Many diseases in ophthalmology are complex and often difficult to diagnose and treat for a multitude of reasons. Although conventional therapies usually work, eye care professionals occasionally need to utilize alternative or adjunctive options to help the patient. Compounded/off-label treatments fall under this umbrella.
Compounded drugs have been an integral part of many treatment plans, not just in ophthalmology, but in medicine as a whole. This is because they provide unconventional, complementary approaches to diseases that may be unpredictable or refractory to standard therapies. (See “FDA Definition for Compounding Medications,” below.) In the case of ophthalmology, for example, topical compounded vancomycin drops treat corneal ulcers effectively, but they are not commercially available. (See “A Brief History of Compounded Medications in Ophthalmology”.)
Before prescribing compounded/off-label treatments, some “disclaimers” need to be discussed. First, the safety and efficacy of many compounded medications may not have been fully investigated, and they are not FDA approved. Second, investigational and off-label uses are left to the judgement of each clinician. Third, consent forms should be considered for compounded/off-label medications to protect the patient and the prescriber. (See p. 38.)
Possibly, the most ideal use of compounded/off-label treatments is for dry eye disease (DED). Here, we discuss why, and the related compounded/off-label treatments.
Why DED
Among the reasons we believe DED is so difficult to treat are:
- The characteristics of the condition. There are multiple triggers and risk factors that contribute to DED, and signs and symptoms do not always correlate.
- Prescription options remain limited in number, and no one treatment is a panacea. Topical cyclosporine (in two different formulations — Restasis [Allergan/AbbVie] and Cequa [Sun Ophthalmics]), lifitegrast (Xiidra, Novartis), and varenicline nasal spray (Tryvaya, Oyster Point Pharma) remain the only prescription options for chronic use for DED. While the former 3 have been shown outstanding in treating the root problem of DED by addressing inflammation, and the latter, a nicotinic acetylcholine receptor agonist, has shown promise in increasing complete tear production through nasal stimulation, DED, like glaucoma, is often a multitreatment disease. This means that a person with more than mild DED may need 2 or 3 different therapies to affect a result.
- Multiple treatment algorithms. While designed to guide the process of DED diagnosis and treatment, the International Task Force guidelines, the Tear Film & Ocular Surface Society Dry Eye Workshop (DEWS I and DEWS II), the ASCRS Cornea Clinical Committee algorithm, and the Corneal External Disease and Refractive Surgery (CEDARS) algorithm, to name a few, each have their own approaches, which can cause confusion. The CEDARS algorithm, in particular, is designed to provide other treatment options, such as compounded medications, when commercially available treatments are not sufficient.2 See “Following the 3 Latest Dry Eye Disease Algorithms,” p. 35.)
FDA DEFINITION FOR COMPOUNDING MEDICATIONS
“Compounding is generally a practice in which a licensed pharmacist, a licensed physician, or, in the case of an outsourcing facility, a person under the supervision of a licensed pharmacist, combines, mixes, or alters ingredients of a drug to create a medication tailored to the needs of an individual patient.”1
A BRIEF HISTORY OF COMPOUNDED MEDICATIONS IN OPHTHALMOLOGY
The use of compounded medications in ophthalmology has a long history. Intraoperative compounded medications, such as “shugarcaine” (to dilate the pupil for cataract surgery); alcohol (for epithelial removal and treatment of ingrowth); mitomycin C (for pterygium and PRK); and intracameral antibiotics, such as moxifloxacin, are quite common.
Additionally, bevacizumab (Avastin, Genentech) and intravitreal antibiotics are compounded med-ications that are the mainstay of the majority retinal practices.
Finally, many anterior segment surgeons have adopted combined compounded medications, such as putting prednisolone acetate, gatifloxacin, and bromfenac into 1 bottle to provide a postoperative topical regimen.
Dr. Ophthalmology
2020 Ophthalmology Road,Ocular City, Any State, 12345
Consent Form for Medication or Device*
When the FDA approves a drug or device for medical use, the manufacturer creates a “label” to explain its use. Once a device/drug is FDA approved, doctors may use it “off-label” for other purposes if they are knowledgeable about the product, base its utilization on the scientific method and sound medical evidence, and keep records of its use and outcomes.
[State the reason for the off-label item.]
[State other options for the off-label item.]
[State the known complications and side effects of the off-label item.]
I understand that [state drug/device] was FDA for [state approval purpose/conditions]. Even so, I wish to have [state treatment] used in/on my eye, and I am willing to accept the potential risks that my doctor has talked about with me. I understand that there may be other, unknown risks and that the long-term effects and risks of [state drug] are not known.
Patient Signature:
______________________________
Date:
______________________________
*This excerpt is sourced/paraphrased from the Ophthalmic Mutual Insurance Company. Visit www.omic.com .
