Widespread off-label drug prescription raises safety concerns

[Bernard]

... Dudley had no idea that the drug she was taking for nerve pain, gabapentin, had been approved in Canada only for epilepsy, and not for pain. Nor could she know that six years later - this past month - the U.S. Food and Drug Administration would announce it will require the makers of gabapentin and other anti-epileptics to warn that their use increases the risk of suicidal thoughts and behaviour.

The drugs are among the most heavily prescribed for "off-label" uses, meaning for conditions for which they have never been approved.

Thousands of times a day in Canada, patients are prescribed drugs off-label. The practice is burgeoning, it is legal and most of it occurs with little to no scientific backing.

Of the 423 million prescriptions filled by drugstores across Canada last year, an estimated one quarter - 89 million prescriptions - were written off-label.

Prozac is being used for obesity. Metformin, a diabetes drug, and topiramate, an anticonvulsant, are also being prescribed for weight loss.

Some of the most widely prescribed drugs for insomnia, including antidepressants and antipsychotics, have never been approved for sleep problems.

People with lower back pain are being treated with drugs approved only for major depressive disorder. Heart drugs are being used to treat cluster headaches.

Critics say that off-label drug prescribing can amount to an uncontrolled experiment, and that not only do most patients not know when a drug is being prescribed for a condition for which it has not been approved, neither do most doctors.

In Canada, the only approved use for gabapentin, the drug Susan Dudley was prescribed, is for patients with epilepsy whose seizures aren't controlled by conventional therapy. But nearly 1.7 million prescriptions were filled for the drug last year alone, according to IMS Health Canada, making it the second most prescribed drug in its class.

Doctors have prescribed gabapentin (marketed under the brand name Neurontin) for bipolar mood disorders, panic disorders, insomnia, migraines, social phobia, hot flashes in post-menopausal women, attention deficit disorder and "for all kinds of pain that it has never, ever been shown to be effective for," says Dr. David Wilkes, a professor of medicine at the University of California Davis.

In January 2008, the American Food and Drug Administration issued an alert to doctors, warning that gabapentin, along with 10 other commonly prescribed antiepileptic drugs, have approximately double the risk of suicidal behaviour or thinking compared with patients given placebos.

A year later, Health Canada says its experts are still reviewing the data.

Critics want restrictions on off-label promotion of drugs toughened and some are calling on doctors to get informed consent from patients every time a drug is prescribed off-label, something physicians are under no obligation to do now.

"The worrisome thing is, most doctors don't know what's on, and what's off-label use," Wilkes says.

Doctors can look up a drug's indication in drug reference guides found in every physician's office. But it takes time, and doctors are pressured more than ever to see more and more patients.
...
Off-label prescribing is often unavoidable. It has been estimated that fewer than 30 per cent of drugs used in children have ever been tested in children.

Some of the highest rates of off-label use are for anticonvulsants, antipsychotics, cardiac medications and antibiotics.

Last November, researchers published a list of 14 widely prescribed drugs that urgently need study for the safety of their off-label uses. Heading that list was Seroquel, an antipsychotic approved for schizophrenia that is being used for bipolar disorder, depression and anxiety. The drug costs $207 US per prescription.

"We are prescribing these drugs (off label) that are often very, very expensive - it's rarely a generic drug, it's always some sort of trade name drug that has been marketed," Wilkes says.
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"Often it's really a shot in the dark, and the patient(s) may be the guinea pigs."

Wilkes says there are key questions patients should ask doctors every time they're prescribed a drug.

"What's the expectation, doctor, that this drug is going to provide the benefit you're saying, that it's going to relieve my back pain or improve my diabetes? Is this drug approved for this? What are the side effects I should be watching for?

"I think we do a horrible job of explaining to patients. We assume the package insert has it. There are 53 billion things mentioned for every drug. What you really need to know is, what are the two or three more common side effects that patients complain of that you should know about. If suicide is one of them, or depression is one of them, them automatically a light bulb goes off in your head because you remember, 'The doctor told me this.'"
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Widespread off-label drug prescription raises safety concerns

This ties in with the following threads:

Suicide Risk From 11 Epilepsy Drugs

Doctors not immune to sales pitches

[RobinN]

Being in a rush, conventional doctors rarely take the time to see what side effects that second and third medication will create. Of course without thinking it is a problem, many people then take an over the counter med for minor symptoms.

A crash waiting to happen.

