman who was almost entirely housebound and on a waiting list for a double lung transplant. She was connected to oxygen tubes 24 hours a day and had an IV line connected to a pump to deliver drugs into her heart with her at all times. The woman said that as soon as she starts to move she gets weak and likened living with PPH to living on Mount Everest without oxygen.
Redux was FDA approved in April, 1996, even though there were already concerns about PPH. Reports of PPH with the drug had appeared in European literature in the 1980's and 1990's.
Two months after its approval, the International Primary Pulmonary Hypertension Study reported that the appetite suppressants (anorectic agents) increased the risk of PPH to between 23 and 46 cases per million, compared to the usual 1-2 cases per million. Redux and Pondimin represented 90% of the anorexigens in the study.
The IPPHS found that "the use of any anorexigen within the previous year was associated with a ten-fold risk of developing PPH, and the risk increased to more than 20-fold with use for longer than three months."
There have also been reports of neuropsychological damage in fen-phen users that can include memory loss, behavioral changes, depression, psychotic breakdowns, and mood swings. A study reported in the September 1997, Journal of the American Medical Association, indicated that Redux and Pondimin can reduce the production of a key brain-signaling chemical and adversely affect memory, cognition and moods.
Critics say this too was a known risk at the time that Redux was FDA approved. In fact, after its approval, a group of neuroscientists sent a letter to the FDA criticizing the agency for ignoring animal tests that suggested that prolonged use of Redux damaged brain tissue.
In litigation, some plaintiffs are going after the doctors for their off-label prescribing. In a Philadelphia PPH jury trial, a doctor was held liable for half of the $8 million verdict for prescribing fen-phen for the plaintiff between 1995 and 1997.
The woman's attorney stated that "the claim against [the prescribing doctor] was that he not only prescribed the drug beyond the two weeks recommended by the manufacturer, but he prescribed it for years . . . and he prescribed it until she [the plaintiff] called him and said that she had heard on CNN when she was in Italy touring that there were side effects," according to Lori Litchman, in the February 24, 2000, Legal Intelligencer.
On the other hand, the drug maker can hardly argue that it was unaware of the widespread off-label use of fen-phen with record profits pouring in from the drugs.
According to one plaintiff's attorney, Paul Rheingold, in Fen-Phen and Redux: A Tale of Two Drugs, "there is blame enough to go around."
The doctors who set up store-front fen-phen clinics and prescribed the drugs are obvious culprits, he said, and so are drug companies that profited financially from the fad and may have neglected to pass on information about deadly side effects.
A national class action settlement has been reached involving claims for valvular heart disease, but the settlement did not include claims for PPH or neurological damage. Lawsuits with those claims are being tried individually.
Wyeth has reportedly allocated $21 billion to cover the costs and damages of fen-phen litigation.