Off-Label Use of Blood Clotting Drug, NovoSeven, Linked to Deaths and Strokes – FDA

According to the FDA, a blood clotting drug for hemophiliacs has been linked to heart attacks, strokes, deaths, and other health complications in patients given the medicine for other types of out-of-control bleeding, such as cerebral hemorrhages.

NovoSeven, manufactured by Danish pharmaceutical company Novo Nordisk (Novo), was released on the market in 1999 after gaining fast-track approval from the FDA.

Originally designed for and approved by the FDA for stopping bleeding in hemophiliacs, the drug has shown promise as a treatment for cerebral hemorrhages, which is a potentially deadly kind of stroke caused by bleeding in the brain.

The majority of the reported complications associated with the drug involved off-label use, instances where the drug was used to treat a condition not specifically approved by the FDA.

While legal, off-label use does not provide doctors with as much information on potential side-effects of drugs as approved uses would. (See discussion of the off-label dilemma below.)

The company said in a statement that off-label use of NovoSeven has resulted in complications in older people and those with underlying heart disease and acute injuries. The risk for approved uses, however, "is thought to be low," the company said.

In October, Novo Nordisk changed the warning in the package insert to include information on side-effects in patients who do not have hemophilia. Novo and is currently conducting studies on the safety of the drug in such patients.

The researchers analyzed 431 reports to the FDA of adverse events, ranging from nausea to death, during the first five years of the drug’s use. According to the study, the drug’s clotting action may have led to problems such as strokes and heart attacks in 185 cases.

Most of those problems involved off-label uses and occurred within 24 hours of the last dose.

Since NovoSeven’s approval for treatment of hemophiliacs in 1999, doctors have found other uses for the drug, including stemming bleeding from surgery, injuries or strokes. Use of NovoSeven increased from 349 patients in 2000 to more than 4,500 in 2004.

"You’re seeing people grasping for what’s on the shelf now, hoping the evidence will follow," said Dr. James Meschia, a neurologist at the Mayo Clinic in Jacksonville, Fla.

The report on the complications caused by NovoSeven appears in the Journal of the American Medical Association. A point worth mentioning is that the drug got fast-track approval as an "orphan drug," which means Novo received financial incentives to develop it because it treats a rare condition and was regarded as having little potential for profit.

Once the off-label use of any drug becomes popular (see below) the manufacturer suddenly has a reason to encourage (albeit improper to do so) that expanded use. (Certainly, the manufacturer has no reason to discourage it.)

Off-label prescribing has the potential to turn an “orphan drug” into a fairly profitable one and a very profitable drug into a blockbuster (see Natrecor, below). Stopping off-label use, once it has caught on, is often extremely difficult.

Unfortunately, as evidenced by any number of disasters, off-label use of any drug can turn into a deadly game of Russian roulette with the patient being the guinea pig.


The off-label prescribing of drugs beyond the scope of their approval by the FDA has become a serious concern in recent years. Dosage levels, medical conditions, and treatment durations for which drugs were never intended or tested make the entire area of off-label use problematic at best. At its worst, the practice can be outright deadly.

Although the FDA discourages and even warns against such uses of drugs the practice is rampant in the industry. This has been especially true in the case of powerful drugs like antipsychotics, heart medications, and antidepressants.

The incredibly strange thing about off-label use, however, is that doctors may prescribe drugs to treat conditions for which the FDA has even denied approval. Thus, while a manufacturer cannot market a drug for an unapproved off-label use, a doctor may prescribe the drug for that use.     

Thus, if a pharmaceutical company is able to subtly (or, even not so subtly) stimulate off-label use of one of its drugs, the return in unanticipated profits can be quite significant. In fact, a clever marketing scheme can turn a restricted approval drug with limited sales potential into one of those prized billion-dollar blockbusters.

Many times, off-label use of a drug is stimulated by doctors themselves who are acting more like marketing agents than as responsible health professionals. One doctor may get a favorable result in an off-label situation and begin touting that use of the drug to colleagues or even other patients.

These “anecdotal” stories of a drug’s success in an area it was never approved for often create an inflated demand for that drug well beyond its true market potential.

