Article Date: 2/1/2012

Targeting Off-Label Drugs and Devices
off-label use

Targeting Off-Label Drugs and Devices

How exactly do off-label medications and contact lenses impact your practice?

Kimberly K. Reed, O.D., F.A.A.O., Davie, Fla.

We often hear about the “off-label” use of drugs or devices, with one of the bestknown examples being the widespread off-label use of bevacizumab (Avastin, Genentech) for wet age-related macular degeneration (AMD) as a substitute for the U.S. Food and Drug Administration (FDA)-approved, yet more expensive drug, ranibizumab (Lucentis, Genentech). (See “Who Decides Whether a Drug is Approved? below.)

But what exactly does “off label” mean? What is the relationship between FDA approval and off-label use of medications? And most importantly, exactly what is your responsibility with regard to the legal issues when choosing medications — and even contact lenses — for your patients?

Here, we will explore these issues.

What is off-label prescribing?

Off-label prescribing is the prescription of a medication in a manner different from that approved by the FDA. (See “What Is The Drug Approval Process?” below.) This involves the use of drugs for unapproved clinical indications — for example, using an antibiotic for the treatment of bacterial corneal ulcers when the drug is specifically FDA-approved only for bacterial conjunctivitis. Off-label prescribing is also the use of drugs in unapproved populations, like treating a six-month-old baby with an antihistamine FDA-approved for use in patients age one and older. And, using an ophthalmic solution to treat an ear infection is considered off-label use.

What is the product label, and where can you find it?

Every drug marketed in the United States has a drug label, which must be included in the drug's packaging. The label for most drugs used in eyecare practices can usually be found on the drug company's website; nearly all newly released drugs have their own websites that include all kinds of useful information, such as adverse events, both for patients and physicians. Publications, such as the Physicians' Desk Reference (PDR) (PDR Network; 2012 Edition), also contain labeling information. Finally, drug advertising materials must also include certain labeling information — often a two-page “disclaimer” follows the actual drug advertisement in magazines and journals.

The FDA sets strict requirements for the information that must be included in the drug label. For example, with anti-microbial agents, usually a list of “susceptible organisms” appears on the drug's label. If a specific microorganism appears on this list, it means that in studies and trials, the drug was shown effective against that particular microorganism. Other pertinent information includes the drug's mechanism of action, clearance, dosing, contraindications, warnings, potential side effects, and — importantly — the “indication.”

The indication is very important for clinical purposes, as it states the purpose for which the drug has been approved. The indication can be very specific, such as “indicated for the treatment of bacterial conjunctivitis caused by susceptible organisms.” Use outside of this indication becomes “off label.”

Who Decides Whether a Drug is Approved?
The Food and Drug Administration's (FDA) Center for Drug Evaluation and Research (CDER) is responsible for ensuring that drugs sold in the United States are safe and effective. They have oversight of both over-the-counter (OTC) and prescription medications. Although the CDER may conduct some minor evaluations of drug safety and effectiveness, they are mostly charged with reviewing research that is presented to them.

Contact lenses have labels

The FDA considers contact lenses medical devices, and as such, they also have a medical label. Contact lens labels include information about FDA-approved wearing schedules. This is where we learn about replacement cycles (two weeks, one month, etc.), as well as whether the lenses can be worn overnight — and if so, for how many consecutive nights. If you prescribe a lens that is approved for six consecutive nights of overnight wear as an extended wear lens, you need to be clear in your instructions to the patient (and equally important, in your chart) about the limitations established by FDA approval. If an unfortunate outcome occurs in a contact lens-wearing patient, you want to ensure that your record clearly and unambiguously prescribes adherence to FDA-approval guidelines.

While off-label use of medications is very common, recommending an off-label wearing schedule for contact lenses is much more risky and should be avoided. There is no potential medical benefit to the patient to wear contact lenses beyond the approved wearing schedule, and the evidence showing risk to one's ocular health is substantial.

Another consideration is the common use of contact lenses as “bandages” for recurrent corneal erosion, corneal abrasion and in post-surgical settings. While some of the commonly available lenses are approved for this purpose, many more are not. It's safest to use one of the lenses that carry FDA approval for bandage use. One exception would be a lens that has not received FDA approval for bandage use, yet is used by a majority of practitioners as a bandage lens, and, therefore, is considered the “standard of care.” In practice, the standard of care would take precedence over the lack of FDA approval.

What Is the Drug Approval Process?
You've no doubt heard of Phase I, II, and III trials. Before conducting these studies, new drugs have to be tested in the laboratory and usually on animals. If they are deemed safe, Phase I studies may be started.
These studies are done on relatively small groups of volunteers, usually people who are otherwise healthy. These studies are designed to test safety in humans and sometimes to determine the dose ranges that are appropriate.
Phase II studies involve patients who may have the condition for which the drug is being tested for use. The drug is evaluated to see whether it's effective for that condition. Safety is also evaluated in Phase II, and dosing ranges may also be studied.
Phase III studies are much more involved, and are comprised of testing large numbers of patients who have been diagnosed with the condition being investigated. These trials go on for longer periods of time than Phase I and II trials. Typically, in a Phase III trial, a new drug is compared against a “gold standard,” or a drug that is considered to be the standard of care.
If a new drug is determined safe and at least equally as effective as the gold standard to which it is being compared — which is also termed “non-inferiority” — then the drug is likely to be approved for sale in the United States. Once the drug is marketed and in use, Phase IV studies are sometimes done to continue to evaluate the drug for unforeseen effects.

