Inform the patient when prescribing an agent off label

Issue: August 2001

If it is clinically appropriate

J. James Thimons, OD: The breadth of pharmaceutical use in optometry has increased exponentially in the past decade. With that, applying therapeutic agents outside of their Food and Drug Administration-approved status has become a routine part of the daily care of our patients. Interestingly, a significant percentage of many drugs’ current uses have never received formal approval. Rather, they have been adopted into clinical practice as a result of refereed literature documenting the substantial amount of work in this area.

While the use of agents for non-approved purposes presents some challenges, practitioners should not refrain from treating patients in this manner — if it is the appropriate therapy — just because the agent is not approved for that indication. In most instances, the agents used at the primary care level have well-established track records and have been used by both specialists and general practitioners to treat a variety of conditions off label. Examples of this include bandage contact lenses, nonsteroidal anti-inflammatory drugs for most of their currently used applications, cyclosporine for dry eye and Alphagan (brimonidine tartrate, Allergan) for post-laser IOP spikes.

While none of these applications are approved, they have become commonly accepted and part of the culture of eye care. In most instances, the off-label use of drugs is safe and effective; however, practitioners must be aware that not all uses fall into that category. In particular, when one decides to use a drug in a way that has no prior clinical experience or support from the refereed professional journals, the practitioner enters a very different area of professional decision making. In such instances, it is entirely appropriate to advise the patient that the drug is being used in an unapproved application. It may also be advisable in certain instances to obtain informed consent prior to initiating therapy, regarding such issues as potential side effects and contraindications.

The use of drugs for nonapproved purposes is an integral and common part of clinical practice. If the practitioner exercises good judgment, follows appropriate administrative and medicolegal guidelines and always keeps the patient informed, it can be a very useful adjunct to clinical practice.

J. James Thimons, OD, is a member of the Editorial Board of Primary Care Optometry News. He can be reached at Ophthalmic Consultants of Connecticut, 75 Kings Highway Cutoff, Fairfield, CT 06430; (203) 334-2020; fax: (203) 334-2401; e-mail: jim.thimons@tlcvision.com. Dr. Thimons has no direct financial interest in the products mentioned in his response, nor is he a paid consultant for any companies mentioned.

Rely on clinical judgment

Bruce E. Onofrey, OD, RPh, FAAO: Off-label use of any medication implies that the drug is used for a reason other than what it is implicitly indicated for. Prescribing drugs in this manner is legal and chiefly depends upon clinical judgment, but it should be supported by clinical evidence of drug efficacy and safety for its chosen usage. Patients given medications for off-label usage should receive informed consent on the risks, benefits and pertinent clinical evidence of drug efficacy and safety. Additionally, the clinicians themselves should have clinical experience using the drug for the particular off-label condition.

Topical steroids are an excellent example of a class of drugs that is used in a broad range of clinical disorders, frequently without a specific indication other than managing general inflammation.

The following statement describes the indicated conditions for prednisolone acetate ophthalmic suspension: “Steroid responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe such as allergic conjunctivitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis, when the inherent hazard of steroid use is accepted to obtain an advisable diminution in edema and inflammation; corneal injury from chemical, radiation, or thermal burns or penetration of foreign bodies.” Now that’s pretty general. Basically, topical steroids are indicated for all inflammatory disorders that have inflammation as a major component of the disease process.

For enlightenment, let’s look at the contraindications to topical steroids: “Prednisolone acetate is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella and also in mycobacterial infection of the eye and fungal diseases of ocular structures.”

It would appear that topical steroids are in fact indicated for the management of any inflammatory condition where the physician feels the risk:benefit ratio favors the benefit side of the equation. Rather than discuss steroid usage in the terms of indications or contraindications, a better choice of terms would be use of topical steroids in controversial conditions. These include allergy, adenoviral disease, herpes simplex and other infectious disorders of the cornea and in corneal injury, such as recurrent erosion.

In the past, a nonsight-threatening, chronic disorder such as allergic conjunctivitis would rarely be treated with topical steroids. The risk:benefit ratio would not allow it. However, today, we have a topical steroid specifically approved for the condition. The safety/efficacy profile of 0.2% loteprednol allows its use in moderate to severe allergic conjunctivitis.

Pseudomembranes and subepithelial infiltrates are common reasons to use topical steroids in adenoviral disease. More controversial is managing conjunctival inflammation itself. Significant inflammation can reduce the population of unicellular glands that provide basal lubrication of the ocular surface. Judicious use of steroids reduces this risk by reducing damaging conjunctival inflammation.

Pure epithelial herpetic keratitis is never treated with topical steroids; however, it is important to recognize the earliest signs of stromal involvement and consider the use of steroids with antiviral cover to minimize permanent corneal scarring with subsequent loss of visual acuity. Likewise, the infectious component of bacterial ulceration must be properly managed with appropriate antibacterial therapy; however, corneal inflammation can result in significant stromal scarring. Use of topical steroids at the appropriate time to minimize loss of vision is controversial, yet occasionally necessary.

The goal of therapy for managing corneal erosion/photorefractive keratectomy (PRK)/phototherapeutic keratectomy (PTK) is corneal re-epithelialization. Following micropuncture/PRK or PTK, corneal epithelialization can be inhibited by inflammation. Use of topical agents is appropriate, but controversial in these situations.

Perhaps the most important concept in the use of topical steroids is the first rule of medicine: Primum non nocere — first do no harm.

Bruce E. Onofrey, OD, RPh, FAAO, is a member of the Editorial Board of Primary Care Optometry News. He can be reached at 9101 Montgomery Blvd. NE, Albuquerque, NM 87111; (505) 275-4226; fax: (505) 275-4203; e-mail: Eyedoc3@aol.com.

If doctor, patient agree to it

Michael Harris, OD, JD, MS: The issue of going off-label involves both the doctor and the patient. The patient needs to understand that the doctor is prescribing the drug for a non-approved, or off-label, use, and he or she needs to understand the risks and consequences of that particular regimen as well as the benefits.

In addition, informed consent must be obtained. My suggestion is to obtain written consent to document the fact that an informed consent discussion occurred and that the patient is aware of the risks and benefits of this proposed use.

Certainly, I would be extremely reluctant to suggest that medications be used off-label for minors. It’s not that it can’t be done, but the potential consequences are significant if something goes wrong.

I urge any doctor who wishes to prescribe for an off-label use to be extremely confident that the drug is appropriate for that use and be willing to face the consequences if his or her judgment is in error. I urge practitioners to take a very cautious approach to using any medication off label. It’s highly unlikely that I would do it myself. It would have to be an extremely rare case where no other approved therapy would work.

One of the primary reasons for my reluctance is the liability issue. If the patient has an adverse reaction to this particular medication, even if the practitioner obtains informed consent, the practitioner may be found liable. Additionally, the action could be viewed as reckless or wanton. That could lead to significantly greater financial responsibility on the part of the prescribing doctor.

I cannot, and will not, recommend that practitioners prescribe medications outside of their indications. If you do go off-label, another issue is the possibility that your malpractice insurance may not protect you. It protects you from acts or omissions in the practice of your profession that may not include going off-label. I don’t know of a particular case where this has been adjudicated, so I cannot say there is any precedent. However, I would guess, based on situations in other professions and other fields, that liability coverage may be challenged.

Michael Harris, OD, JD, MS, is associate dean and clinical professor at the University of California. He is also an attorney-at-law and a member of the State Board of California. He can be reached at University of California School of Optometry, Berkeley, CA 94720-2020; fax: (510) 643-5109. Dr. Harris has no direct financial interest in the products mentioned in his response, nor is he a paid consultant for any companies mentioned.