In the case of Natrecor, nothing good can be said concerning the manner in which the drug has been promoted and marketed and the failure to report at least two product-related additional deaths during its clinical testing.

Natrecor, or nesiritide, was approved by the FDA in 2001 to treat congestive heart failure or acute decompensating heart failure in which patients experience shortness of breath and the heart fails to adequately pump blood to other organs in the body.  

Natrecor is manufactured by Scios, a company which was bought by Johnson & Johnson in 2003.  As many as 600,000 patients have been treated with the drug since its approval.

Natrecor was, and still is, supposed to be used for the sole purpose of treating hospitalized patients with the aforementioned heart conditions.

Despite this express limitation on its approved use; Natrecor became an increasingly popular option in outpatient clinics nationwide where it is used for far longer periods than it was originally approved for.  

Some outpatient clinics even established programs to administer Natrecor twice weekly for up to 12 weeks.  This type of use is considered to be extremely dangerous as no study has been conducted to confirm whether long-term use is either safe or effective.  

This “off-label” use of Natrecor has lead to the discovery of severe side-effects and a subsequent push from medical experts and consumer advocates for the manufacturer to conduct further large-scale, longitudinal studies of the drug.

Dr. Jonathan Sackner-Bernstein, a cardiologist at North Shore University Hospital in New York and an avid opponent of the overuse of Natrecor, co-wrote several journal articles that provide data which links Natrecor to kidney problems and elevated death rates.  

Sackner-Bernstein’s patients taking Natrecor were 80% more likely to die within the next 30 days than patients who had received other treatments such as diuretics or vasodilators.  

The issues relating to kidney safety were known prior to and during the process of FDA approval of the drug and are specifically noted in the drug’s labeling. Yet the increased risk of mortality was not entirely known or appreciated until the drug became widely used in outpatient clinics for extended periods of time.  

This particular problem would take on added significance when, as discussed below, it was revealed that Scios had failed to disclose data on at least two additional Natrecor-related deaths that took place during clinical testing.

Although Scios argued that the Sackner-Bernstein paper included studies done at higher doses than are advised on the drug’s label, those higher (unapproved and risky) doses are precisely what patients are being exposed to when they receive the treatment outside of hospitals.
Natrecor was never approved to be used as frequently as was (and may still be) being used in outpatient clinics.  Sackner-Bernstien and other experts, including fellow cardiologist Keith Aaronson, have attempted to show that Natrecor should not be administered in outpatient settings and that the drug’s label should indicate the serious problems associated with unrestricted off-label usage.

In the July 14, 2005 edition of the New England Journal of Medicine, Dr. Eric Topol of the Cleveland Clinic (and also an outspoken critic of Vioxx) was highly critical of the way in which Scios was marketing Natrecor. He even went so far as to state that the drug should be off the market because the FDA was never given sufficient data upon which to have based its approval.  

Natrecor has been aggressively marketed with sales of the drug now reaching almost $700 million this year.  This is because Natrecor is an expensive option, costing nearly 50 times (yes, 5,000%) more than standard therapy options. That’s like paying $10,000 for a $200 iPod or $19.50 for a 39-cent postage stamp.

Natrecor is billed to insurance companies at up to $700 per session.  When used in hospitals for emergency situations, as intended, the cost, while high, is somewhat controllable.  When patients receive this treatment dozens of times in outpatient clinics, however, the cost quickly spirals out of control.  

In addition to other questionable marketing strategies, Scios provided doctors with promotional materials advising them on how to bill Medicare for Natrecor uses that are clearly not approved by the FDA.  

The Scios reimbursement guide, also available through a toll-free number, told doctors to use Medicare codes that treat Natrecor like chemotherapy allowing them to bill for larger Medicare reimbursements.

As a result, Medicare managers became concerned that reimbursements for Natrecor treatments in outpatient clinics would skyrocket as a result of the information that Scios was supplying to medical professionals.

In May 2005, Johnson & Johnson announced that in compliance with the FDA, it would revise the labeling for Natrecor to include data indicating an increased risk of mortality within 30 days for Natrecor patients compared with patients taking a placebo or other treatments.  

