Clinical judgment, standard of care is key

Minimize risk in off-label prescribing

Off-label use of a drug is common in health care, but pharmacists agree that they must minimize the risk by relying on their clinical judgment and the standard of care.

"Off-label use" means ordering or prescribing a drug to treat a condition for which it has not received review and approval by the U.S. Food and Drug Administration (FDA). It also applies to drugs prescribed, or ordered, for a different population group, such as children instead of adults, or at a different dose or duration than what was reviewed and approved by the FDA, and subsequently, a different (than what was deemed by the FDA to have a favorable risk-benefit ratio) population or subgroup, according to FDA regulations.

Since the FDA considers the off-label prescribing of drugs a practice of medicine, pharmacists must protect patients and themselves in the review of such use. To do this, pharmacists usually rely on their clinical judgment and the standard of care, says Brian Hemstreet, PharmD, BCPS, assistant professor at the Department of Clinical Pharmacy at the University of Colorado Health Sciences Center in Denver.

Sometimes the assumption is made that for a certain indication approved by the FDA for one drug, every drug in that class will be effective for that indication. That is not always the case, though, Hemstreet says. "Sometimes, there are significant enough differences within the class of drugs that you may not get exactly the same effect as you would with the one with the indication."

To make that determination, therefore, he recommends first looking at the literature. If the literature about the off-label use is sparse, Hemstreet then compares the pharmacology of the drug. "If it looks fairly similar, you can be pretty sure that it is going to have the same effect."

The pharmacokinetic properties, however, may be different. The dosage may need to vary from the approved indication, too. The patient also may have enhanced effects for the off-label use.

"Once you go off-label, you have to use your clinical judgment as to whether the patient population you are treating for that indication is going to put the patient at any more risk for an adverse event based on the experience in the labeled indications," Hemstreet says.

The risk decreases as most physicians use the drug for the off-label indication, even if the drug manufacturer has never gotten the drug approved for that use.

"Sometimes things start getting to be standard of care, and there is not really an incentive for the pharmaceutical company to do the research and the controlled clinical trials that would be required to get something approved," says Marissa Schlaifer, RPh, director of pharmacy affairs for the Academy of Managed Care Pharmacy (AMCP) in Alexandria, VA.

The off-label use of medications is more promi-nent in certain patient populations, such as pediatrics. "Many drugs are used in pediatrics without an FDA indication. Insurance carriers and the medical community recognize that," says Tim Stacy, RPh, MBA, system director of pharmacy at Children’s Healthcare of Atlanta.

In pediatrics, you rely on history, and the standards of care in the pediatric community, Stacy says. Lexi-Comp’s Pediatric Dosage Handbook is a primary resource. "On order entry, the pharmacist has to check all doses. Our new computer system will have those built in so we will have the dosage system linked eventually to our standards."

MCOs follow structured program

Managed care organizations (MCOs) differ from some health organizations in that they follow a structured program when reviewing a drug for off-label use. As AMCP says in its position statement about off-label drug use, "each pharmaceutical agent on the market should be used only in accordance with generally accepted medical practices."

The review process depends upon the situation, says Schlaifer. An older, inexpensive drug that has a common off-label use, for instance, may be covered without a review. An example of this would be the use of the propranolol, a hypertensive drug often used off-label to treat migraines.

A newer drug prescribed for a use that hasn’t gone through a full review process, however, would be flagged with an edit in the system before the prescription could be filled. Generally, if this is a one-time occurrence, prior authorization pharmacists will handle the review, Schlaifer says. "They are basically looking for whether the off-label use is considered standard of care. If they can look in the literature and find out this is a common, well-accepted use of the medication, they are going to approve it."

If literature is not available to support the off-label use or more commonly, if the literature says the off-label use has shown no benefit to the patient, the MCO might not cover the drug for that use.

A lack of literature supporting an off-label use, however, does not guarantee that the drug won’t be covered. Physicians, for example, may begin telling an MCO that a drug is being used more often in a certain off-label use — with benefit to the patient. For this review, the MCO can present the information to the pharmacy and therapeutics (P&T) committee. If the drug is in a specialized area, such as in cancer or AIDS treatment, a panel of physicians in that specialty may first review the information and make a recommendation to the P&T committee. "If there is any disagreement or any gray area where maybe current practice has gotten ahead of the literature, then the review would generally go to a committee," Schlaifer says.

AMCP says that it supports MCOs in its consideration of these criteria before deciding whether to provide coverage of FDA-approved drugs for certain off-label uses:

• Whether the drug has been proven effective and accepted for the treatment of the specific medical condition for which it has been prescribed according to the current edition of the United States Pharmacopeia Dispensing Information, Volume I, or the American Hospital Formulary Service Drug Information compendium.

• Whether the drug is recommended for the particular condition involved, and has been proven to be safe and effective for that condition according to formal clinical studies, the results of which have been published in peer-reviewed professional medical journals.

A medication’s cost may logically seem to be a deciding factor in whether a drug is reviewed, but Schlaifer says that is not always the case. Oncology physicians, for example, often request — and receive approval for — the off-label use of high-dollar drugs to treat patients with different cancers, she says.

"You use objective criteria and cost is not the deciding factor," Schlaifer says. "It’s whether the medication is appropriate and generally accepted and there is literature to support it. Once you have stopped to review it, no matter the cost, you want to know if the literature supports the use."