1/15/2021 - optometricedu.com

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©2019 Alltech, Inc. All rights reserved.

February 2021

Christopher Putnam, OD, PhD, FAAO

Clinical PotpourriOff-Label Medication Use in Primary Care

Optometry


OVERVIEW

• Food and Drug Administration

• Proper Use of Off-Label Drugs

• Pharmacokinetics and Pharmacodynamics

• Godfather of Off-Label Use• Bevacizumab (Avastin)

• Anti-infectives• 4th generation fluoroquinolones• Topical ganciclovir (Zirgan 0.15%)• Povidone iodine (Betadine 5%)• Topical azithromycin (Azasite 1%)

• Anti-inflammatory / Immunosuppressant • Prednisolne acetate (Pred Forte 1.0%)• Difluprednate (Durezol 0.05%)• Topical NSAIDs• Cyclosporine (Restasis 0.05%)

• Mucolytic agents (Acetylceysteine)

• Glaucoma • Alpha Adrenergic Agonists • Carbonic Anhydrase Inhibitors • Beta-blockers


OVERVIEW• Oral Medications

• Doxcycycline• Atorvastatin • Selenium • L-lysine therapy• Prednisone (bioequivalency)

• Central serous chorioretinopathy treatment• Mineralcorticoid antagonist • Antimycobacterials

Case Report

• Take Home Points

• What’s now?Pre-Clinical DiagnosisCo-management of Systemic Conditions

• What’s next?Patient-tailored health plans for at-risk populationsIntegrated systemic management / supplementation strategiesEnhanced bioavailability vs bioequivalence

• Risk calculator to incorporate:Clinical biomarkers + bioequivalence + Genetic risk


OCULARANATOMY


SYSTEMICANATOMY


OCULARPHYSIOLOGY

+ SYSTEMIC

DISEASE

• Although the diversity of systemic disease is broad, basic shared ophthalmic characteristicsinclude:

• Inflammation• Oxidative Stress• Mitochondrial dysfunction

• Vascular and inflammatory changes can manifest as retinal dysfunction

• Fundamental understanding of the pharmacodynamics of available medications can create therapeutic avenues


Pharmacokinetics vs.

Pharmacodynamics


Food and Drug Administration

• Approval Process• Timelines and Milestones• Barriers to Entry


FDA Approval Process• FDA is a public-health agency whose mission is to oversee the use and marketing of regulated medical

products

• 5 Step Approval Process • Preclinical phase – Basic science • Phase one clinical trial – Establish drug safety in healthy subjects using small cohorts of 20‐80 • Phase two clinical trial – RCT to assess the drug's efficacy using hundreds of participants (30% success rate)• Phase three clinical trial ‐ Large population trial to test ideal dosage, patient population and other factors• New drug application ‐ Includes trial data, preclinical information and details on manufacturing process.

*If FDA accepts the application for review, the agency has 10 months to decide* FDA can hold an advisory committee meeting where independent experts assess data and make recommendation

• When a drug is approved, the FDA issues a label that describes and defines:• Specific medical indication• Dose• Dosage form• Side effects • Chemical structure.

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FDA Approval Process• When a drug is approved, the FDA issues a label that describes and defines:

• Specific medical indication• Dose• Dosage form• Side effects • Chemical structure

• Scope of use is defined by the FDA label

• Basis for the Centers for Medicare & Medicaid Services (CMS) coverage as outlined in a National Coverage Determination (NCD)


On-Label and Off-Label Clinical Studies of FDA–Approved Ophthalmic TherapeuticsOphthalmology (2020)


Association of Off-label Drug Use and Adverse Drug Events in an Adult PopulationJAMA Intern Med (2016) 176(1):55-63OBJECTIVETo monitor and evaluate off-label use of prescription drugs and its effect on adverse drug events (ADE) in an adult population.

DESIGN, SETTING, AND PARTICIPANTSCohort of 46,021 patients who received 151,305 incident prescribed drugs was assembled from primary care clinics in Quebec, Canada using EMR documentation of treatment indications and treatment outcomes. Prescriptions were followed up from the date of the prescription to the date the drug use was discontinued, the end of treatment or the end of follow-up. Adverse drug events in off-label use with and without strong scientific evidence. Analysis used multivariate marginal Cox proportional hazards regression for clustered data with the drug as the unit of analysis.

RESULTSTotal of 3484 ADEs were found with an incidence rate of 13.2 per 10,000 person-months. The rate of ADEs for off-label use was higher (19.7) than that for on-label use (12.5). Off-label use lacking strong scientific evidence had a higher ADE rate (21.7) compared with on-label use. However, off-label use with strong scientific evidence had the same risk for ADEs as on-label use. The risks for ADEs were higher for drugs approved from 1981 to 1995 (14.4) and for those used by women (14.3), patients receiving 5 to 7 drugs (12.1), and patients receiving anti-infectives (66.2).

CONCLUSIONS AND RELEVANCE Off-label use of prescription drugs is associated with ADEs. Caution should be exercised in prescribing drugs for off-label uses that lack strong scientific evidence. Future electronic health records should be designed to enable postmarketsurveillance of treatment indications and treatment outcomes to monitor the safety of on and off-label uses of drugs


FDA Approval ProcessBarriers to Entry

• Executing the trials necessary to get FDA approval can be very costly.

• Inexpensive treatments would never recoup high cost of the approval process

• Running a clinical trial may not be feasible.

• FDA approval is very specific and limited

• Beneficial uses of a drug or device always evolve over time

** In reality, many treatments that have not gone through the FDA-approval process have demonstrated effectiveness and are widely used (quite a few are even standard of care)

** Many clinical trials reported in the peer-reviewed literature were not done under FDA supervision


Proper Use of Off-Label

Medications

• Off-Label Defined• Investigational Use• Informed Consent• Insurance Carrier Criteria


Off-Label Use Defined Any use of a drug not listed on the label is considered off-label to include:• Utilizing an approved drug for a condition or indication other than the condition for which it is

approved

• Prescribing an approved drug at a different dose, frequency or route of administration than specified in the label

• Treat a child when the product is approved to treat adults

Although the FDA label has important marketing implications, use of an approved product is not restricted by the FDA to the limitations of the label• Providers are allowed to use FDA-approved drugs in the treatment of a specific patient as medical

practice

FDA recognizes that off-label use of drugs by providers is often appropriate and may represent the standard of care• Example: Intravitreal antibiotics for reducing the incidence of post-operative endophthalmitis despite

the fact that no FDA-approved drugs for endophthalmitis prophylaxis

**Legal implications of off-label drug use primarily involve risk management issues**


Investigational Use• Investigational use suggests the use of an approved drug in the context of a clinical

study protocol• If primary intent is to develop information about drug safety or efficacy or if the off-

label use involves a route of administration, dosage level, subject population or other factor significantly increases the risks associated with the use of the drug, submission of an Investigational New Drug (IND) application is required


Informed Consent• FDA approval status does not necessarily define appropriate medical practice nor

regulate medical practice• Medical practice is the therapeutic relationship between a physician and an individual

patient and this decision must fall within the standard of care

SAMPLE INFORMED CONSENT TEMPLATE FOR A DRUG OR DEVICE

When a drug or device is approved for medical use by the FDA, the manufacturer produces a label to explain its use. Once a device/medication is

approved by the FDA, physicians may use it off-label for other purposes if they are well-informed about the product, base its use on firm scientific method and sound medical evidence, and maintain records of its use and effects.

[State purpose of the off-label drug/device.]

[State alternatives to the off-label drug or device.]

[State known complications and side effects of the off-label drug/device.]

I understand that [state drug/device] was approved by the FDA for [state approval purpose/conditions]. Nevertheless, I wish to have [state

treatment/procedure] performed on my eye/used in my eye and I am willing to accept the potential risks that my physician has discussed with me. I

acknowledge that there may be other, unknown risks and that the long-term effects and risks of [state drug/device] are not known.©2019 Alltech, Inc. All rights reserved.

Insurance Carrier Criteria • Question then becomes "when does off label drug use become the standard of care?"

• Answer depends on who is defining the standard of care. • Payers may use specific definitions of the standard of care to establish coverage determinations

based upon such factors as supporting authoritative literature, expert consensus, scientific rationale and local or national medical practice patterns.

Off-label use of U.S. FDA approved drugs as prescribed by a physician to treat chronic, disabling, or life-threatening illnesses may be considered medically necessary when approved by the FDA for at least one indication, AND one of the following:

• Is recognized in one of the following prescription drug reference compendium for treatment of the indication for which the drug is prescribed

1. Thompson Micromedex Drug Dex Compendium (Drug Dex);2. American Hospital Formulary Service Drug Information (AHFS DI);3. National Comprehensive Cancer Network's Drugs and Biologics Compendium;4. The United States Pharmacopoeia-Drug Information; OR

• Is supported by qualified clinical research that appears in peer-reviewed scientific literature specific for treatment of the indication for which the drug is prescribed

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Godfather of Off-Label Use • Bevacizumab (Avastin)


Off-Label Medication UseBevacizumab (Avastin)

• FDA-approved for treating various cancerous tumors both alone and in combination with other cancer treatments

• MOA: Selectively binds circulating VEGF, thereby inhibiting the binding of VEGF to its cell surface receptors. This inhibition leads to a reduction in microvascular growth of tumor blood vessels and thus limits the blood supply to tumor tissues.