While that was a good start, doctors and other medical professionals were still advocating further studies of Natrecor to determine the health risks associated with the drug.  

Milton Packer, a cardiologist at the University of Texas, Southwestern, is concerned that Scios, like Vioxx maker Merck, had not done adequate studies to make sure that its drug is safe.  Although the FDA approved the drug in 2001, many doctors argue that today the vote might be closer and Natrecor would probably wind up with a tougher label.

Although a spokesperson for Scios argued that the company could not control how doctors prescribe the drug, Scios itself greatly contributed (or even created) the problem by affirmatively providing doctors with information on how to maximize their billing of Natrecor for off-label uses. Once again, it’s all about the money.

Many experts consider it ethically irresponsible for a pharmaceutical company to promote an off-label (and potentially harmful) use of a medication for no other apparent reason than financial gain.

On July 20, 2005, Johnson & Johnson acknowledged it had received a subpoena from the United States Attorney’s office in Boston requesting documents related to the sales and marketing of Natrecor.

As a result of this virtual tidal wave of disapproval concerning the questionable tactics associated with the marketing of Natrecor, Johnson & Johnson added a clear disclaimer to its hotline used by doctors seeking information on how to charge Medicare and insurance carriers for the drug. The disclaimer clearly seeks to discourage the heretofore rampant off-label use of Natrecor.  

The disclaimer warns of the “lack of clinical data” regarding off-label use of the drug and that Scios “does not recommend Natrecor for this use.” Johnson & Johnson now plans to follow up on the panel’s suggestions.

In the case of another drug, Rituxan, similar allegations surfaced only last week. Consider the following Associated Press article that appeared on January 11 on; “Former worker sues Genentech over drug marketing”

“A former Genentech Inc. employee has accused the biotechnology company and marketing partner Biogen Idec Inc. of illegally promoting cancer drug Rituxan as a treatment for arthritis, a use not yet approved by regulators.

Paul McDermott, who worked for Genentech in Falmouth, Maine, from March 2004 until April 2005, filed a whistleblower lawsuit in July 2005 in U.S. District Court in Maine alleging the companies’ marketing of Rituxan defrauded government health-care programs.

The suit also says Genentech fired McDermott in retaliation for bringing the matter to the attention of Genentech executives McDermott’s lawsuit is the latest legal challenge facing Genentech over Rituxan’s marketing. In October 2004, Genentech received a subpoena from the U.S. Attorney’s Office in Philadelphia seeking documents related to the promotion of Rituxan. Genentech is cooperating with that investigation, which it said was both civil and criminal in nature.

The promotion of off-label uses of pharmaceuticals has gotten other drug companies in trouble. In 2004, Warner-Lambert pleaded guilty to federal charges that it promoted epilepsy drug Neurontin for off-label uses beginning in the 1990s. Pfizer Inc., which acquired Warner-Lambert in 2000, agreed to pay $430 million to resolve criminal charges and civil liabilities in the case.

The U.S. Food and Drug Administration approved Rituxan in 1997 as a treatment for a type of non-Hodgkin’s lymphoma. U.S. sales of the drug grew to $1.8 billion last year. Studies have shown Rituxan also potential to treat rheumatoid arthritis.

Biogen and Genentech have applied for FDA approval to market Rituxan as such a treatment and a decision is expected by late February.
It’s generally legal for doctors to prescribe FDA-approved drugs in ways that haven’t yet been approved by the FDA, and so-called ‘off-label’ prescriptions are common. But drug companies are generally barred from actively promoting off-label uses of their drugs.

McDermott worked as a ‘professional educational liaison’ for Genentech, according to the lawsuit, a job that involved recruiting doctors to promote the use of Rituxan as a treatment for rheumatoid arthritis.

He alleges Genentech sent sales representatives to the offices of rheumatologists, even though Genentech had no products approved by the FDA for such treatments.

Also, McDermott alleges Genentech and Biogen used ‘sham’ consulting agreements to pay rheumatologists whom the companies identified as being ‘key opinion leaders,’ who were expected to influence other doctors to begin prescribing Rituxan for arthritis.

The lawsuit alleges that Biogen, the company that discovered Rituxan, had similar marketing practices for the drug.”

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