Today, the concept of prescribing a medication off-label is far from a rogue decision by a practitioner when it comes to choosing the best course of treatment for patient care.
Indeed, it is not uncommon or new for ophthalmic drugs, technically unproven as a Food & Drug Administration (FDA) approved indications, to be prescribed off-label.¹ In fact, it is estimated that off-label usage can be as high as 90% in the pediatric population and 40% in adults.²

Does Off-Label Meet Standard of Care? Eye care professionals regularly prescribe medications off-label.2 It is practically impossible to identify all potential uses of a product while it is going through the initial FDA approval process. This makes the practice of off-label use common all over the world. “The optometry license does not prevent you from treating to the standard of care. So, as long as it is in your patient’s best interest, any time (to prescribe off-label) is appropriate,” says Dr. Bloomenstein. Good medical practice and the best interests of the patient require that physicians use legally available drugs according to their best knowledge and judgment.1 If physicians use a product for an indication that is not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the products’ use and effects.1 “Off-label prescribing is common as long as there is some published literature, discussion in clinical circles and at meetings about the off-label use of a medication,” says Dr. Autry. Experimenting with a drug off-label without expert discussion or literature to back up your treatment decision is not generally advisable. “If it is being discussed at meetings and in journals, then I say use it,” Dr. Autry adds. “I do believe off-label use has become an acceptable standard of care in certain conditions,” adds Dr. Karpecki. “I think we have to use our knowledge to make the right decision. A prudent doctor would choose the best, broadest spectrum antibiotic, such as Besivance (besifloxacin, Bausch + Lomb) for keratitis even if it is approved only for conjunctivitis. The decision to prescribe off-label should be based on research available and what the average prudent optometrist would do in a similar situation. Finally, doctors should use their knowledge to apply the best possible medication that will best help a patient with their condition.” Adds Randall Thomas, O.D.: “Doctors have to be vigilant and consistently read expert peer- reviewed literature and learn the science and facts about the off-label use of a medication.”

Essentially, off-label is the use of a medication or product for a different indication, age group, dosage or administration than approved by the FDA. Once a drug has gained FDA approval for an indicated use, physicians generally may legally prescribe the drug off-label. However, it is illegal for drug manufacturers to promote off-label usage of their product. 

Once a drug is approved for a specific indication, drug manufacturers typically won’t pursue additional indication approvals due to added expense and time. “The FDA process is costly and arduous, thus most manufacturers want to demonstrate safety and efficacy,” says optometrist Marc Bloomenstein of the Schwartz Laser Eye Center, in Scottsdale, Ariz. “However, to get a broader approval may take years and more money.”

“Getting something approved through the FDA is a struggle, especially in patient populations with certain disease states,” explains optometrist and registered pharmacist Jill Autry of the Eye Center of Texas, in Houston. This can be especially true with pediatric populations. For example, a recent study reported nearly four out of five hospitalized children receive medications that have been tested and approved only for adults.³

“Eight years ago, I treated a local pediatrician with who had a severe adenovirus with 5% Betadine solution,” says optometrist Randall Thomas, of Concord, N.C. “I told her it was off-label. She laughed and said 90% of what she prescribes is off-label.”

The prevalence and clinical importance of prescribing drugs for unlabelled uses are substantial, and the prescribing of drugs for unlabeled use is often necessary for optimal patient care.¹

Even prescribing a medication at a different dosage than indicated is a common off-label use. For example, a recent study that performed a meta-analysis to estimate the intraocular pressure-lowering efficacy and safety of alpha-adrenergic agonists (AAs), beta-adrenergic antagonists (BBs), and topical carbonic anhydrase inhibitors (CAIs), when used in combination with a prostaglandin analog, reported that the CAIs and AAs are commonly administered two times daily in clinical practice, despite the fact they are only approved by the FDA for three times daily use.⁴

“Prescribing off-label is routine practice in the management of patients today,” says optometrist Cynthia Heard, of the Southern College of Optometry, in Memphis, Tenn. “Many times, practitioners will experiment with treatment options if mention of it starts to show up in the literature in the form of case studies or small prospective studies. If the rationale is there, many practitioners will prescribe off-label to note the outcome. Sometimes we try unproven treatments (by clinical trial determination) on ourselves or family members before considering it for someone else.”    

The benefits for prescribing off-label depend on the specific nature of your prescription, adds Dr. Bloomenstein (see “Off Label: More Benefits than Detriments,” below). “Often times, some of the best medications are only approved for limited use and are not discussed with the doctor by the manufacturer.” An example of that is seen with the newer class of antibiotics. “Most antibiotics are only approved for treating conjunctivitis. Yet, surgical prophylaxis is where these medications can really shine,” he says.