• Commonly used off-label to treat retinal vascular diseases, especially nvAMD including NVM formation as a result of myopic degeneration and POHS and DME

• “Management exudative conditions with Avastin has been embraced by the ophthalmologic profession without definitive guidelines from clinical trial data. The reality with Avastin is that this really is the larger molecule of the FDA-approved version, Lucentis. Off-label use gives the patient the opportunity to utilize the medication at fraction of the cost of the FDA-approved version. The benefits have been shown to be equal and short of any side-effects.”


Comparative Study of Intravitreal Bevacizumab (Avastin) versus Ranibizumab(Lucentis) in the Treatment of Neovascular Age-Related Macular DegenerationOphthalmologica (2009) 223:370-375Aims:Retrospective analysis of safety + efficacy of bevacizumab (Avastin) vs ranibizumab (Lucentis) in the treatment of nvAMD

Methods:Primary outcome measures were:

• Best-corrected visual acuity (BCVA) • Central foveal thickness (CFT) assessed by SD-OCT

Results:• Bevacizumab group included 184 injections (average of 4.7 per eye) • Ranibizumab group included 187 injections (average of 5.5 per eye)• Mean logMAR BCVA at 1 month improved by 0.18 in the bevacizumab group (p=0.009) and by 0.13 in the

ranibizumab group (p=0.004). • Mean CFT decreased 7.7% in the bevacizumab group (p=0.016) and 5.9% in the ranibizumab group (p=0.017).

Conclusions:• Bevacizumab and ranibizumab treatments resulted in similar gains in BCVA and reduction in CFT• Intravitreal bevacizumab appears to be as safe and effective as intravitreal ranibizumab in the treatment

of exudative AMD


Peer-Reviewed Off-Label

Medications

Anti-infectives• 4th generation fluoroquinolones• Topical ganciclovir (Zirgan 0.15%)• Povidone iodine (Betadine 5%)• Topical azithromycin (Azasite 1%)*


Off-Label Medication Use4th Generation Fluoroquinolones

FDA-approved for:• bacterial conjunctivitis

MOA: Direct inhibition of DNA synthesis by targeting 2 bacterial enzymes (DNA gyrase and topoisomerase) responsible for notching, coiling and sealing during replication

Off-label uses identified in the literature include:• Bacterial keratitis• Corneal ulcers • Pre- and post-surgical prophylaxis of infection


Fourth Generation Fluoroquinolones: New Weapons in the Arsenal of Ophthalmic AntibioticsAm J Ophthalmol (2002)133:463– 466.PURPOSE: Differences in the susceptibility patterns and the potencies of 4th generation FQs (gatifloxacin-GAT and moxifloxacin-MOX) were compared with 3rd generation (levofloxacin-LEV) and 2nd generation FQs (ciprofloxacin-CIP and ofloxacin-OFX).

METHODS: Minimum inhibitory concentrations (MICs) of 93 bacterial endophthalmitis isolates were determined to CIP, OFX, LEV, GAT, and MOX using E-tests. The National Committee of Clinical Laboratory Standards (NCCLS) susceptibility patterns and the potencies of the MICs were statistically compared.

RESULTS: With in vitro tests, Staph aureus isolates that were resistant to CIP and OFX were statistically most susceptible (P=.01) to MOX. Coagulase negative Staphylococci that were resistant to CIP and OFX were statistically most susceptible (P=.02) to MOX and GAT. Strep viridans were more susceptible (P=.02) to MOX, GAT, and LEV than CIP and OFX. Strep pneumoniae was least susceptible (P=.01) to OFX compared with the other FQs. Susceptibilities were equivalent (P=.11) for all other bacterial groups. In general, MOX was the most potent FQ for gram (+) bacteria (P=.05) while CIP, MOX, GAT, and LEV demonstrated equivalent potencies to gram (-) bacteria.

CONCLUSIONS: This in vitro study indicated that 4th generation FQs appear to cover bacterial resistance to the 2nd and 3rd generation FQs, were more potent than the 2nd and 3rd generation FQs for gram (+) bacteria, and are equally potent for gram (-) bacteria. Clinical studies will need to confirm these results.


Off-Label Medication UseTopical Ganciclovir (Zirgan 0.15%)

Ganciclovir is FDA-approved for:• herpetic keratitis

MOA: inhibition of the viral DNA replication by selective polymerase inhibition

Off-label uses identified in the literature include:• Adenoviral keratoconjunctivitis

• Epidemic keratoconjunctivitis (EKC)• Pharyngoconjunctival fever (PCF)


Antiadenoviral effects of ganciclovir in types inducing keratoconjunctivitis by quantitative polymerase chain reaction methodsClin Ophthal (2014) 8:315-320Purpose: Most common external ocular viral infections are caused by several human adenovirus (HAdV) types. Ganciclovir has been reported to inhibit CMV, HSV types 1 and 2, VZV and Epstein–Barr virus. Ganciclovir ophthalmic gel, 0.15% (Virgan®) is commercially available for CMV or HSV keratitis. We investigated the in vitro anti-HAdV activity of ganciclovir in several common types currently inducing keratoconjunctivitis.

Materials and methods: Adenovirus types 3 (HAdV3; species B), 4 (species E), and 8, 19a, and 37 (species D) were used. After treatment with serial dilutions of ganciclovir for 24 hours, adenovirus was cultured for 7 days and adenoviral DNA was quantitatively measured by real-time PCR

Results: The 50% cytotoxic concentration of ganciclovir was 212 mg/mL. The 50% effective concentration of ganciclovir obtained by real-time PCR ranged between 2.64 and 5.10 mg/mL. A significant inhibitory effect of ganciclovir on adenoviral proliferation was found in all types in a dose-dependent manner. The selectivity index of ganciclovir ranged between 41.6 and 80.3.

Conclusion: Ganciclovir showed significant inhibitory activity against HAdV3, 4, 8, 19a, and 37 which induce epidemic keratoconjunctivitis. These results indicate that ganciclovir is a possible candidate for the treatment of HAdVkeratoconjunctivitis ©2019 Alltech, Inc. All rights reserved.

Off-Label Medication UsePovidone Iodine (Betadine 5%)

FDA-approved for:periocular region preparation and irrigation of the ocular surface and often used for the prevention and treatment of skin infections and the treatment of wounds

MOA: free form iodine rapidly penetrates microbial cell membranes and oxidizes proteins, nucleotides and fatty acids in the cytoplasm and cytoplasmic membrane.

Off-label uses identified in the literature include:• adenoviral keratoconjunctivitis

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Treatment of Epidemic Keratoconjunctivitis with 2% povidone–iodineJ Ocular Pharm Therapeutics (2012) 28(1), 53-58.

Purpose:Analyze the outcome of treating epidemic keratoconjunctivitis (EKC) with 2% povidone–iodine (PVP-I) solution.

Methods:PVP-I was applied to the affected eyes 4 times a day for a week. Data collection included history, symptoms, and signs at the initial presentation and at 1 week. Main outcomes were the recovery rate within a week of treatment and drug tolerability.

Results:Of 172 enrolled, 61 participants completed the study. EKC occurred bilaterally in 40 participants (66%). Single eye from each participant was included for analysis. Time elapsed before treatment was 2.1 (1.46) days and recovery rate within 1 week of treatment was 77% (95% CI, 65.1–85.8). Twenty-eight participants (45.9%) recovered within a 1 week after the onset. Application of PVP-I was sustained until recovery or completing a 7-day trial in 78.7%. No severe ocular or systemic adverse effects have been reported related to this treatment.

Conclusions:Ocular application of 2% PVP-I was tolerable. This measure successfully relieved ocular discomfort from EKC in 79% of the study group within 1 week. A randomized, controlled trial is required to verify the benefit of this measure.


Off-Label Medication UseTopical Azithromycin (Azasite 1%)

FDA-approved for:• Bacterial conjunctivitis • 1st commercially available ophthalmic formulation of azithromycin

MOA: Interferes with bacterial protein synthesis by binding to the 50S subunit of the ribosome inhibiting translation of mRNA. Nucleic acid synthesis is not affected

Off-label uses identified in the literature include:• blepharitis by decreasing pro-inflammatory mediators and

MMP-9 inhibition

• Proprietary mucoadhesive delivery system called DuraSite®• stabilizes and sustains the release to the ocular surface• solubilizes azithromycin at a high concentration and • slows the drug loss by releasing the drug over a period of time

in a predictable manner©2019 Alltech, Inc. All rights reserved.

Efficacy of topical azithromycin ophthalmic solution 1% in the treatment of posterior blepharitisAdv Therapy (2008) 25:858PURPOSE: Comparison the efficacy of topical azithromycin ophthalmic solution 1% (Azasite) combined with warm compresses to warm compresses alone in patients with posterior blepharitis

METHODS:Twenty-one patients diagnosed with posterior blepharitis were randomized in an open-label study to receive either azithromycin plus warm compresses (10 patients), or compresses alone (11 patients). All patients were instructed to apply compresses to each eye for 5–10 minutes twice daily for 14 days. Each eye in the treatment group used Azasite BID for the first 2 days followed by once daily for the next 12 days.