Is off-label prescribing legal?

Although off-label use of FDA-approved medications is not regulated by the FDA or any other oversight agency, the practice is legal — except with certain controlled substances, such as the opioids.

The FDA's website instructs, “Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment.” The FDA dictates three responsibilities for physicians using medications off-label:

► Be well-informed about the product.
► Base its use on scientific rationale and sound medical evidence.
► Maintain records of the product's use and effects.

In practical terms, this means that in order for practitioners to legally and ethically use a medication off label, they must meet two criteria: First, the medication has to be approved for some clinical purpose — that is, it can't be an experimental drug. Second, compelling evidence has to exist that the drug is useful, safe and effective for the condition which it has been prescribed. For most of the drugs we use commonly, this is an easy matter.

In addition, the practitioner has the responsibility to inform the patient that the drug is useful, but not approved, for the purpose they are recommending to the patient. Patients have the right to accept or decline the treatment recommendations outlined by their physician. I've never had a patient decline the off-label use of a drug, but I have had patients refuse treatment.

Marketing: where off-label is off limits

While physicians have a fair amount of freedom in using medications off-label, the drug companies that manufacture and market the drugs are strictly prohibited from marketing the drug for off-label uses. This is a fairly complex subject, and has prompted a re-evaluation by the major drug manufacturers of their sales and promotion practices. Even the seemingly innocuous practice of providing samples of medications to practices has been restricted by many leading ophthalmic pharmaceutical companies. As an example, providing samples of antibiotics, that are technically “only” approved to treat bacterial conjunctivitis, to a cataract-surgery-based practice could be construed as “marketing” the off-label use of the drug for pre- and post-operative infection control.

Other drug companies have addressed these strict marketing regulations by creating a physician resource network comprised of practitioners who talk with colleagues about the possible risks and benefits of off-label use of medications. While any discussion of off-label use is strictly off limits for the sales and marketing team members, these restrictions do not apply to discussions between and among healthcare practitioners. The off-label use of drugs is very different than off-label marketing, and drug companies risk facing hefty fines if they cross this line.

Why don't drug companies just apply for approval for more indications?

Drug companies spend enormous sums of money in research and development to bring new drugs to market. Each specific trial requires that very strict protocols be developed and implemented. In addition, researchers must be paid, subjects compensated for their time and any potential risks, and study data analyzed and compiled.

If a drug is approved for one specific indication, it can be marketed and sold. The inevitable result is that pretty quickly after a drug is marketed, practitioners start looking for new uses for the drug, based upon their clinical experience with other, similar medications. When these new applications seem to have merit, the results are published in peer-reviewed journals, where other practitioners can learn about fellow practitioners' results with expanded applications of the drugs. Initially, this might take the form of small scale, anecdotal reports, but typically larger-scale studies are initiated that reinforce the use of the drug for more purposes than are explicitly indicated on the drug label, and the information seeps throughout the healthcare community. (For example, the “Common Non-FDA Approved Uses” listed in Table 1, are based on such clinical experience.)