Compounded/Off-Label DED Treatments
Compounded and off-label therapies have been used for years with some evidence-based, and a lot of anecdotal success, often providing a safe and effective option for our DED patients. They are:
- Topical hormones. An aqueous-deficient patient may benefit from topical hormones, such as medroxyprogesterone acetate 1%, progesterone 0.5%/testosterone 0.5% in a 50:50 combination, and dehydroepiandrosterone (DHEA) 0.5 to 1.0% b.i.d. to 6 times daily. The reason: These drops may have anti-inflammatory success and improve the signs and symptoms of DED. Topical medroxyprogesterone may also reduce corneal ulceration and perforation, and has been used for treatment of alkali injuries.3
- Topical albumin. When autologous serum may not be available, topical albumin, used b.i.d. to 6 times a day, is a beneficial option. The reason: Albumin is a major component of human serum. It is commercially available in a purified form for non-ophthalmic use. Animal models showed healing of corneal erosions using 5% to 10% serum albumin.4,5 Additionally, a case series of patients with Sjögren’s syndrome showed improvement in corneal staining with 5% albumin q4h after 4 weeks.4Topical compounded dapsone 0.25% and tacrolimus 0.03% are anti-inflammatory and have shown anecdotal success in DED patients as well. Additionally, topical spironolactone (0.005 mg/cc), in addition to its anti-inflammatory properties, may have some effect on lipid modification, decreasing fibrosis, and improving wound healing.6
- Compounded options for meibomian gland dysfunction (MGD)–related dry eye. These include topical metronidazole ointment, 0.75% used at bedtime, topical doxycycline drops 0.025% to 0.1% b.i.d., and topical clindamycin ointment 1% used at bedtime. These have antibiotic and anti-inflammatory effects, similar to use for facial acne. Topical androgens (such as DHEA) and spironolactone, may also be beneficial for blepharitis/MGD. (See “Treating Other Forms of Ocular Surface Disease,” above.)
- Vitamin A ointment. For patients with an evaporative tear film based on goblet cell loss (e.g., conjunctival scarring or chronic chemical or medication exposure), this treatment (compounded all-trans-retinoic acid, 0.01% or as an OTC preparation) used at bedtime, may help replenish goblet cells.
- Off-label use of commercially available immunomodulators/antibiotics. Patients who have posterior blepharitis or MGD have been shown to benefit from commercially available cyclosporine and lifitegrast b.i.d. and topical azithromycin (AzaSite, Akorn) at bedtime.
TREATING OTHER FORMS OF OCULAR SURFACE DISEASE
In addition to DED, a host of other ocular surface diseases may benefit from compounded medications.
For years, ophthalmologists have used a compounded topical tacrolimus as an ointment (0.02%) for the eyes and lids, or as drops (0.02% or 0.03%) used b.i.d. to treat vernal or atopic keratoconjunctivitis because of its T-cell immunosuppression. Like cyclosporine, tacrolimus is a calcineurin inhibitor. Atopic, vernal, and giant papillary conjunctivitis have both a type I (histamine response) and type IV (T-cell or delayed) hypersensitivity response. Therefore, an effective way to treat these patients is with a histamine and mast cell stabilizer, along with a topical cyclosporine, lifitegrast, or a tacrolimus drop. Incidentally, a new commercially available formulation of cyclosporine (Verkazia, 0.1%, Santen) launched to treat vernal keratoconjunctivitis.
Topical N-acetylcysteine 5% to 20% (Mucomyst, E.R. Squibb & Sons, LLC) q.i.d. has been compounded as a drop for filamentary keratitis because of its mucolytic, antiinflammatory, and anticollagenase activity.
Topical sodium citrate drops (10%) q.i.d. may help with corneal melts.
Options for corneal and conjunctival intraepithelial neoplasia and squamous cell carcinoma include topical interferon or 5-FU (1%) drops q.i.d.
Conjunctival melanoma or primary acquired melanosis with atypia may benefit from compounded mitomycin C drops (0.04%) q.i.d.
Band keratopathy is often treated by performing an epithelial keratectomy with compounded ethylenediaminetetraacetic acid (0.4% to 3.0%, with the usual dose being 1%) chelation.
Finally, superior limbic keratoconjunctivitis is often treated by conjunctival excision with or without amniotic membrane transplantation or cautery. However, chemical cauterization with a compounded 0.5% to 1% silver nitrate is quite effective.
A Helping Hand
Topical compounded/off-label treatments can be excellent options when a clinician needs more than what is commercially available to help patients achieve relief from DED. CP
References:
- Human drug compunding. US Food and Drug Administration. (Accessed March 2, 2022). https://www.fda.gov/drugs/guidance-compliance-regulatory-information/human-drug-compounding .
- Milner MS, Beckman KA, Luchs JI, et al. Dysfunctional tear syndrome: dry eye disease and associated tear film disorders–new strategies for diagnosis and treatment. Curr Opin Ophthalmol. 2017;28 (Suppl 1):3-47.
- Newsome NA, Gross J. Prevention by medroxyprogesterone of perforation in the alkali-burned rabbit cornea: inhibition of collagenolytic activity. Invest Ophthal Vis Sci. 1977;16(1):21-31.
- Shimmura S, Ueno R, Matsumoto Y, et al. Albumin as a tear supplement in the treatment of dry eye. Br J Ophthalmol. 2003;87(10):1279-1283.
- Higuchi A, Ueno R, Shimmura S, Suematsu M, Dogru M, Tsubota K. Albumin rescues ocular epithelial cells from cell death in dry eye. Curr Eye Res. 2007;32(2):82-88.
- Watsky WA, Lu X, Chen Z, Yee R. Effects of spironolactone on corneal epithelium may contribute to beneficial dry eye effects. Paper presented at: Annual meeting of the Association for Research in Vision and Ophthalmology; May 1 to 7, 2020, Baltimore, MD.
