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The "Off-Label" Use of Prescription Drugs - Multi-Billion Dollar Scam that Puts the Public at Risk

Apr 1, 2006

To be sure, some people look at a glass and see it as half-full, while others see the same glass as being half-empty. This is certainly true in the case of prescription drugs where even a medication that will undoubtedly kill a percentage of the people who take it will have its supporters in the medical profession as well as among the people taking the drug.

For example, the multiple sclerosis (MS) drug, Tysabri, which everyone agrees will kill some of the patients who take it, has significant support among MS sufferers and their families since it offers them a ray of hope in an otherwise desperate situation. Many of those people journeyed to Washington DC recently to offer emotional pleas to an FDA panel to recommend the re-approval of the controversial drug.

One particular area of pharmaceutical practice in which there is a wide gulf between good and bad is in the realm of off-label use of FDA approved drugs. While pure scientists and ethical medical professionals see the search for off-label drug therapies as an important means by which to extend the use of already approved drugs to additional applications where they may prove extremely beneficial, there is a dark side to the practice that is driven by corporate greed and professional arrogance. It is in this context that money is the driving force and the public's wellbeing is at risk.

A recent article titled "The Major Role of Clinicians in the Discovery of Off-Label Drug Therapies" (Medscape 4/14/06; Phamacotherapy 2006;26(3):323-332) is most laudatory and supportive of the ethical and well-intentioned search for safe and appropriate off-label uses for drugs already approved by the FDA.

Buried on the sixth page of the article, however, is the unequivocal declaration that: "We should make it clear that we are not advocating unfettered experimentation on the part of clinicians. Misapplication of drug therapy has as great a potential for harm as it does to help. There is an obvious and appropriate concern with the widespread dissemination of incorrect information in drug therapy."

Thus, while there is no disputing that responsibly conducted clinical research using FDA approved drugs has resulted in some very significant and successful off-label drug therapies, there have been, and continue to be, many highly questionable ventures into off-label drug experimentation and promotion that smack of little else but greed and a lack of concern for consumer safety.

Off-label prescribing occurs when a drug is used in a way for which it was not intended or as a therapy, cure, or treatment for one or more conditions for which it has not been approved. While this type of use can lead to a more expansive application of a successful drug, it can also cause a higher incidence of known side effects as well as unforeseen adverse reactions that can be quite serious or even deadly. 

The off-label prescribing of drugs beyond the scope of their FDA approval 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. There is also the problem of off-label prescribing to age groups (infants, adolescents, and seniors) for which no, or insufficient, clinical data exists. At its worst, the practice can be downright deadly.

The incredibly strange thing about off-label use, however, is that doctors may prescribe drugs to treat conditions for which the Food and Drug Administration 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.    

The FDA is also at odds with pharmaceutical companies and physicians who prescribe medications to patients with conditions that those drugs are not approved to treat.  When the FDA approves a drug, it expects that pharmaceutical companies will adhere to the conditions of that approval and will not tell doctors that it can be prescribed for other unapproved conditions. 

Consequently, the FDA also expects that doctors will not take it upon themselves to decide that a drug can be prescribed to a patient who does not have any of the symptoms or conditions that the drug is approved to treat.  It is a problem that has many layers and, as a result, is hard to control. 

While this problem continues to pervade the world of pharmaceuticals, recently there has been more attention given to off-label pitches and prescribing.  The U.S. Department of Justice (DOJ) announced in March of 2006 that from now on there will be a change in the way that drug companies are permitted to market prescription medications and other therapeutic products. 

The following are some examples of the types of problems raised by indiscriminate or inadequately tested off-label uses:

  • Medical professionals are concerned about the increasing prevalence of off-label usage as it pertains to children and adolescents. Medication is being prescribed in massive quantities to children despite lack of FDA approval, and even when such uses have been discouraged. Just as it is highly dangerous for an adult to take medication that is not approved for a condition they may have, it is extremely dangerous for a child to take a medication that is only approved for adults or is only approved to treat one type of a condition. Dosage issues have a heightened impact on off-label prescribing to children because of their weight and developing bodily systems.
  • Medco Health Solutions, a managed-care company, conducted a study of children and young adults and found that there was an 85 % increase in the use of sleeping pills between 2002 and 2004.  According to this study, about 15% of people under age 20 who received sleeping pills were also being given drugs to treat attention deficit (ADD) and hyperactivity disorder (ADHD), drugs which have been known to cause insomnia. These results were troubling as very few drugs are approved by the FDA for use in children. In fact, no sleep medication has been approved for children under 18.  Expensive marketing campaigns for existing sleep aids like Ambien and the introduction of Lunesta have probably accounted for part of the increase in sleeping pill use and off-label prescribing of these medications.  Dr. Gregg Jacobs, an assistant professor of psychiatry at Harvard Medical School is concerned that drug companies inflate the beneficial effects of their products while downplaying their side effects.  He believes that prescriptions are often given to people who might benefit more from cognitive behavioral therapy, a treatment that doesn't have the side effects of medication.
  • In 2004, the FDA announced that some antidepressants were linked to an increased risk of suicide in adolescent patients.  In this same year, the FDA issued a black-box warning for all anti-depressants to inform patients about the increased risk of suicide for children and adolescents.  A Stanford University School of Medicine study now indicates, however, that certain antidepressants were potentially misused prior to the FDA's decision to issue the 2004 "black-box" warnings.  While medical professionals recommend that adolescents receive treatment for depression through a combination of psychotherapy and medication, researchers found that between 1995 and 2002, antidepressants began replacing mental health counseling as the sole treatment for depression in adolescents.  Prozac is the only antidepressant that has been approved for use in children under 18 yet the study found that doctors were prescribing other anti-depressants to adolescents.  This restriction, however, has not inhibited doctors from prescribing other medications for patients who have not responded to Prozac. This "off-label" use of these other antidepressants is not prohibited even though those drugs are not intended to treat children and adolescents.  While there are currently ongoing clinical trials being conducted to determine the safety of other anti-depressants for children and adolescents, the Stanford researchers argue that physicians should still try Prozac before prescribing any other antidepressants to young patients.
  • Roche Holding AG and Genentech were forced to "temporarily suspend recruitment of patients into a clinical trial assessing the use of colon cancer drug Avastin after surgery."  The trial was designed to see how patients respond when given either conventional chemotherapy drugs or an Avastin-based combination. The Phase III trial that goes by the name AVANT, is a final-stage test meaning the drug was nearing the point when a New Drug Application would have been expected.  According to Reuters, William Burns, Roche's head of pharmaceuticals, said the decision would not cause a financial impact.  Some analysts believe, however, that "while numbers are unlikely to change, it raises the risk that Avastin will not be approved in further indications or that off-label use will be more limited."
  • After a promising study in the July 2005 edition of the American Journal of Psychiatry reported that children with autism characterized by tantrums, aggression, and/or self-injury respond favorably to the antipsychotic medication, risperidone (Risperdal), off-label usage of the drug began to appear. Risperdal is manufactured by Jannsen Pharmaceuticals, a division of Johnson & Johnson and is approved for the treatment of schizophrenia, not autism.  The FDA has been especially strict about off-label usage of antipsychotic medications because of the severe side-effects that can surface as a result.  In the case of risperidone (Risperdal), while it might very well be that favorable results were obtained, it would be quite inappropriate to use a limited 6-month study involving only 101 subjects to conclude the drug is "safe" for children.  Risperdal has a long list of side effects associated with the drug such as abdominal pain, abnormal walk, agitation, aggression, anxiety, chest pain, constipation, coughing, decreased activity, diabetes, diarrhea, difficulty with orgasm, diminished sexual desire, dizziness, dry skin, erection and ejaculation problems, excessive menstrual bleeding, fever, headache, inability to sleep, increased dreaming, increased duration of sleep, indigestion, involuntary movements, joint pain, lack of coordination, nasal inflammation, nausea, overactivity, rapid heartbeat, rash, reduced salivation, respiratory infection, sleepiness, sore throat, tremor, underactive reflexes, urination problems, vomiting, and weight gain.  