RESULTS:Twenty patients completed the study. At visit 2, patients in the Azasite group demonstrated significant improvements in MGD, MG secretions, and eyelid redness as compared with the compress group. In the Azasite, MGD resolved completely in 3 patients and MG secretion returned to normal in 2 patients; no such results were seen in the compress group. Furthermore, a higher percentage of patients in the Azasite group rated overall symptomatic relief as excellent or good.

CONCLUSION:Azithromycin ophthalmic solution in combination with warm compresses provided a significantly greater clinical benefit than warm compresses alone in treating the signs and symptoms of posterior blepharitis.


Off-Label Medication Use – A Cautionary Tale of Improper Marketing Topical Azithromycin (Azasite 1%)JUNE 17, 2015 5:11PMMerck to pay $5.9 million for misleading marketing of pink eye drug

NEW YORK (Reuters) - Merck & Co Inc has agreed to pay $5.9 million to resolve claims that a former unit fraudulently promoted a drug used to treat pink eye for unapproved purposes, U.S. authorities announced on Wednesday. Manhattan U.S. Attorney Preet Bharara said Inspire Pharmaceuticals, which Merck acquired in 2011 and later sold, promoted its drug AzaSite to healthcare providers for uses the FDA had not approved as safe and effective. While the FDA had approved AzaSite for treating bacterial conjunctivitis, Inspire sought more revenue by marketing the drug for the non-approved treatment of another eye condition, blepharitis, according to a lawsuit.

The lawsuit said that from 2008 through May 2011, Inspire misleadingly marketed to doctors purported anti-inflammatory properties of AzaSite that were not supported by substantial evidence or clinical experience. The marketing caused doctors to prescribe AzaSite for uses not covered by federal healthcare programs, which paid millions of dollars in false claims, the lawsuit said. As part of the settlement, which will go to the United States and various state governments, Inspire made several admissions related to its conduct, Bharara’s office said.

Lainie Keller, a Merck spokeswoman, said the company was “glad to put this behind us,” adding that the conduct at issue occurred prior to Merck acquiring Inspire, which it later sold to Akorn Inc in 2013. The case is U.S. v. Inspire Pharmaceuticals Inc, U.S. District Court, Southern District of New York, No. 10-7450.



Medications

Anti-inflammatory / Immunosuppressant • Prenisolone acetate 1.0%• Difluprednate (Durezol 0.05%) • Topical NSAIDs• Cyclosporine (Restasis 0.05%)


Off-Label Medication UseTopical corticosteroids


Off-Label Medication UseTopical prednisolone acetate (Pred Forte 1%)

FDA approved for:• inflammation of the palpebral and bulbar conjunctiva,

cornea and anterior segment of the globe• 1st FDA label received in 1975

MOA: Disrupt the inflammatory cascade by immobilizing arachidonic acid, downregulating cytokine pathways (including the VEGF), stabilizing cell membranes and mast cell granules, inhibiting leukocyte interaction and slowing diapedesis.

** Emerging evidence of that corticosteroids also effect gene expression involving inflammation, angiogenesis, oxidative stress and apoptosis

Off-label uses identified in the literature include:• moderate to severe dry-eye syndrome


Topical 0.1% prednisolone lowers nerve growth factor expression in keratoconjunctivitis sicca patientsOphthalmology (2006) 113(2):198-205PurposeTo compare nerve growth factor (NGF) levels on the ocular surfaces of normal control and non–Sjögren’s KCS subjects and to investigate the effect of topical 0.1% prednisolone on NGF levels in KCS patients.

MethodsProspective, double-masked, comparative RCT utilizing 41 KCS patients and 23 matched controls. subjects.Baseline tear NGF levels were measured using enzyme-linked immunosorbent assays. KCS patients received 0.1% prednisolone drops in one eye and 0.1% hyaluronic acid drops in the other TID for 28 days. Impression cytology and immunostaining for NGF on conjunctival epithelium were performed on both groups.

ResultsKCS patients were found to have baseline tear NGF concentrations higher than matched controls (P<0.0001). In KCS patients, prednisolone treatment for 28 days resulted in a decrease in tear NGF levels, symptom scores, and IC scores, whereas hyaluronic acid treatment had no such effect. Measurements taken at both 14 and 28 days indicated that neither prednisolone nor hyaluronic acid treatment affected breakup time or Schirmer values.

ConclusionKCS patients showed elevated levels of tear NGF which were decreased by treatment with 0.1% prednisolone. Ocular surface NGF may play an important role in ocular surface inflammation processes associated with dry eyes.


Off-Label Medication UseDuflurprednate suspension (Durezol 0.05%)

FDA-approved synthetic steroid indicated for: • post-surgical inflammation

MOA: Disrupt the inflammatory cascade by immobilizing arachidonic acid, downregulating cytokine pathways (including the VEGF), stabilizing cell membranes and mast cell granules, inhibiting leukocyte interaction and slowing diapedesis.

**Emerging evidence of that corticosteroids also effect gene expression involving inflammation, angiogenesis, oxidative stress and apoptosis

Off-label uses identified in the literature include:• Iritis and uveitis with underlying systemic association

(Crohns and IBD)• Central retinal ischemic conditions

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Difluprednate 0.05% versus Prednisolone Acetate 1% for Endogenous Anterior Uveitis - Pooled Efficacy Analysis of Two Phase 3 StudiesOcular Immun and Inflamm (2019) 27:3, 484-496

Purpose: To analyse pooled data from 2 similar phase 3 non-inferiority studies comparing difluprednate 0.05%versus prednisolone acetate 1% in patients with endogenous anterior uveitis.

Methods: Patients received difluprednate alternating with vehicle or prednisolone acetate for 14 days (8 drops/day in both groups), followed by tapering from day 14 to 28. All patients were observed until day 42.

Results: More patients on difluprednate than on prednisolone acetate were cleared of A/C cells on day 21 (71.3% vs 54.7%; p = 0.02); results were similar at the other time points. Treatment withdrawals were higher with prednisolone acetate than difluprednate (19.8% vs 7.4%; log-rank p = 0.02). Study discontinuation due to lack of efficacy was also higher with prednisolone acetate than difluprednate (14.0% vs 0%; p = 0.0002 [pre-specified exploratory analysis]).

Conclusions: More difluprednate-treated eyes were quiet following 21 days of treatment, and difluprednate-treated patients were much less likely to be withdrawn from the study because of treatment failure.


Off-Label Medication UseTopical Non-steroidal Anti-Inflammatory Drugs (NSAIDs)


Off-Label Medication UseTopical Non-steroidal Anti-Inflammatory

FDA-approved for:• pain and inflammation associated with cataract surgery

MOA: Inhibition of cyclooxygenase enzymes (COX-1 or COX-2) activity and disruption in the synthesis of key inflammatory (prostaglandins) and clotting (thromboxanes) mediators

Off-label uses identified in the literature include:• Allergic conjunctivitis, DES and CME


The Use of Topical Steroids and NSAIDs in the treatment of Diabetic Macular EdemaInvest Ophthal Vis Sci (2020) 61:4884 Purpose :Investigation of the use of topical steroid and NSAID drops in the treatment of DME to either delay intravitrealinjections or to replace the need for them.

Methods :Retrospective chart review of retina patients at LSU Health Care Network. Charts were collected using ICD-10 codes for both NPDR and PDR associated with macular edema in type 1 and type 2 diabetics. Data was collected at baseline, 1 month, and 3-6 months after initiation of therapy. BCVA change, central macular thickness on OCT and degree of retinopathy were documented at each subsequent visit. Treatment failure was defined as worsening of CMT>20 microns or involvement of alternate therapy options.

Results:A total of 39 eyes met criteria. Eighty-seven percent (n= 34) had follow up at 1 month, 77% (n=30) had follow up at 3-6 months. The CMT at the baseline visit compared to the 4-week follow up visit (34 eyes) showed an improvement in 35%, and worsening in 32% of patients, with 26% of patients failing treatment. At the 3-6 month visit, 40% (30 eyes) improved, 23% worsened, and 7% failed treatment when compared to baseline.

Conclusions :Our project demonstrates a viable alternative to intravitreal injections for those patients who are either unable to or choose not to commit to intravitreal injections in the treatment of DME.


Off-Label Medication UseTopical Cyclosporine (Restasis 0.05%)

FDA-approved for:• keratoconjunctivitis sicca and DES

MOA: Calcineurin inhibitors that binds to lymphocytes preventing activation IL-2 which inhibits T-cell-mediated immune responses.

Myriad of off-label uses identified in the literature to include:• Uveitis• post-surgical dryness• atopic keratoconjunctivitis / vernal keratoconjunctivitis• PKP rejection prevention• Thygeson’s keratitis, • superior limbic keratoconjunctivitis (SLK)• herpetic stromal keratitis



Medications

• Mucolytic agents (Acetylceysteine)

• Anti-Glaucoma • Alpha Adrenergic Agonists • Carbonic Anhydrase Inhibitors • Beta-blockers


Off-Label Medication UseMucolytic Agents (Mucomyst** 10% or 20%)

FDA-approved as: • mucolytic agent in bronchiopulmonary conditions

MOA: decreasing free radicals and inhibition of inflammatory factors

**NAC is thought to increase GSH concentrations by replenishing intracellular cysteine levels

Off-label uses identified in the literature include:• vernal and giant papillary conjunctivitis and • filamentary keratitis **prepared for topical ocular use by diluting the commercial preparation to 2% to 5% with artificial tears


Efficacy of topical N-acetylcysteine as a multicomponent treatment for severe dry eye syndrome J Ophthal (2020) 3:494

Purpose:To assess the efficacy of topical 5% N-acetylcysteine as a part of multicomponent treatment for severe DES associated with increased mucin production

Methods: Record review of 15 patients examined and treated for severe DES. At baseline, there was biomicroscopic evidence of mucous discharge in the conjunctival fornix, corneal epitheliopathy in the form of punctate fluorescein staining, and desquamated epithelium consistent with severe DES.