Of course, when deciding whether to prescribe an ophthalmic medication off-label, be sure that you are following the proper standard of care (see “Does Off-Label Meet Standard of Care?” right).

Below is a snapshot of some common and not so-common uses of off-label ophthalmic drugs.

Antibiotics
• Fourth-generation fluoroquinolones. “The most common medication I use off-label—almost daily—is the fourth-generation fluoroquinolones for the treatment of infectious keratitis,” says optometrist Ernie Bowling, Rome, Ga.

This classification of drugs (moxifloxacin, gatifloxacin, besifloxacin) is approved for the treatment of bacterial conjunctivitis, but these are commonly used off label for treating bacterial keratitis and corneal ulcers. It is thought that newer drugs in this drug class have fewer resistant bacterial strains than older second and third-generation fluoroquinolones, because of their two-step inhibitory reaction against bacteria that takes far longer to build up resistance, Dr. Heard adds.

“We use topical antibiotics pre- and post-ocular surgery as standard of care, but these medications are not approved for surgical prophylaxis of infection,” Dr. Autry says. “If an ophthalmologist did not use an antibiotic around surgery, however, and the patient developed endophthalmitis, the doctor would be sued for not following standard of care even though there is not FDA labeling to suggest this practice.”

• Topical azithromycin. AzaSite (azithromycin ophthalmic solution, Inspire Pharmaceuticals) is a 1% topical formulation of azithromycin in a gel-like vehicle called DuraSite (InSite Vision) that is approved for bacterial conjunctivitis. While no topical medications have received FDA approval for blepharitis, a number of clinical trials have shown AzaSite’s effectiveness against blepharitis.^5,6 AzaSite contains properties that decrease pro-inflammatory mediators found in the tears, and it also inhibits matrix metalloproteinases, Dr. Heard adds.

Glaucoma Drugs
• Alphagan P. Alphagan P (brimonidine, Allergan) is indicated for the lowering of intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Brimonidine possesses inherent properties that may cause pupil myosis.⁷ This feature is useful in individuals who have had refractive surgery procedures, such as LASIK, or who may complain about poorer quality of night vision or haloes around lighted objects because of larger pupils at night. Sometimes brimonidine is used to decrease the size of the pupil to facilitate better nighttime vision, Dr. Heard says.

• Prostaglandins. Typically used in the treatment of glaucoma, these drugs can be successfully used off-label to stabilize IOP in radial keratotomy patients with fluctuating refractions, Dr. Autry says. Using a prostaglandin to lower IOP in patients with Fuch’s’ dystrophy may be useful in controlling corneal edema. While this can be done with any ocular hypotensive (except for a CAI)—the prostaglandins are the easiest to use, she adds.

• Iopidine. Iopidine (aproclonidine, Alcon) can be used for the diagnosis of ocular sympathetic denervation, or Horner’s syndrome (HS). The classic diagnosis typically requires a topical solution of cocaine, Dr. Autry says. But because cocaine is a scheduled II controlled substance, it is problematic to obtain and keep in the office.

Instead, the practical and reliable ocular hypotensive agent aproclonidine has a weak direct action on alpha-1 receptors and therefore minimal to no clinical effect on the pupils of normal eyes, she adds. Patients with HS have denervation supersensitivity of the alpha-1 receptors in the iris stroma of the affected eye, making the pupil dilator responsive to apraclonidine.

Off-Label: More Benefits, Less Detriments Off-label prescribing generally offers the potential of cross over benefits to help other disease states and ultimately provide better patient care. For example, topical ophthalmic antibiotics are approved only for bacterial conjunctivitis, but they are used regularly as a staple treatment for bacterial keratitis and in prophylaxis after surgery. “I hear people all the time say, ‘I don’t know if I should use a certain drug for a certain condition since it is off-label,’ and I remind them that we use antibiotics off-label every day,” says Dr. Autry. Since the inception of the fluoroquinolone, surgeons having been using this “big gun’” to eradicate any bugs that may cause harm during the surgery, says Dr. Bloomenstein. “This benefits the patient with safety and better outcomes for surgery.” Whether it’s antibiotics or glaucoma medications, another benefit of off-label prescribing is relief from symptoms that a medication approved for one thing may have come as an ancillary side effect, such as the ability of Alphagan-P to whiten red eyes or to help alleviate glare and halos. Patients may also perceive that you are taking a broader interest in their treatment and well-being, Dr. Bloomenstein adds. “Confidence is gained by your patient when they see that you know your class of drugs and that you are able to find a treatment that may not be totally mainstream.” Another benefit: A patient receives treatment that may effectively manage his or her condition with minimal side effects. “Some conditions are also very time sensitive in nature, and off-label use of drugs may preserve vision more so than (a) currently approved treatment,” says Cynthia Heard.

