off-label

Off-label use is the practice of prescribing pharmaceuticals for a purpose outside the scope of a drug's approved label, most often concerning the drug's indication. In the United States, the Food and Drug Administration (FDA) requires numerous clinical trials to prove a drug's safety and efficacy in treating a given disease or condition. If satisfied that the drug is safe and effective, the drug's manufacturer and the FDA agree on specific language describing dosage, route and other information to be included on the drug's label. More detail is included in the drug's package insert.

However, once the FDA approves a drug for prescription use, they do not attempt to regulate the usage of the medicine, and so the physician makes decisions based on her or his best judgment. It is legal in the United States and in many other countries to use drugs off-label, including controlled substances such as opiates, even though it is a common misconception that it is unlawful to do so. Actiq, for example, is commonly prescribed off-label even though it is a Schedule II controlled substance. However, it is unlawful to market, advertise or otherwise promote the off-label use of drugs, including controlled substances.

Off-label use of medications is very common. Up to one-fifth of all drugs are prescribed off-label and amongst psychiatric drugs, off-label use rises to 31% (Radley, et al. 2006).^[1] New drugs are often not tested for safety and efficacy specifically in children. Therefore, it is believed that 50-75% of all medications prescribed by pediatricians in the U.S. are for off-label applications.^[2]

Some drugs are used more frequently off-label than for their original, FDA-approved indications. A 1991 study by the U.S. General Accounting Office found that one-third of all drug administrations to cancer patients were off-label, and more than half of cancer patients received at least one drug for an off-label indication^{[citation needed]}. Frequently, the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs. An example is the use of tricyclic antidepressants to treat neuropathic pain. This old class of antidepressants is now rarely used for clinical depression due to side effects, but the tricyclics are often effective for treating pain.

Law

The examples and perspective in this section deal primarily with the United States and do not represent a worldwide view of the subject. Please improve this article or discuss the issue on the talk page. (March 2009)

In the United States, FDA regulations permit physicians and other healthcare practitioners to prescribe approved medications for other than their intended indications. Marketing information for the drug will list one or more indications, that is, illnesses or medical conditions for which the drug has been shown to be both safe and effective. Pharmaceutical companies are not allowed to promote a drug for any other purpose without formal FDA approval.

However, once a drug has been approved for sale for one purpose, physicians are free to prescribe it for any other purpose that in their professional judgment is both safe and effective, and are not limited to official, FDA-approved indications. This off-label prescribing is most commonly done with older, generic medications that have found new uses but have not had the formal (and often costly) applications and studies required by the FDA to formally approve the drug for these new indications. However, there is usually extensive medical literature to support the off-label use.

In 1993, the US Food and Drug Administration (FDA) approved gabapentin, marked by Pfizer under the name "Neurontin", only for treatment of seizures. Pfizer subsidiary Warner-Lambert used activities not usually associated with sales promotion, including continuing medical education and research, to promote gabapentin, so that within 5 years the drug was being widely used for the off-label treatment of pain and psychiatric conditions. In 2004, Warner-Lambert admitted to charges that it violated FDA regulations by promoting the drug for pain, psychiatric conditions, migraine, and other unapproved uses. ^[3] The company paid $430 million to the federal government to settle the case.^[4]

Access to pharmaceutical industry documents have revealed marketing strategies used to promote drugs for off-label use. ^[5] The United States federal government is aggressively pursuing criminal and civil cases against pharmaceutical companies and their employees for promoting off-label uses of prescription drugs.^[6] Between 2003 and 2008, U.S. federal prosecutors and state attorneys general brought more than a dozen cases against drug makers for off-label marketing and won more than $6 billion in criminal and civil settlements.^[7]

The position of the British General Medical Council on off-label prescribing may be found here.

Veterinary medicine

The veterinarian has a much smaller pharmacopeia available than does the human practitioner. Therefore, drugs are more likely to be used "off-label"—typically, this involves the use of a human medication in an animal, where there is no corresponding medication licenced for that species. This problem is compounded in "exotic" species (such as reptiles and rodents) where there are very few, if any licenced medications. In addition, especially in Europe, equine veterinarians are forced to use many drugs off-label, as the horse is classified as a food-producing animal and many veterinary drugs are labeled specifically not for use in animals intended for human consumption.

Examples of off-label use (and non-use)

• Actiq (oral transmucosal fentanyl citrate), a Schedule II controlled substance, is used off-label to treat moderate to severe chronic, non-malignant pain even though it is FDA-approved solely for break-through pain in cancer patients.^[8]
• Bevacizumab has been used against wet age-related macular degeneration, as well as macular edema from diseases such as diabetic retinopathy and central retinal vein occlusion.^[9]
• Buprenorphine has been shown experimentally (1982-1995) to be effective against severe, refractory depression.^[10][11]
• Carbamazepine, or Tegretol, has been used as a mood stabilizer and is accepted treatment for bipolar disorder.^[12]
• Gabapentin, approved for treatment of seizures and postherpetic neuralgia in adults, is used off-label for a variety of conditions including bipolar disorder, essential tremor, hot flashes, migraine prophylaxis, neuropathic pain syndromes, phantom limb syndrome, and restless leg syndrome.^[13]
• Methotrexate (MTX), approved for the treatment of choriocarcinoma, is frequently used for the medical treatment of an unruptured ectopic pregnancy.^[14] There is no FDA-approved drug for this purpose and there is little incentive to sponsor an unpatented drug such as MTX for FDA-approval.
• The SSRI medication sertraline is approved as an anti-depressant. It is also commonly prescribed off-label to help men suffering from premature ejaculation.^[15]
• Stimulants such as Amphetamine (Adderall) and Methylphenidate (Ritalin) are indicated for childhood attention deficit disorder (ADD/ADHD), but are often prescribed to treat this condition in adults, as well. Atomoxetine (Strattera), a non-stimulant norepinephrine reuptake inhibitor is currently the only drug (In the United States) indicated for adult ADD.^{[dubious – discuss]} In Australia dextroamphetamine is indicated for adult ADHD treatment. While Atomoxetine is also indicated for the treatment in Australia, it only has a minor percentage of the drugs prescribed for the condition, due to its prohibitively high price, as it is currently not subsidised by the Government's Pharmaceutical Benefits Scheme, whereas the stimulant medications methylphenidate and dextroamphetamine are. Stimulants are also used off-label to treat depression, usually in conjunction with a standard antidepressant drug.

See also

• Pharmaceutical marketing
• FDA

References

External references

• Article about the Bioethics of off-label prescribing.
• Recent FDA proposal to loosen off-label marketing restrictions.