Results: After 3 months of topical 5% NAC, 86.6% of patients reported tolerance to the drug and improvement of subjective symptoms along with biomicroscopic evidence of a reduced conjunctival signs and decreased epithelial desquamation. Mean Schirmer’stest increased from 3.4±2.3 to 5.0±1.7mm and TBUT values increased from 4.2±2.6s to 6.4±1.7s, respectively. Conjunctival impression cytology showed the presence of mucin substance with diffused, differentiated epithelial cells without signs of degeneration and adequate superficial conjunctival epithelial cell layer.

Conclusions: Topical 5% N-acetylcysteine QID as a part of multicomponent treatment showed a substantial mucolytic effect for severe DES resulting in the development of an adequate superficial conjunctival epithelial cell layer. Findings of this study allow us to recommend topical 5% N-acetylcysteine for severe DES patients with increased viscous mucin in the conjunctival fornix


Oral guaifenesin for treatment of filamentary keratitis - pilot studyOcular Surface (2018) 17(3):565-570.Purpose:Pilot study to evaluate the safety and efficacy of oral guaifenesin in reducing the signs and symptoms of filamentary keratitis

Methods: Prospective, uncontrolled open-label pilot study. Twelve patients with non-Sjögren dry eye disease (DED) and secondary filamentary keratitis received treatment with oral guaifenesin 600 mg BID for 4 weeks. Adverse events, change in the number of corneal filaments, corneal fluorescein staining (NEI grading system) and symptoms (Ocular Surface Disease Index) were assessed

Results: Before starting oral guaifenesin, all patients were on topical medical therapy for their condition. After 4 weeks of treatment, the number of filaments decreased from 5.8 ± 2.9 to 2.1 ± 2.2 (p=0.04), CFS score decreased from 7.3±3.2 to 6.5±3.1 (p=0.5), and OSDI score decreased from 55.6±25 to 46.1±31 (p = 0.2). One patient discontinued the medication due to gastrointestinal side effects.

Conclusions: Oral guaifenesin was safe and generally well tolerated and demonstrated modest efficacy in reducing the severity of filamentary keratitis. Placebo-controlled investigations would be justified to evaluate the therapeutic efficacy of oral guaifenesin as a mucolytic in treatment of filamentary keratitis

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Off-Label Medication UseAlpha-Adrenergic Agonists (Apraclonodine)

FDA approved for:• control or prevention of postsurgical IOP in patients

following argon laser trabeculoplasty, argon laser iridotomyor Nd:YAG posterior capsulotomy

MOA: reduction of aqueous flow via stimulation of the alpha-adrenergic system

Off-label uses identified in the literature include:• Mild ptosis (including botulism injection-induced) • DDx of Horner’s syndrome

• Weak direct action on alpha-1 receptors with minimal to no clinical effect on normal pupils

• Horner’s patient have alpha-1 receptor denervation making the pupil dilator hyper-responsive to apraclonidine


Upper Eyelid Resposne to Topical 0.5% AproclonidineOphthal Plast Reconstr Surg (2018) 34:13-19Purpose: To describe the change in upper eyelid position in a self-reportedly normal population after the administration of topical 0.5% apraclonidine in each eye.

Methods: One hundred self-reportedly normal subjects received a 1-time administration of topical 0.5% apraclonidine in each eye. Digital photographs were taken at baseline and then 30 and 45 minutes following apraclonidineinstillation. Marginal reflex distance was determined via image analysis of acquired digital photographs. The horizontal corneal diameter was used as a constant measurement scale in each photograph.

Results: The mean increase in i-marginal reflex distance post-administration of 0.5% apraclonidine was +0.70 ± 0.60 mm (range, −0.94 to +2.66 mm) after 30 minutes and +0.68 ± 0.59 mm (range, −0.69 to +2.54 mm) after 45 minutes. Of the 200 total eyelids in 100 subjects, 181 (90.5%) had an increase in i-marginal reflex distance at 30 minutes. Of the 100 subjects, 85 (85%) had a bilateral increase in i-marginal reflex distance, 4 (4%) had a bilateral decrease, and 11 (11%) had a unilateral increase with a contralateral decrease.

Conclusions: Given its predominant small-amplitude upper eyelid elevating effect, topical apraclonidine may be a useful off-label alternative treatment for mild upper eyelid ptosis and in eyelid asymmetry due to eyelid retraction through use in the contralateral eye.. ©2019 Alltech, Inc. All rights reserved.

Off-Label Medication UseAlpha-Adrenergic Agonists (Brimonidine)

FDA approved for:• reduction of elevated IOP in patients with primary open-angle

glaucoma or ocular hypertension.

MOA: both reduces aqueous humor production and stimulates aqueous humor outflow through the uveoscleral pathway (Toris et al 1995).

Off-label uses identified in the literature include:• Glare• Conjunctival hyperemia• Reduction in ischemic injury following BRVO and CSME


Effect of brimonidine tartrate 0.15% on night-vision difficulty and contrast testing after refractive surgery Cataract & Refractive Surg (2008) 34(9), 1538-1541.Purpose: To evaluate the efficacy of brimonidine tartrate ophthalmic solution 0.15% in patients with night-vision difficulties after laser refractive surgery.

Methods: Six patients with significant night-vision complaints after refractive surgery were enrolled in this study after other treatable causes of night-vision difficulty such as residual refractive error and dry eye were excluded. Low-contrast visual acuity (LCVA) over a range of contrasts (1.25% to 25%) and small letter contrast sensitivity were tested at photopic (100 cd/m2) and mesopic (1 cd/m2) luminance levels, with and without a standard glare source. Measurements were repeated 1 hour and 1 month after the use of brimonidine tartrate.

Results: One hour after using brimonidine tartrate 0.15% solution, patients had significant improvement in LCVA, LCVA with glare, and contrast sensitivity. After 1 month of treatment, all 6 patients reported subjective improvement in night vision and there was a significant difference in performance in mesopic LCVA and mesopic LCVA with glare. The mean pupil size before administration of brimonidine tartrate ophthalmic solution 0.15% was 6.44 mm ± 1.11 (SD). Pupil size 1 hour after instillation had decreased to 4.53 ± 1.27 mm and at 1 month had increased to 6.50 ± 0.94 mm.

Conclusions: Brimonidine tartrate ophthalmic solution 0.15% improved contrast sensitivity and acuity and decreased night-vision difficulty for up to 1 month in patients with significant complaints after refractive surgery


Effect of brimonidine tartrate 0.15% on scotopic pupil size and upper eyelid position: controlled trial.Eye (2020) 1-4.Purpose: Evaluate the effect of brimonidine tartrate 0.15% ophthalmic solution on pupil size under scotopic condition and upper eyelid position

Methods: Seventy-two eyes of 36 healthy subjects used a single drop of brimonidine tartrate 0.15% ophthalmic solution in the right eye and artificial tear was instilled in the left eye. Pupil size was measured using an infra-red pupillometer under scotopic condition before and at 30 min, 2, 4, 6, 8 and 10 h after instillation. Measurement of margin reflex distance was performed using a millimeter ruler before and after at 10 min after instillation.

Results: Mean age of the subjects was 32.19 ± 11.43 years (range 10–52 years), 17 were female and 19 were male. Before brimonidineinstillation, the mean pupil size was 6.09 ± 1.03 mm in the brimonidine eyes and 6.06 ± 1.04 mm in the control eyes. There was a significant decrease in mean pupil size at 30 min (4.45 ± 1.04), 2 h (4.49 ± 1.06), 4 h (4.59 ± 1.06), 6 h (4.89 ± 1.06) and 8 h (5.38 ± 1.02) after instillation compared to before in brimonidine eyes (p < 0.001 for all). There was a significant miosiscontinued for at least 6 h (5.95 ± 1.03) in control eyes (p < 0.001). There was no significant change in MRD1, before and after instillation both in brimonidine and control eyes.

Conclusions: Brimonidine tartrate 0.15% had a significant miosis under scotopic condition for at least 8 h after instillation and had a significant miosis on the untreated eye for at least 6 h.


Experimental and clinical evidence for brimonidine as an optic nerve and retinal neuroprotective agent: an evidence-based reviewArchives of Ophthalmology (2009)127(4), 402-406.ObjectiveReview the available evidence for the neuroprotective qualities of brimonidine tartrate in optic nerve and retinal injury. References for this study were obtained by running a search of the PubMed database using keywords brimonidine, neuroprotection, ischemic optic neuropathy, and α2-adrenergic agonists. References focusing on ocular hypertension were excluded.

