Off-Label Uses of Prescription Drugs?An Overview

Beta-blockers for migraine prophylaxis; anticonvulsants for pain, headaches, and bipolar disorders; oral contraceptives for premenstrual disorders?all of these constitute off-label uses of drugs originally approved by the FDA for other conditions. Off-label use of prescription drugs (also known as unlabeled, unapproved, or out-of-label use) refers to the practice of prescribing drugs or devices for uses not identified in the labeling of a drug.

This topic, while eliciting much interest today, remains a very controversial area. The controversies include (1) the fact that these uses are not subject to the rigorous approval process; (2) that such uses may be perceived as experimental in nature; and (3) that such uses may impede incentives to evaluate the drug for its off-label use. With the emphasis on curbing health care costs, coverage and reimbursement for off-label use of drugs also have become issues.

In November 2003, Knight-Ridder Newspapers (November 2, 2003) published an investigative series on the perils of off-label prescribing. Yet, this common practice embraced by health care providers is not only legal but common ground in medicine today. Pharmacists encounter situations on a daily basis where they may question why a drug is prescribed. Thus, the pharmacist may be faced with a judgment call as to the appropriateness of a drug for a particular use.

Role of the FDA

The FDA is cognizant of the fact that these "unapproved" uses are acceptable and may be appropriate in the course of medical treatment. In fact, many drugs presently on the market were originally discovered in a serendipitous manner that led to sound therapeutic outcomes. Interestingly, sildenafil, approved by the FDA for the treatment of erectile dysfunction, was originally approved for chest pains (due to its mechanism of action). Aspirin was used for years off label to reduce the incidence of heart attacks until its approval for this indication in 1998.

When a physician prescribes a drug not specifically indicated in its labeling for a particular condition, his or her action is based on sound documentation of safety in the literature, as well as expert medical judgment. Off-label drug use may involve certain risks, but generally speaking it is based on scien- tific studies involving extensive research that outpaces the revision and approval process at the FDA.

Off-label uses are common in the areas of pain management, oncology, and especially pediatrics. Little information is available or submitted to the FDA as to dosage, adverse effects, and effectiveness of drugs for children, because of the lack of scientific studies in this population. (The issue of including children in certain studies is presently the subject of federal legislation.)

Approval Process for Off-Label Use

The FDA has the authority to handle all drug approvals once the drugs are proven to be safe and effective. Before 1998, pharmaceutical companies were required to submit certain applications to the FDA before giving health care practitioners written information as to unapproved uses of their products. The FDA has subsequently allowed for more flexibility by waiving the waiting period and permitting the dissemination of information to health care practitioners, provided that the following criteria are met concerning the information:

• It concerns a drug or device that has been approved, licensed, or cleared for marketing by the FDA
• It is in the form of an unabridged reprint or copy of a peer-reviewed scientific or medical journal article, or an unabridged reference publication, about a clinical investigation that is considered scientifically sound by qualified experts
• It does not pose a significant risk to the public health
• It is not false or misleading
• It is not derived without permission from clinical research conducted by another manufacturer
• It includes certain disclosures (eg, that the new use has not been approved by the FDA), the official labeling, and a bibliography of articles relating to the new use

If a manufacturer has not submitted a supplemental application for new use to the FDA, the manufacturer could begin disseminating information if it has done any of the following:

• Certified that it has completed the necessary studies and that a supplemental application will be submitted within 6 months
• Provided an adequate protocol and reasonable schedule for the necessary studies and certified that the application will be submitted within 36 months of the initial dissemination
• Received an exemption from the requirement to submit an application on the grounds that the necessary studies would be unethical or economically prohibitive

Should the FDA determine that the additional information is not objective and balanced, it can require the manufacturer to provide additional objective and scientifically sound information or an objective statement prepared by the FDA as to the effectiveness or safety of the new proposed use. Manufacturers also have an ongoing responsibility of informing the FDA of additional information about the disseminated new drug uses, and the FDA has the right to order that the dissemination of the additional information cease in the event that off-label use is not effective or may pose a significant risk to public health.

General Guidelines

So, what is a pharmacist to do when a drug is prescribed for off-label use? Years ago, pharmacists simply did not question why a drug was prescribed, or whether it was for use unapproved by the FDA. Pharmacists now realize that they must ask why a medication was prescribed and must question its appropriateness before it is actually dispensed. Naturally, pharmacists also must realize that a prescription for an off-label use does not produce an automatic refusal to dispense. The American Academy of Pediatrics and other professional organizations have established guidelines for prescribing FDA-approved drugs for other uses than those listed in the FDA labeling. Considerations regarding such use generally encompass the following conditions:

• The drug is approved by the FDA
• The drug is recognized by the American Hospital Formulary Service Drug Information, the US Pharmacopoeia Dispensing Information, vol I, or 2 articles from major peer-reviewed journals that have been validated supporting the proposed use for the specific medical condition as safe and effective
• It is medically necessary to treat the specific medical condition, such as a life-threatening or chronic condition
• The off-label use is medically necessary and "noninvestigational"

Role of Health Care Practitioners

The practice of prescribing off label is a decision to be made by the treating health care practitioner based on data available on the drug and the clinical status of a patient. The decision to do so certainly carries risks and may expose a practitioner to legal action involving negligent use of a drug that may be ineffective or unsafe. In fact, the labeling of the drug may not be comprehensive enough to cover special monitoring or adverse effects.

Yet, in many cases off-label use has become the standard of care. A failure to follow this standard could be considered negligent care, because the practice is necessary for life-threatening illnesses where the benefits may outweigh the risks. Off-label use of drugs will continue to be an integral part of medicine, and pharmacists can continue to dispense drugs for purposes not officially approved by the FDA but based on sound scientific evidence and published literature.