[Bernard]

Pfizer Inc. was slapped this week with a record $2.3 billion in fines for illegally marketing some drugs, but critics say even that eye-popping total is unlikely to end the sometimes-dangerous practice of promoting drugs for unapproved uses.

The penalty pales compared to the billion dollars or more in annual revenue that blockbuster drugs generate, and new government guidelines stir worry that the marketing of medicines for unapproved uses will become easier.

"Drug companies will continue to market off-label unless the financial downside makes it unprofitable," said Dr. Adriane Fugh-Berman, a Georgetown University associate medical professor.

Off-label marketing is a tricky issue. Doctors say prescriptions for uses not noted on a drug's package label — the fine-print insert that comes with the prescription — play a crucial role in treating patients, especially those with deadly illnesses and few treatment options.

However, the Food and Drug Administration prohibits companies from promoting their drugs for uses it has not approved.

Huge fines for those caught violating these rules usually just nibble at drug company sales totals.

Pfizer's fine is the largest health care fraud settlement in U.S. Justice Department history. But that $2.3 billion total stands small compared to the $44.2 billion in pharmaceutical sales the world's largest drugmaker rang up last year.

"$2.3 billion looks like a lot of money," Fugh-Berman said. "But these are highly profitable drugs. It will not take them very long to make up that deficit."

The Georgetown professor has served as a paid witness in court cases over drug marketing and founded the watchdog Web site pharmedout.org.
...
Prosecutors said Pfizer promoted four prescription drugs, including the discontinued pain killer Bextra and the blockbuster Lyrica, for epilepsy and nerve pain such as fibromyalgia, as treatments for medical conditions not approved by federal regulators. Lyrica alone registered $2.6 billion in sales last year.

Authorities also accused the drugmaker of plying doctors with free golf, massages and resort junkets.

In 2004, Pfizer also paid $430 million to settle allegations it marketed the epilepsy drug Neurontin for pain and psychiatric illnesses. A plaintiff's attorney in a civil case over the drug has estimated that Pfizer made about $10 billion in Neurontin sales for unapproved uses from 1999 to 2004.

But Pfizer by no means corners the market on off-label marketing fines.

Earlier this year, Indianapolis-based Eli Lilly & Co. agreed to pay $1.42 billion to settle a case over the marketing of its top seller Zyprexa, an anti-psychotic drug.

Court documents say Lilly made "hundreds of millions of dollars" through off-label Zyprexa promotions, but it's hard to pin down the exact impact of improper marketing.

Zyprexa's annual U.S. sales nearly doubled between 1999 and 2003, to $2.64 billion. But company officials note that regulators approved some additional uses for Zyprexa in that span, and that gave doctors more information about its safety and effectiveness.

The drug industry — and even some doctors — downplay the frequency of illegal promotions and their effect on off-label prescriptions, which give doctors treatment flexibility.

For example, the standard treatment for years for severe psoriatic arthritis was methotrexate, but the drug actually was approved to treat rheumatoid arthritis, said Dr. Eric Ruderman, a rheumatologist at the Northwestern University Feinberg School of Medicine.

"If you had to stick to labeling, you couldn't treat people," said Ruderman, who has done some consulting work for Abbott Laboratories and received research grants from several drugmakers.

Ruderman noted that common uses often are technically off-label because it's expensive — and often unprofitable — for companies to pursue FDA approval for every possible use of their drug.

Still, Ruderman said off-label marketing is never appropriate and noted that decisions about off-label use should be left to doctors weighing "published evidence" supporting it.

Under new rules established this year by the FDA, salespeople may distribute to doctors copies of scientific journal articles that discuss off-label uses. Industry critics see that as a potentially dangerous loophole.

The rules come with qualifiers. For instance, the articles should come from peer-reviewed journals, and the reports cannot be edited by the drugmaker.

Despite the precautions, Fugh-Berman calls the guidance "a horrible idea."

"When you go to the Volvo dealer, do you really expect an accurate comparison of their cars with other manufacturer's cars?" she said.

The drug industry says that it does a much better job policing against off-label marketing than it did 10 or 15 years ago and that most companies have mandatory training.

Fugh-Berman said fines alone will not end off-label marketing, but they can curb the practice when coupled with corporate integrity agreements like one the Justice Department imposed on Pfizer. These can force companies to disclose doctor payments or other information they'd rather keep under wraps.

"Our sense is that companies fear corporate integrity agreements more than fines," Fugh-Berman said. "We don't want fines to become just another line item in their budget."

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