ResultsForty-eight articles addressing 1 of 4 criteria for neuroprotection were included. The literature confirms that brimonidinetherapy meets the first 3 criteria for neuroprotection: receptors on its target tissues, adequate penetration into the vitreous and retina at pharmacologic levels, and induction of intracellular changes that enhance neuronal resistance to insults or interrupt apoptosis in animal models. Brimonidine did not meet the final neuroprotective criterion of success in humans.

ConclusionsExperimental evidence has demonstrated that brimonidine is a potential neuroprotective agent. However, to date, clinical trials have failed to translate into similar efficacy in humans.

** To be deemed neuroprotective, an agent must meet the following 4 criteria: (1) receptors on its target tissues such as the optic nerve or retina, (2) adequate penetration into the vitreous and retina at pharmacologic levels, (3) induction of intracellular changes that enhance resistance to insult or interrupt apoptosis in animal models (4) demonstration of similar efficacy in clinical trials


Off-Label Medication UseCarbonic Anhydrase Inhibitors (Dorzolamide 2%)

FDA approved for:• Treatment of high IOP due to open-angle glaucoma or

ocular hypertension

MOA: Catalyzes the reversible reaction involving the carbonic anhydrase isoenzyme II CA-II)

Inhibition of CA-II in the eye decreases aqueous humor secretion by slowing Na2+ and fluid transport

Off-label uses identified in the literature include:• CME related to RP, Usher’s, choroidemia and

chemotherapy toxicity• CSC


Topical dorzolamide therapy for taxane-related macular edema.Eye (2013) 27(1), 102-104.Case reportA 59-year-old female with metastatic breast cancer presented with decreased vision following paclitaxel–NAB infusion. The visual acuity was 20/50 in both eyes. Fundus examination and diagnostic testing revealed bilateral non-leaking CME. A monocular trial of dorzolamide 2% TID was initiated in the OD. Paclitaxel–NAB was also stopped. Two weeks later, OCT showed marked reduction of CME (−114 μm) in the treated eye compared with the fellow eye (+28 μm). Given the improvement, bilateral dorzolamide was initiated. One month later, near-complete resolution of CME was noted in both eyes with visual acuity improvement to 20/20.

This report suggests a possible therapeutic efficacy for topical carbonic anhydrase inhibitors in the treatment of taxane-induced CME. Topical dorzolamide has been reported to decrease edema for non-leaking CME from other conditions (eg, retinitis pigmentosa, X-linked retinoschisis, Usher’s syndrome). Although systemic acetazolamide has also been reported for treating taxane-related CME, topical dorzolamide may be a useful treatment alternative given its limited systemic side effects. This report highlights the importance of ophthalmic evaluation of patients with visual complaints during chemotherapy. ©2019 Alltech, Inc. All rights reserved.

Efficacy of topical carbonic anhydrase inhibitors in reducing duration of chronic central serous chorioretinopathy.Translational Vision Science & Technology (2020) 9(13), 6-6.Purpose:Topical CAIs can influence retinal fluid distribution, but their role in treating CSCR)has not been studied. We examined the efficacy of a topical CAI (dorzolamide) in treating chronic CSCR.

Methods:Prospective, nonrandomized, controlled intervention study of patients with chronic CSCR of at least 3 months duration. Observed controls (n = 15) were recruited consecutively from 2016 to 2017; treated cases (n = 18) were recruited from 2018 to 2019. Controls were observed without active intervention, whereas treated cases were treated with topical dorzolamidefor 3 months. The study end points were change in central macular thickness (CMT), change in best corrected visual acuity (BCVA), and proportion of eyes achieving complete resolution of subretinal fluid (SRF). All end points were at 3 months.

Results:Patients who received topical CAI had greater reduction in CMT (−145.6 µm) compared to observed controls (−45.1 µm) at 3 months (P = 0.015). A higher proportion of treated patients achieved complete resolution of SRF compared to observed controls (77.8% vs. 40.0%, P = 0.04) at 3 months. However, change in BCVA at 3 months was similar in both groups (P = 0.12).

Conclusions:Topical CAI resulted in more rapid reduction of CMT compared to observation. These results, if confirmed in other studies, suggest topical CAI may be a viable treatment option for patients with chronic CSCR.

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Off-Label Medication UseBeta-blockers (Timolol 0.5%)

FDA approved for:• Treatment of elevated intraocular pressure in patients

with ocular hypertension or open-angle glaucoma

MOA: blockade of beta-2 receptors in the blood vessels leads to a decrease in peripheral vascular resistance reducing blood pressure and likely decreases the secretion of aqueous humor in the eye

Off-label uses identified in the literature include:• Migraine management• Pediatric hemangiomas


Timolol eye drops in the treatment of acute migraine attacks: Randomized crossover studyJAMA Neurology (2018) 75(8), 1538-1541.Purpose: To evaluate timolol 0.5% eye drops in the treatment of acute migraine

Methods: Participants ≥ 18 years old were randomized to receive timolol maleate 0.5% or artificial tears at 1 drop in both eyes at onset and 30 minutes after. Four 50-μL drops of timolol, 0.5%, represent 1 mg of timolol, which compares with an oral prophylactic dos-age of 10 to 30 mg of timolol daily. Participants were seen monthly for 5 visits over 4 months and crossed over at the 2-month mark with a 3-day washout period. A data sheet for each migraine instructed participants to rate their migraine attacks on a scale of 0 to 3 in terms of severity. At the conclusion of the study, the participants were also asked to rate the effectiveness of each drop on a scale of 1 to 4 to decide whether they would use the timolol in place of or in addition to current treatments. The aim of this pilot study was to determine the effect size of timolol on migraine headaches.

Results: Total of 198 migraine attacks were studied among 10 participants. The overall effectiveness of timolol was 2.4 compared with 1.4 with the placebo. Four participants found timolol highly effective compared with placebo while 1 participant found the opposite. The average percentage of headaches with a severity of none or mild at 2 hours was 57% with placebo compared with 78% with timolol. No adverse events, including hypotension or bradycardia, were observed. Power analysis suggests that 172 randomized participants or 86 cross-over participants would be needed to achieve statistical significance.

Conclusions: Topical timolol 0.5% is an effective abortive treatment for some patients with migraines. Future research should focus on identifying which patients will respond and at what dosage.


Topical Timolol Maleate Treatment of Infantile HemangiomasPediatrics (2016) 138(3): 1-11.BACKGROUND: Off-label use of ophthalmic timolol maleate, a β-blocker used for infantile hemangioma (IH) treatment as a topical counterpart to oral propranolol. Our goal was to retrospectively assess timolol’s effectiveness, discern characteristics associated with response, and document reported adverse events.

METHODS: A multicenter retrospective cohort study of 731 patients treated with topical timolol was completed at 9 centers. Inclusion required an IH suitable for timolol in the treating physician’s judgment and access to clinical details including photographs. Primary outcome measures were efficacy assessed by using visual analog scales for color and for size, extent, and volume from review of digital photographs taken as standard of care.

RESULTS: Most IHs were localized (80.1%) and superficial (55.3%). Risk of disfigurement was the most common indication for therapy (74.3%). Duration of therapy (P < .0001), initial thinness (P = .008), and subtype (P = .031) were significant predictors of response. Best response occurred in superficial IHs <1 mm thick. Fifty-three (7.3%) required subsequent therapy with systemic β-blocker. Adverse events were mild, occurring in 25 (3.4%) patients. No cardiovascular side effects were documented.

CONCLUSIONS: Timolol seems to be a well-tolerated, safe treatment option with moderate to good effectiveness, demonstrating best response in thin, superficial IHs regardless of pretreatment size. Timolol can be recommended as an alternative to systemic β-blockers and watchful waiting for many patients.


Topical Timolol Maleate Treatment of Infantile HemangiomasPediatrics (2016) 138(3): 1-11.


Off-Label Medication UseBeta-2 blocker + CAI (Timolol 0.5% + Dorzolamide 2%)

FDA approved for: • reduction of elevated IOP in open-angle glaucoma or ocular

hypertension who are insufficiently responsive to beta-blockers.

MOA: blockade of beta-2 receptors in the blood vessels leads to a decrease in peripheral vascular resistance reducing blood pressure and likely decreases the secretion of aqueous humor in the eye

Off-label uses identified in the literature include:Macular edema managementRecalcitrant migraine


Effect of Adjuvant Topical Dorzolamide-Timolol vs Placebo in NeovascularAge-Related Macular Degeneration - Randomized Clinical TrialJAMA Ophthalmol (2020) 138(5):560-567Purpose: To compare the short-term effect of topical dorzolamide-timolol vs placebo in eyes with neovascular AMD that have persistent exudation following intravitreal anti-VEGF injections

Methods: Multicenter, randomized placebo‐controlled clinical trial enrolling 52 nvAMD patients who had persistent exudation despite intravitreal anti‐VEGF injections at 4‐week, 5‐week or 6‐week intervals. Patients were randomized to use dorzolamide‐timolol or artificial tears for the study duration. Anti‐VEGF intervemtions were continued at the same intervals.