Dry Eye
• Restasis. Restasis (cyclosporine ophthalmic emulsion, Allergan) is indicated for the treatment of dry eye. Restasis is one of the most frequently prescribed topical medications, Dr. Autry says.

Off label, Restasis has myriad uses, according to Dr. Bloomenstein, including post-LASIK dryness, post-cataract surgery, allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, corneal transplant rejection prevention, post-corneal transplant glaucoma, meibomian gland dysfunction, Thygeson’s keratitis, superior limbic keratoconjunctivitis and herpetic stromal keratitis.

• Topical steroids. “In dry eye, corticosteroids work extremely well,” says optometrist Paul Karpecki of Lexington, Ky. “Steroids have a strong anti-inflammatory component and are one of the most effective treatments for moderate and even severe dry eye in patients.”

• Allergy medications. (Mast cell stabilizers, antihistamines and non-steroidal anti-inflammatory drugs (NSAIDs) can also be used off-label to treat dry eye. Additionally, allergy medications can be used off-label for red eye control and pterygium, Dr. Bloomenstein adds.

Uveitis
• Durezol. Durezol (difluprednate ophthalmic emulsion, Alcon) was recently released as a topical synthetic steroid indicated for post-surgical inflammation. Its off-label use includes iritis and uveitis. “We recently had success with a patient with Crohn’s disease and severe uveitis who we put on Durezol. I am not sure if any another steroid would have done as well,” Dr. Karpecki says.

• Immunomodulatory agents. Currently, the majority of immunomodulatory agents are used off-label in the treatment of uveitis. With proper dosing and monitoring of patients, these medications have a long track record of safety and efficacy in the treatment of uveitis and systemic autoimmune disease.⁸

Anti-Viral
• Zirgan. Zirgan (gancyclovir ophthalmic 0.15% gel, Bausch + Lomb), also recently released, is approved for herpes keratitis. “I have already had great experience using this for patients with epidemic keratoconjunctivitis,” Dr. Karpecki says. “Not a lot of medications work well with this condition, and patients are very grateful with the results.”

Retinal Surgery
• Avastin. Avastin (bevacizumab, Genentech) is FDA- approved for treating various cancerous tumors both alone and in combination with other cancer treatments. The drug is also commonly used off-label to treat retinal vascular diseases, especially wet age-related macular degeneration, Dr. Bowling says. 

“Avastin has now been studied in limited trials to determine its effectiveness in managing age-related macular degeneration, neovascular membrane formation as a result of myopic degeneration and ocular histoplasmosis, and diabetic macular edema. Management of these conditions with Avastin has been embraced by the ophthalmologic profession without definitive guidelines from clinical trial data,” Dr. Heard says.

“The reality with Avastin is that this really is the larger molecule of the FDA-approved version, Lucentis. However, this affords the patient the opportunity to utilize the medication at cost, which is a fraction of the FDA-approved version. The benefits have been shown to be equal and short of any side-effects,” Dr. Bloomenstein adds.

NSAIDs
• NSAIDs. Most non-steroidal anti-inflammatory drugs are indicated only for the treatment of pain and inflammation around of cataract surgery. “We use topical NSAIDs for multiple uses––from allergy prevention and/or treatment of dry eye to cystoid macular edema,” Dr. Autry says.

Other Drugs
• Povidone iodine. Povidone is often used for the prevention and treatment of skin infections and the treatment of wounds. Povidone iodine 5% (Betadine 5% Sterile Ophthalmic Prep Solution, Alcon) for the eye is indicated for prepping of the periocular region (lids, brow and cheek) and irrigation of the ocular surface (cornea, conjunctiva and palpebral fornices). Many eye physicians are now using this solution in the treatment of adenoviral keratoconjunctivitis, Dr. Bowling says.

• Mucolytic agents. Acetylceysteine has been clinically used as a mucolytic agent in bronchiopulmonary conditions. Available as Mucomyst (Bristol-Myers Squibb), off-label ophthalmic uses include the treatment of vernal and giant papillary conjunctivitis and filamentary keratitis. A commercial ophthalmic formulation containing acetylcysteine is not currently available, but it can be prepared for topical ocular use by diluting the commercial preparation to 2% to 5% with artificial tears of saline solution.⁹

“As more O.D.s get more comfortable with medically managing their patients, the use of medications off-label should become more common place,” Dr. Bloomenstein says. “Knowing the mode of action for the medication can help doctors fine find other avenues of treatment.”

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