Risperdal may mask signs and symptoms of drug overdose and of conditions such as intestinal obstruction, brain tumor, and Reye's syndrome (a dangerous and often fatal neurological condition that may follow viral infections, usually occurring in children). Risperdal can also cause difficulty when swallowing, which in turn can cause a type of pneumonia.  Risperdal may cause Neuroleptic Malignant Syndrome (NMS), a condition marked by muscle stiffness or rigidity, fast heartbeat or irregular pulse, increased sweating, high fever, and high or low blood pressure. Unchecked, this condition can prove fatal.  The list goes on and on, another reason why the drug should not be taken lightly or prescribed off-label to individuals who do not need it or do not stand to benefit from the drug.
  • One of the most prominent examples of off-label usage occurred with the drug Natrecor.  Natrecor, or nesiritide, manufactured by Scios, 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.  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 quickly became a popular drug in outpatient clinics nationwide where it is used for far longer periods than it was originally approved for.  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 other experts, including fellow cardiologist Keith Aaronson, have attempted to show that Natrecor should not be administered in outpatient settings because of its connection to acute kidney problems and that the drug's label should indicate the serious risks associated with off-label usage.  It was revealed that 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.  Although Scios argued that the Sackner-Bernstein paper included studies done at higher doses than are advised on the drug's label, those higher 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 it is being used in outpatient clinics.  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.  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.  In June, the panel of cardiologists convened by Johnson & Johnson and headed by the highly respected heart researcher, Harvard's Dr. Eugene Braunwald, recommended strict limitations on Natrecor, including not using it for scheduled "tune-ups" or even administering it outside the hospital.  The panel specifically recommended that Natrecor only be used in cases of an acute type of heart failure when the patient actually shows up at the hospital; that it should not be used in place of diuretics, the first-line treatment for heart failure; and never used for outpatients, scheduled appointments, or to improve kidney function.  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 troubling thing about the Natrecor saga is that it was the manufacturer that was behind the indirect (and improper) promotion and encouragement of the off-label use of its very expensive drug.
  • Several studies revealed that there are significant risks associated with the off-label use of atypical anti-psychotic drugs such as Abilify, Zyprexa, Seroquel, Risperdal, Clozaril, Geodon, and Symvyax in elderly patients.  While these drugs are approved to treat mental illnesses such as schizophrenia and depressive episodes associated with bipolar disorder, they are not approved for treating dementia in elderly patients. Nonetheless, doctors have been prescribing them extensively for this off-label use. After this off-label prescribing came to light, Health Canada and the FDA requested that all manufactures of atypical antipsychotic drugs include a warning of these risks.  The warning should also state that these drugs are not approved for treating dementia in elderly patients.
  • According to the FDA, NovoSeven, a blood clotting drug for hemophiliacs manufactured by Danish pharmaceutical company Novo Nordisk (Novo) and released on the market in 1999, 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.  The drug was approved by the FDA for stopping bleeding in hemophiliacs. 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.  NovoSeven 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.  The majority of the reported complications associated with the drug, however, involved off-label use, instances where the drug was used to treat a condition not specifically approved by the FDA.  In October 2005, Novo Nordisk changed the warning in the package insert to include information on side-effects in patients who do not have hemophilia. After analyzing data from 431 reports to the FDA of adverse events, ranging from nausea to death, during the first five years of the drug's use, it was determined that those problems were directly related to off-label uses.
  • On December 21, 2005, Eli Lilly and Co. agreed to pay $36 million to settle criminal charges and civil allegations regarding their marketing of Evista, a drug approved for treating post-menopausal women with osteoporosis.  The company allegedly marketed the drug inaccurately.
  • On October 17, 2005, Serono S.A., a Swiss pharmaceutical company, plead guilty to two felonies and paid $704 million to settle criminal and civil charges relating to the deceptive marketing of Serostim, an AIDS drug.  The two felony charges facing Serono were conspiracy to distribute an unapproved and adulterated medical device and conspiracy to pay illegal remuneration to heath care providers to induce referrals to pharmacies for Serostim-payment which was made by Medicaid.  This was the largest settlement ever made for off-label promotion or advertising of an FDA approved product.