Results: All 27 patients (100%) assigned to dorzolamide-timolol and 23 of 25 (92%) assigned to placebo were analyzed for the primary outcome. Mean (SD) age was 78.4 (7) years, and 34 of 50 patients (68%) were women. Mean baseline logMAR VA was 0.361±0.26 (approximate Snellen equivalent, 20/50). Comparing the dorzolamide-timolol with placebo group from baseline to visit 3, mean (SD) change in central subfield thickness was −36.6±54μm (treatment) vs 1.7±52.3μm (control), maximum PED height was −39.1±65μm (treatment) vs 1.1±16μm (control) and change in VA from baseline to visit 3 was −2.3±5 (treatment) vs 0.3±1 (control) letters

Conclusions: Findings suggest use of dorzolamide‐timolol in patients with nvAMD with persistent exudation resulted in anatomic but not visual acuity improvements compared with placebo at approximately 3 months


Efficacy of adjuvant topical timolol-dorzolamide with intravitreal bevacizumab injection in diabetic macular edema - contralateral eye studyJ Current Ophthal (2019) 31:168-171

Purpose: To assess the efficacy of adjuvant topical timolol-dorzolamide with intravitreal bevacizumab (IVB) injection on anatomic and functional results in eyes affected with diabetic macular edema (DME)

Methods: Interventional prospective contralateral pilot eye study enrolling patients with bilateral DME who were treatment‐naïve. Enrolled patients received a treatment plan of topical timolol‐dorzolamide twice daily in the right eye. Three monthly bilateral IVB injections 1.25 mg/0.05 mL were also planned. Baseline central macular thickness (CMT) was measured by SD‐OCT and BCVA and IOP were collected at enrollment and 1 month after the 3rd injection.

Results: Eleven patients with DME were included. BCVA and CMT improved in both eyes while IOP decreased in OD but did not change in the OS. Repeated measures ANOVA analysis identified the decrease in CMT and improvement in BCVA improvement were statistically significant in the OD

Conclusions: Findings suggested that adjuvant topical timolol‐dorzolamide in combination with IVB may further reduce central macular thickness in eyes with DME.


Topical Aqueous Suppression and Closure of Idiopathic Full-Thickness Macular HolesOphth Surg, Lasers and Imag Retina (2019) 50(2):e38-e43

Abstract:

Hydration of retinal tissue has been proposed as a potential model of macular hole (MH) formation in addition to tractional forces of the vitreous and internal limiting membrane (ILM).

Carbonic anhydrase inhibitors have previously been utilized in the treatment of CME in outer retinal diseases. There has been recent interest in the use of topical aqueous suppression as a potential medical therapy for MHs.

In this case series, four eyes with small (<300 μm) full-thickness MHs were treated with topical dorzolamide-timolol for 1 month. Two eyes achieved closure of the MH without surgical intervention, whereas the other two required pars plana vitrectomy with ILM peel.

Future studies are required to investigate the role of topical aqueous suppression in the management of MHs.



Medications

Oral Medications• Doxcycycline• Atorvastatin 40mg and 80mg• Selenium 100ug BID • L-lysine therapy • Prednisone*

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Off-Label Medication UseOral Doxycycline

FDA approved tetracycline-class antimicrobial indicated for:Plague due to Yersinia pestisCholera caused by Vibrio choleraTrachoma caused by Chlamydia trachomatisInclusion conjunctivitis caused by Chlamydia trachomatisSyphilis caused by Treponema pallidum Prophylaxis of malaria

MOA: inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit

Off-label uses identified in the literature include:Dry eye syndrome Recurrent corneal erosion Meibomian gland dysfunction


Topical azithromycin and oral doxycycline therapy of meibomian gland dysfunction: a comparative clinical and spectroscopic pilot study.Cornea (2013) 32(1), 44.PurposeProspective, observational, open label clinical trial documenting improvement in both clinical signs and symptoms of disease as well as spectroscopic characteristics of the meibomian gland lipids after therapy with topical azithromycin ophthalmic solution and oral doxycycline treatment.

MethodsSubjects with symptomatic MGD were recruited. Signs of MGD were evaluated with a slit lamp and symptoms were measured by the response of subjects to a questionnaire. Meibum lipid-lipid interaction strength, conformation and phase transition parameters and content were measured using Fourier transform infrared spectroscopy (FTIR). Terpenoids, short chain CH3 moieties, lipid oxidation, wax, cholesterylesters and glycerides were measured with a proton nuclear magnetic resonance (1H-NMR) spectrometer.

ResultsTopical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion towards normal. Compared to 4 weeks of azithromycin treatment reported in our previous study, oral doxycycline treatment was slightly less effective in improving foreign body sensation and the signs of plugging and secretion. In subjects with clinical evidence of MGD, tear film lipids were brought closer to normal with azithromycin treatment than doxycycline treatment. Treatment with doxycycline but not azithromycin restored the FTIR scores and relative area of the 1H-NMR resonance. Both doxycycline and azithromycin treatment restored the levels of the relative areas of the 1H-NMR resonance to normal levels. The level of meibum protein and meibum lipid oxidation were not influenced by azithromycin or doxycycline treatment.

ConclusionsThe mechanism of action of doxycycline may be different than that of azithromycin in therapy of MGD. It is notable that when carotenoids in meibum are low, as in MGD, the tear film is unstable and patients have the signs and symptoms of dry eye. When carotenoids are restored with azithromycin and doxycycline treatment, tear film stability is restored and patients no longer have the signs and symptoms of dry eye. ©2019 Alltech, Inc. All rights reserved.

Treatment of recurrent corneal erosion syndrome using the combination of oral doxycycline and topical corticosteroid.Clin Exp Ophthal (2008) 36(1), 8-12.PurposeTo assess the efficacy of the combination of oral doxycycline and topical corticosteroids, both of which have been shown to inhibit key metalloproteinases, in the treatment of recurrent cornel erosion

MethodsRetrospective single-observer case series involving all patients with recurrent corneal erosion syndrome who were treated at a community-based clinic with oral doxycycline and topical corticosteroid between January 2000 and July 2007.Twenty-one patients were identified. All received oral doxycycline 50 mg BID and topical fluoromethalone 0.1% TID for at least 4 weeks.

ResultsAt 8 weeks, 15/21 patients (71%) were symptom free. All but one of these patients reported an improvement in symptoms. Of those patients not lost to follow up, 15/18 patients (83%) and 11/15 patients (73%) denied any symptoms suggestive of relapse at 6 and 12 months, respectively. Among the patients in remission was one who had responded poorly to other treatments including ocular lubricants, epithelial debridement, serum eyedrops, anterior stromal puncture, and phototherapeutic keratectomy.

ConclusionTreatment of recurrent corneal erosion syndrome with the combination of oral doxycycline and topical corticosteroid is effective. It may help patients with recurrent corneal erosion syndrome who have failed other forms of treatment. This non-invasive treatment modality should also be considered as the first treatment option when conservative management with ocular lubricants fails.


Effect of low-dose doxycycline therapy in chronic meibomian gland dysfunction. (2005) Korean J Ophthal 19.4: 258-263PURPOSEInvestigate the effect of low dose doxycycline (20 mg) therapy in patients with chronic meibomian gland dysfunction that were refractory to conventional therapy.

METHODS:Randomized prospective study enrolled 150 patients (300 eyes) with have chronic MGD and without response to lid hygiene and topical therapy for more than 2 months. All topical therapy was stopped for at least 2 weeks prior to beginning the study. Authors randomly divided the patients into 3 groups1) high dose group (doxycycline, 200 mg, twice a day), a 2) low dose group (doxycycline, 20 mg, twice a day) and a 3) control group (placebo). 4) After one month, TBUT and Schirmer tests, and analyzed the degree of symptomatic improvement.

RESULTS:Both the high and low dose group showed statistically significant differences after treatment in TBUT, Schirmer test, the number of symptoms reported and the degree of improvement of subjective symptoms. However, there was no statistically significant difference between the high and low dose group after treatment. The high dose group (18 patients, 39.13%) reported side effects more frequently than did the low dose group (8 patients, 17.39%) (P=0.002).

CONCLUSIONS:Low dose doxycycline (20 mg BID) therapy was effective in patients with chronic MGD that were refractory to conventional therapy


Off-Label Medication UseOral Atorvastatin 40mg and 80mg

FDA approved for:• Risk reduction of MI, stroke and angina in patients with

multiple risk factors including CHD and CHF • Reduce elevated total-C, LDL-C, apo B and TG levels

and increase HDL-C in adult patients

MOA: competitively inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase decreasing cholesterol production in the liver and increasing LDL-C receptors

Off-label uses identified in the literature include:• Decreased atrophic AMD risk

Consider adding Co-Q10 Decreased muscle wasting in statin users


Regression of Some High-risk Features of AMD in Patients Receiving Intensive Statin TreatmentEBioMedicine (2016):198-203Objective:Studying the effects of high-dose statins, similar to those showing regression of atherosclerotic plaques, in AMD.

Design: Pilot multicenter open-label prospective clinical study of 26 patients with diagnosis of AMD and the presence of many large, soft drusenoid deposits. Patients received 80 mg of atorvastatin daily and were monitored at baseline and every 3 months with complete ophthalmologic exam, best corrected visual acuity (VA), fundus photographs, optical coherence tomography (OCT), and blood work (AST, ALT, CPK, total cholesterol, TSH and creatinine).

Results: Twenty-three subjects completed a minimum follow-up of 12 months. High-dose atorvastatin resulted in regression of drusen deposits associated with vision gain (+3.3 letters, p = 0.06) in 10 patients. No subjects progressed to advanced neovascular AMD.