Table 1. Commonly Used Ophthalmic Medications and Their Approved Indications:
Drug Trade Name (Generic Name) FDA Indication/Label Dosing for Indicated Use Common, Non-FDA Approved Uses
Vigamox (moxifloxacin 0.5%) Bacterial conjunctivitis caused by “susceptible bacteria” TID X 7 days Bacterial corneal ulcers (dosing varies, e.g. every 10 minutes x 1 hour then q2 h x 18 h; once or twice overnight; then taper with improvement)
Zymar (gatifloxacin 0.3%) Bacterial conjunctivitis caused by “susceptible bacteria” Q2h x first 2 days, then QID x 5 days Bacterial corneal ulcers (see example dosing for Vigamox, above)
Moxeza (moxifloxacin 0.5%) Bacterial conjunctivitis caused by “susceptible bacteria” BID Bacterial corneal ulcers (dosing varies, usually somewhat less frequent than for Vigamox, above)
Zymaxid (gatifloxacin 0.5%) Bacterial conjunctivitis caused by “susceptible bacteria” Q2h x first day, then BID-QID (dosing varies, usually somewhat less frequent than for Vigamox, above)
Azasite (azithromycin 1%) Bacterial conjunctivitis caused by “susceptible bacteria” BID x 2 days then QD Anterior and posterior blepharitis; prophylaxis for neonatal conjunctivitis
Zirgan (ganciclovir 0.15% ointment) Dendritic corneal epithelial ulcers caused by herpes simplex virus 5 times a day, then TID once epithelium heals Other infectious and inflammatory herpetic eye disease; varicella zoster ophthalmicus; epidemic keratoconjunctivitis; severe follicular conjunctivitis from other causes
Bromday (bromfenac 0.09%) Post-cataract inflammation and pain QD Ocular inflammation from other causes (QD)
Nevanac (nepafenac 0.1%) Post-cataract inflammation and pain TID Ocular inflammation from other causes
Durezol (difluprednate ophthalmic) Post-surgical inflammation and pain BID - QID Ocular inflammation from other causes, especially anterior uveitis (BID-QID+)
Lotemax (loteprednol etabonate 0.5%) Steroid-responsive anterior segment inflammation; post-operative ocular inflammation Varies; q1h – QID Anterior segment inflammation in patients with and without a history of steroid response
Lotemax ointment (loteprednol etabonate 0.5%) Post-operative ocular inflammation ¼″ ribbon QID Anterior segment inflammation in patients with and without a history of steroid response
Alrex (loteprednol etabonate 0.2%) Seasonal allergic conjunctivitis QID Anterior segment inflammation in patients with and without a history of steroid response
Besivance (besifloxacin 0.6%) Bacterial conjunctivitis caused by “susceptible bacteria” BID Bacterial corneal ulcers (dosing varies, usually somewhat less frequent than for Vigamox, above)
Acular (ketorolac) Itching caused by seasonal allergic conjunctivitis QID Various mild anterior segment inflammatory conditions
Voltaren (diclofenac sodium 0.1%) Postoperative inflammation (cataract); postoperative pain and photophobia (refractive surgery) QID Various mild anterior segment inflammatory conditions

Off-label use can become the standard

In many instances the off-label use of the drug becomes the standard of care, despite the lack of FDA approval. (See “Systemic Drugs That Are Commonly Prescribed Off-Label, below.) One good example is the prevalence of the use of fourth- and fifth-generation fluoroquinolones in treating bacterial corneal ulcers. Most practitioners use mono-therapy with the new fluoroquinolones more often than FDA-approved agents, although interestingly, corneal specialists are more likely (24%) than general practitioners (11%) to opt for traditional therapy in the form of fortified tobramycin and cefazolin in some patients.1

Table 2. Systemic Drugs That Are Commonly Prescribed Off-Label:
Drug Name Approved Use Off-Label Use
Abilify (aripiprazole) Antipsychotic; add-on antidepressant Dementia, Alzheimer's Disease
Desyrel (trazodone) Antidepressant Insomnia
Gabitril (tiagabine); Lamictal (lamotrigine) Antiseizure Depression
Inderal (propranolol) Hypertension Performance/Test Anxiety
Neurontin (gabapentin) Antiseizure; Post-Herpetic Neuralgia Migraines, Restless Leg Syndrome

An even more dramatic example is the widespread off-label use of bevacizumab to treat neovascular AMD. Its closely related cousin ranibizumab is more expensive. Although the topic is still somewhat controversial, a 2011 study revealed that roughly 65% of Medicare claims for neovascular AMD treatment involved bevacizumab, while only about 35% involved ranibizumab.2 This is one of the very few examples of Medicare providing reimbursement for an off-label drug.

Often, drug companies don't want to tempt fate by initiating FDA trials for an additional indication for a medication that is already successfully being used off label. There is always the risk that carefully conducted clinical trials will fail to show superiority of the new drug vs. previously approved treatment options — and that might mean reduced sales.

Table 1 lists some examples of topical ophthalmic medications and their common off-label uses. Although these new medications often become first-line therapy for an off-label use, patients must still give their legal informed consent for the non-FDA-approved use of the drugs. A note in the patient's medical chart (“Pt accepts off-label use”) will help protect you should the patient experience a poor outcome from treatment.

Acting responsibly

The off-label use of ophthalmic medications is very common, and when done in a responsible manner, is a vital part of every-day practice. Make sure to document your discussions with your patients; include that they consent to the off-label use you are proposing. Keeping informed about new drug and device approvals, as well as the medical literature detailing outcomes of off-label use of approved medications, is important so that you and your patients can make informed management decisions. OM

1. Hsu HY, Nacke R, Song JC, et al. Community opinions in the management of corneal ulcers and ophthalmic antibiotics: a survey of 4 states. Eye Contact Lens. 2010 Jul;36(4):195-200.
2. Brechner RJ, Rosenfeld PJ, Babish JD, Caplan S. Pharmacotherapy for neovascular age-related macular degeneration: an analysis of the 100% 2008 medicare fee-for-service part B claims file. Am J Ophthalmol. 2011 May;151(5): 887-895.e1. Epub 2011 Feb 18
.

Dr. Reed is an associate professor and director of Educational Effectiveness & Outcomes Assessment at the Nova Southeastern University College of Optometry in Fort Lauderdale, Fla. E-mail her at kimreed@nova.edu, or send comments to optometricmanagement@gmail.com.


Optometric Management, Volume: 47 , Issue: February 2012, page(s): 26 - 32 64