It is surprisingly easy for a powerful and potentially dangerous drug to go from its approved use to off-label prescribing to patients for whom the drug was never tested or intended. Consider the following hypothetical situation.

Earlier this month the FDA approved injectable VIVITROL as a treatment for alcohol dependence. The manufacturer's own literature reveals a number of factors that make the drug extremely dangerous and in need of the careful monitoring planned for those taking the medication.

VIVITROL is a powerful opioid antagonist that will act to blockade the effects of opiates and opioid-containing medications. This would include all opioid analgesics, and opioid -containing medications such as cough, cold, and antidiarrheal drugs. As a result, a number of serious problems can occur.  

One is that patients taking VIVITROL will attempt (on their own) to overcome the blockade by administering inappropriately high doses of exogenous opioids. This is dangerous and could lead to a potentially fatal overdose, respiratory arrest, or circulatory collapse.

Another is that the drug will be used for its opioid-blockading effect as a treatment for opiate dependence. VIVITROL is not approved for that purpose and can cause fatal consequences if used inappropriately.

The clinical trial found VIVITROL users twice as likely as those taking a placebo to suffer depression or mood variations.

There was also an increased rate of suicidality among the VIVITROL subjects, with two completed suicides among the group. As a result: "Families and caregivers of patients being treated with VIVITROL should be alerted to the need to monitor patients for the emergence of symptoms of depression and suicidality and to report such symptoms to the patient's health care provider."

Clinical drug interaction studies with VIVITROL have not been performed. No clinical testing was done with respect to children or adolescents and there is insufficient data with respect to geriatric patients.

While all of this information has been released by the manufacturer and it is clear that there is no intent on the part of that manufacturer to promote or encourage any off-label use of this powerful and potentially dangerous drug, there is simply no guarantee that doctors will not push the boundaries of the FDA approval.

Who is to say that, faced with an alcoholic teenager or senior, a doctor will not opt to treat the condition with VIVATROL? Is there that much of a difference between a 17-year-old and an 18-year-old or between a 55-year-old and a 60-year-old? Assuming all of them are afflicted with chronic alcoholism, why not try to use all available therapies to help cure them? Is stretching the age-appropriateness of the drug by a few years or possibly even a few months, risky?

As the drug becomes more accepted and available, there will always be the possibility that doctors treating alcohol dependence will seek to extend VIVATROL therapy to younger or older alcoholics. The intent may be to help additional patients beat a serious disease by carefully expanding the scope of the FDA approval - good. It could, however, be nothing more than a means by which to make more money in medical fees -bad.

Unfortunately, the doctor's intent does not matter; the dangers from the unapproved off-label use will be exactly the same. The current regulatory rules, however, would not prevent a doctor from either well-intended or profit-driven experimentation. And therein lays the danger.    

In an age when consumer awareness of which medications are available as therapies for particular conditions is on the rise, a little knowledge can be dangerous. Patients very often go to a doctor and insist that they want a specific drug when really there may be better and safer treatments available for their particular condition or ailment. 

In many cases, doctors will not try to talk a patient out of an off-label prescription as they stand to gain a financial reward for successfully filling a monthly or yearly quota of a particular prescription.  Some pharmaceutical companies even improperly advise doctors about which drugs can be prescribed for off-label uses. Sometimes, the doctor will write the prescription for no other reason than to keep a patient from changing physicians.

Every patient should find out as much as they possibly can about a drug so that they too can make an informed decision about whether a particular drug is right for them. Impulsive or uninformed decisions are not a good idea. Thus, patients should not be afraid or ashamed to question their doctors when an off-label prescription is written. A patient should not simply rely on doctors and pharmaceutical companies to be honest about the approved uses of prescription drugs. 

In the end, however, it is the doctor who must make the determination as to whether an off-label prescription is appropriate or advisable. In that way, doctors are given enormous leeway that even a drug's manufacturer does not have. It is that virtually unfettered discretion that all doctors should exercise with only the greatest caution and professionalism.

As part of the increased monitoring of off-label prescribing, the DOJ is doing its part to make sure that drugmakers are aware that improper promotion and marketing practices will not be tolerated and will be prosecuted. The DOJ maintains that it will aggressively prosecute illegal off-label promotion of drugs and scrutinize questionable marketing strategies carried out by pharmaceutical companies and reinforced by medical professionals.  The DOJ argues that any post-approval advertising of an FDA-approved drug should reflect the existing label negotiations between the pharmaceutical company and the FDA as opposed to bending or blatantly disregarding them. 

While responsible medical testing may prompt qualified clinicians to explore off-label therapies with the goal of helping mankind, indiscriminate and inappropriate experimentation must be strongly discouraged. Profit-driven (and illegal) promotion of off-label uses must also be carefully monitored and prosecuted if necessary.

As always, if you believe you or a loved one has been injured by any prescription or over-the-counter (OTC) medication, please do not hesitate to contact Parker & Waichman at for a free consultation. Our firm is currently engaged in, or investigating the possibility of, litigation involving several prescription and OTC drugs. We invite you to review the extensive materials provided on our award winning Web site with respect to any particular drug or medical device profiled there.

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