Conclusions: High-dose statins may result in resolution of drusenoid pigment epithelial detachments and improvement in VA, without atrophy or neovascularization in a high-risk subgroup of AMD patients. Confirmation from larger studies is warranted.


Atorvastatin Promotes Phagocytosis and Attenuates Pro-Inflammatory Response in Human RPE CellsScientific reports (2017) 7(1):1-12.

Abstract:Study results show that statins, a well-tolerated class of drugs with rare serious adverse effects, help preserve the phagocytic function of the RPE while also exhibiting anti-inflammatory properties. These characteristics make statins a potential effective medication for the prevention and treatment of AMD. Similar effects were observed when evaluating two other hydrophobic statins, lovastatin and simvastatin.

Results:• Lipophilic statins increase the phagocytic function of ARPE-19 cells• Atorvastatin increases the phagocytic function of ARPE-19 cells in a dose-dependent manner• Atorvastatin increases ARPE-19 cell membrane fluidity• Atorvastatin protects ARPE-19 from impairment of phagocytosis induced by cholesterol crystals and ox-LDL• Atorvastatin inhibits IL-6 and IL-8 secretion induced by cholesterol crystals and ox-LDL in ARPE-19 cells


Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trialsMayo Clinic Proceedings 2015 90(1):24-34)ObjectiveEvaluation of coenzyme Q10 (CoQ10) supplementation efficacy on statin-induced myopathy. A search of MEDLINE, Cochrane Library, Scopus, and EMBASE databases (November 1, 1987, to May 1, 2014) to identify randomized controlled trials investigating the impact of CoQ10 on muscle pain and plasma creatine kinase (CK) activity as 2 measures of statin-induced myalgia.

ResultsWe included 6 studies with 302 patients receiving statin therapy: 5 studies with 226 participants evaluated the effect of CoQ10 supplementation on plasma CK activity, and 5 studies (4 used in the CK analysis and 1 other study) with 253 participants were included to assess the effect of CoQ10 supplementation on muscle pain. Compared with the control group, plasma CK activity was increased after CoQ10 supplementation, but this change was not significant (p=.38). Likewise, CoQ10 supplementation had no significant effect on muscle pain despite a trend toward a decrease (standardized mean difference, –0.53; p=.20). No dose-effect association between changes in plasma CK activity (slope, –0.001; p=.33) or in the indices of muscle pain (slope, 0.02; p=.67) and administered doses of CoQ10 were observed.

ConclusionThe results of this meta-analysis of available randomized controlled trials do not suggest any significant benefit of CoQ10 supplementation in improving statin-induced myopathy. Larger, well-designed trials are necessary to confirm the findings from this meta-analysis. ©2019 Alltech, Inc. All rights reserved.

Off-Label Medication UseSelenium

Supplement not regulated by FDA

MOA: Within the thyroid, selenium is required for antioxidant function and metabolism of thyroid hormones responsible for conversion of T4 to T3 and stability of TSH production in the hypothalamic-pituitary axis

Off-label uses identified in the literature include:• GRASS protocol for decreased proptosis in thyroid eye

disease

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Selenium supplementation for patients with Graves’ hyperthyroidism (GRASS trial): study protocol for a randomized controlled trial. Trials (2013) 14(1), 119.Purpose:• Investigate if selenium supplementation plus standard treatment with anti-thyroid drugs will lead to a decrease in anti-thyroid

drug treatment failure, faster and longer lasting remission and improved quality of life in patients with Graves’ hyperthyroidism.

Methods:• Randomized, blinded, multicenter clinical trial including patients ≥18 years or older with a diagnosis of active Graves'

hyperthyroidism within the last two months• 492 participants, randomized (1:1) to two tablets of 100 μg selenium once daily for the 24 to 30 months intervention period versus

two identical placebo tablets once daily. The • Primary outcome is the proportion of participants with anti-thyroid drug treatment failure at 24 to 30 months• Secondary outcomes are: 1) thyroid-specific quality of life during the first year after randomization

2) TSH-receptor antibody levels levels at 18 months and at 24 to 30 months 3) Hyperthyroid and ocular symptoms at 12 months and at 24 to 30 months

Results:• Both FT4 and FT3 decreased more in the selenium group than the control, while the TSH level increased more in patients receiving

selenium supplementation (p < 0.05). Anti-TSH receptor antibody level was significantly lower in patients receiving selenium supplementation (p = 0.04). The percentages of patients with normal anti-TSH receprot antibody level at 6 months was also significantly higher in the selenium group (19.0 vs. 0 %, p = 0.016). Kaplan-Meier survival curve showed patients receiving selenium supplementation had a significantly higher rate of remission than controls (Log-rank test p = 0.008).

Conclusions:• Selenium supplementation can enhance the effect of antithyroid drugs in patients with Graves’ disease.


Age-related macular degeneration in a randomized trial of selenium and vitamin E in men: the Select Eye Endpoints (SEE) study (SWOG S0000B).Acta ophthalmologica (2020)Abstract:Unavailable


Off-Label Medication UseL-lysine

Supplement not regulated by FDA

Proposed MOA: HSV cells synthesize higher levels of arginine and lower levels of lysine than human host cells. Increasing cellular lysine concentrations disrupts HSV’s balance between lysine and arginine and inhibits viral replication

Off-label uses identified in the literature include:• Adjunctive herpes simplex virus prophylaxis


Lysine for Herpes Simplex Prophylaxis - Review of the EvidenceIntegrated Med (2017) 16(3):42-46

Objective:To summarize the research evidence for use of L-lysine to prevent HSV disease recurrence

Methods/Design:Two scientists conducted a literature search of EMBASE, Medline, AMED, and CINAHL for the expanded terms lysine and herpes simplex or HSV in the title field and then independently screened the abstracts for clinically relevant articles. Disagreements on article inclusion were discussed before the literature was reviewed to see whether lysine is effective for preventing herpes simplex relapse.

Intervention:Oral L-lysine supplements were taken daily.

Results:L-lysine supplementation appears to be ineffective for prophylaxis or treatment of herpes simplex lesions with doses of less than 1000 mg/d without low-arginine diets. Doses ≥3000 mg/d appear to improve patients’ subjective experience of the disease.

Conclusion:Longer duration controlled studies of daily lysine doses exceeding 1200mg/d are required to definitively test its role in herpes simplex prophylaxis. Patients with cardiovascular or gallbladder disease should be cautioned and warned of the theoretical risks of lysine supplementation..


Comprehensive Safety Assessment of L-Lysine Supplementation from Clinical Studies - Systematic ReviewJ Nutr (2020) 150(Supp 1): 2561S-2569S

ObjectiveThe objective of this study was to assess the clinical safety of L-lysine supplementation of a regular diet

MethodsPubMed, Cochrane Library, Ichushi Web, and EBSCOhost search using the relevant keywords, “L-lysine” and “clinical trial” was conducted. To investigate all adverse events observed during intervention trials, we included all intervention studies with orally ingested L-lysine without restricting background factors, environment, study designs, and sample sizes.

ResultsIdentified 71 articles that included 3357 study subjects. The L-lysine doses ranged from 16.8 to 17.5 g/d, and the dosing period ranged from 1 to 1095 d. The observed adverse events were mainly subjective gastrointestinal tract symptoms; however, the risk analysis for incidence of gastrointestinal symptoms was not statistically significant (risk ratio of 1.02).

ConclusionThe provisional no-observed-adverse-effect level in healthy human subjects was based on gastrointestinal symptoms and identified at 6000 mg/d.


Off-Label Medication UseOral Prednisone

FDA approved as an:anti-inflammatory or immunosuppressive agent for certain allergic, dermatologic, gastrointestinal, hematologic, ophthalmologic, nervous system, renal, respiratory, rheumatologic, specific infectious diseases or conditions and organ transplantation

MOA: Decreases inflammation via suppression of the migration of polymorphonuclear leukocytes and reversing increased capillary permeability and suppressing expression of inflammatory mediators

Off-label* uses identified in the literature include:Oral treatment of ON


Effect of Treating Acute Optic Neuritis With Bioequivalent Oral vs Intravenous Corticosteroids: Randomized Clinical TrialJAMA Neurology (2018) 75.6): 690-696

ObjectiveTo compare visual recovery following acute optic neuritis with high-dose IV corticosteroid vs. bioequivalent corticosteroid treatment

Methods• Single-blind RCT with 6-month follow-up was conducted at a single tertiary care center • Patients 18 to 64 presenting within 14 days of acute optic neuritis onset without any recovery at time of randomization and

without history of optic neuritis in the same eye, were screened. • Inclusion criteria included best-corrected visual acuity (BCVA) of 20/40 or worse and corticosteroids deemed required • 55 participants were enrolled and randomized. Primary analysis was unadjusted according to the intention-to-treat principle

InterventionsParticipants were randomized 1:1 to the IV methylprednisolone sodium succinate (1000-mg) or oral prednisone (1250-mg)

Results:• At 1 month and 6 months, P100 latency in the IV group improved by 62.9ms and the oral group improved by 66.7ms with

no significant difference between groups (P =.07)• For BCVA, recovery between the groups did not reach statistical significance at 1 month or 6 months • Improvements in low-contrast BCVA were not significantly different between treatment groups at 1 or 6 months

Conclusions:• Bioequivalent doses of oral corticosteroids may be an alternative to IV corticosteroids to treat acute optic neuritis


Visual outcome is similar in optic neuritis patients treated with oral and i.v.high-dose methylprednisolone: a retrospective study on 56 patientsBMC neurology (2018) 18.1: 1-7Background• To investigate visual recovery after treatment of acute optic neuritis with oral vs IV high-dose methylprednisolone

Methods• Retrospective analysis of patients treated with oral or intravenous high-dose (≥500 mg per day)

methylprednisolone for acute ON of unknown or demyelinating etiology. • Twenty-eight patients were included in each treatment group. • Visual acuity was measured with the Snellen letter chart, pseudo-isochromatic plates and Humphrey Field

Analyzer

Results:• Treatment results were similar in the two groups at follow-up with no significant difference in visual acuity

(p = 0.54), color vision (p = 0.18), visual field mean deviation (p = 0.39) or the number of significantly depressed test points (p = 0.46).

Conclusions:• The results show no clinical disadvantage of using oral high-dose corticosteroids compared to

intravenous administration in the treatment of acute ON which would facilitate the clinical management of these patients.



Medications

Central serous chorioretinopathy treatment• Mineralcorticoid antagonist • Antimycobacterials

Case Report

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Mineralcorticoid antagonists

• Eplerenone (Inspra) – selective aldosterone receptor antagonist (K+ sparing diuretic)• Mineralocorticoid receptor is involved in human ocular chorioretinopathy. J Clin Invest 122.7 (2012):

2672-2679.• 4 patients using 25mg QD x 1 week then 50mg QD x 1-3 months• Significant reduction in SRF, CRT and intraretinal cystic formation

• Mineralocorticoid receptor antagonism treatment of chronic central serous chorioretinopathy: a pilot study. Retina 33.10 (2013): 2096-2102

• 13 patients using 25mg QD x 1 week then 50mg QD x 1-3 months• Significant reduction in SRF, CRT and BCVA at 1 month and 3 months

• Spironolactone (Aldactone) – less selective aldosterone receptor antagonist (K+ sparing diuretic)• Spironolactone in the treatment of central serous chorioretinopathy–a case series. Clin & Exp

Ophthal 252.12 (2014): 1985-1991• 18 subjects using 25mg BID X 1-3 months• Significant improvements in SRF, CRT and BCVA at 3 months

Off-Label Medication UseCentral Serous Chorioretinopathy


Antibiotics• Rifampin (Rifampicin)

• Oral Rifampin treatment for long-standing chronic central serous chorioretinopathy. Clinical & ExpOphthal 254.1 (2016): 15-22

• 12 subjects (14 eyes) using 300mg BID x 3 months• Significant improvements in BCVA, CRT, choroidal thickness. SRF reduced in 9 eyes and resolved in 4 eyes.

• Rifampin for treatment of central serous chorioretinopathy. Invest Ophthal & Vis Sci 52.14 (2011): 2137-2137• Retrospective evaluation of 5 subjects using 300mg BID x 3 months• 3 subjects showed decreased CRT and 2 remained unchanged while 3 subjects showed no BCVA improvement and 2

subjects improved >3 lines • Oral rifampin utilization for the treatment of chronic multifocal central serous retinopathy. Brit J

Ophthal 96.1 (2012): 10-13• Patient with chronic CSR and persistent SRF x 2 years completely resolved using oral rifampin 300mg BID x 1month

**cytochrome P450 induction is thought to favorably alter the metabolism of endogenous steroids

Circadian-rhythm hormone • Melatonin (melatonin receptor 1 + 2 agonist)

• Therapeutic benefit of melatonin in refractory central serous chorioretinopathy. Eye 29.8 (2015): 1036-1045• 8 subjects using 3mg melatonin TID x 1 month• Significant improvements in BCVA and CRT with 3 subjects showing complete resolution

Off-Label Medication UseCentral Serous Chorioretinopathy


Central Serous Chorioretinopathy

• Case Report


Central Serous ChorioretinopathyCase Report • 39YO Caucasian male presented for difficulty focusing with OD at distance and near x 1 week

• Appreciated changes in color vision perception in OD compared to OS and metamorphopsia OD • Denied recent injuries or trauma, flashes/floaters, contact lens wear, recent illness or travel outside

country • LEE: >2 years ago @ civilian practice • FMHx: unremarkable • PMHx: unremarkable • (-) current medications• (+) H/O smoking 2-3 packs/d• NKDA

Distance VAscOD: 20/100 PH: 20/80 and OS: 20/20 OS Pupils: ERRL (-) APD OD, OS EOM: FROM OU w/ (-) pain CVF: FTFC OU Amlser grid: distortion inferior ¾ OD and (-) scotoma or distortion OS PIP I: 10/14 OD and 14/14 OSGAT: 16mmHg OD and 18 mmHg OS


Central Serous ChorioretinopathyCase Report SLE• L/L – unremarkable OD, OS• Conj - unremarkable OD, OS• Cornea - unremarkable OD, OS• A/C – unremarkable OD, OS• Iris - unremarkable OD, OS• Lens - unremarkable OD, OS

DFE• C/D – 0.40/0.40 OD, OS w/ healthy neuroretinal rim and distinct margins OD, OS• Macula – Significant elevation extending temporally from ONH OD / unremarkable OS • Vessels – 2/3 A/V ratio OD, OS• Vitreous – Trace syneresis OD, OS• Periphery – (-) H/T/B OD, OS


Central Serous ChorioretinopathyCase Report #1






Central Serous ChorioretinopathyCase Report #1• Due to the almost 1000um of elevation, a phone call was made to Okinawa ophthalmology clinic

• Murphy’s Law: Both ophthalmologists off-island for the holiday season for the next 2 weeks.

• Referral management recommended consult with Tripler Army Medical Center. A phone call was placed to ophthalmology on-call at the Tripler Army Medical Center happened to be a retinal specialist (anti-Murphy’s Law?)

• Reviewed the patient’s medical record, current encounter and all photos and testing performed

• Recommended 2 capsules of rimfampin 300mg BID for 30 days and F/U after finishing therapy• Suggested FA at that time if there was no improvement

• Patient’s PCM was notified of the treatment and the patient was scheduled for F/U in 30 days

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Central Serous ChorioretinopathyCase Report Distance VAscOD: 20/30 and OS: 20/20 OS Amlser grid: (-) scotoma or distortion OD, OS PIP I: 12/14 OD and 14/14 OSGAT: 15mmHg OD and 15mmHg OS

SLE• L/L – unremarkable OD, OS• Conj - unremarkable OD, OS• Cornea - unremarkable OD, OS• A/C – unremarkable OD, OS• Iris - unremarkable OD, OS• Lens - unremarkable OD, OS

DFE• C/D – 0.40/0.40 OD, OS w/ healthy neuroretinal rim and distinct margins OD, OS• Macula –unremarkable OD, OS • Vessels – 2/3 A/V ratio OD, OS• Vitreous – Trace syneresis OD, OS• Periphery – (-) H/T/B OD, OS


PEER-REVIEWED OFF-LABEL

MEDICATIONS

• Take-Home Points

• Opportunities

• Limitations

• What’s Next?

• Topical Difluprednate 0.05% QID + Dorzolamide 2% TID x 4-12 weeks• DME• CME• RVO

• Timolol 0.5% 2gtts spaced by 15 minutes PRN • Acute migraines

• Dorzolamide 2% TID x 4-12 weeks• CSC• CME

• Timolol 0.5% + Dorzolamide 2% (adjunctive therapy) x 4-12 weeks • nvAMD• Macular Holes

• Topical Apraclonidine 0.5% BID PRN• Mild ptosis

Take Home Points:Optometric Off-Label Use

• Oral Prednisone 1250mg QD x 3 days• Optic Neuritis

• Spironolactone (Aldactone) 25mg BID x 4-12 weeks• Rifampin (Rifampicin) 300mg BID x 4-12 weeks

• CSC

• L-lysine 1000mg TID x 4 weeks• HSV

• Selenium 100ug BID x 6 months • Proptosis associated with thyroid eye disease (TED)

Take Home Points:Optometric Off-Label Use


Opportunity…

• Off-label medication use creates adjunctive therapies

• Off-label medication use can shorten duration and severity of disease condition

• Off-label medication use can reduce need for more invasive therapies

• PCM teaming exemplfies integrated medicine ©2019 Alltech, Inc. All rights reserved.

Limitations…• Optometry is typically outside an integrated healthcare

setting• Private practice• Corporate settings

• Off-label medication use may not be standard of care

• Adverse reactions to off-label medication use can expose the provider to liability


What’s next?• Evidence-based off-label therapy

• Pilot data drives larger scale, RCTs that can fundamentally change how medications are utilized

• Off-label algorithms • Clinical Findings • Drug Class• Dosage / Duration• Recommended follow-up and testing

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Takeaways…• Optometry is not just ocular health as it relates to systemic health.

• Primary care optometry is systemic health as it relates to the eye

• Off-label medication use should be pharmacologically sound and backed by research

• Adjunctive therapy can provide meaningful medical treatment during the time between referral and specialist follow-up

• PREVENTATIVE medicine is the BEST medicine

©2019 Alltech, Inc. All rights reserved. ©2019 Alltech, Inc. All rights reserved.

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1/15/2021 - optometricedu.com