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OPHTHALMICTHERAPEUTIC UPDATE

Tammy P. Than, MS, OD, FAAOUAB School of Optometry

tthan@uab.edu

Disclosure

Nothing to disclose

FDA Update What Would You Do Next? 64 YOWF

Acute Bilateral Non-granulomatous AU

Clinical Ocular Toxicology Fraunfelder F, Fraunfelder W, Chamber W

2008

WHO Causality Assessment of Suspected Adverse Drug Reactions

Certain

Probable/Likely

Possible

Unlikely

Conditional/Unclassified

Unable to assess/Unclassifiable

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Bisphosphonates

Indication: osteoporosis

“Rare to get such a clear-cut positive rechallenge data of a drug-induced ocular side effect as with this class of drugs” Clinical Ocular Toxicology

Fraunfelder F, Fraunfelder W, Chamber W

2008

Bisphosphonates

Conjunctivitis

Uveitis

Episcleritis

Scleritis

Topamax™Topiramate

FDA Category DSafety not established < 2 YO

Indications:EpilepsyMigrainesOff-label

Bipolar disorder, depression, neuropathic pain, smoking cessation, idiopathic intracranial HTN

Topamax™ Ocular side effects (2001)

Acute myopia and 2° angle closure

May be associated with supraciliaryeffusion resulting in anterior displacement of the lens and iris

± mydriasis

Usually within first month

Pediatric population too!

First line treatment is d/c Topamax

Qsymia

Approved 7/17/2012

Phentermine Sympathomimetic anarectic

Topiramate ER Capsules contain 23, 46, 69 or 92 mg!

Obese (BMI 30)

Overweight (BMI 27) with at least one weight-related comorbidity

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Adverse Events 20,402 (2004 – 2012)

VF Defects: 43 (0.2%)

Gilenya®

fingolimod

Novartis Pharmaceuticals

sphingosine 1-phosphate receptor modulator

Blocks lymphocyte leakage from lymph nodes

MA?

Gilenya®

1st oral disease modifying treatment for relapsing multiple sclerosis to reduce the frequency of clinical

exacerbations

To delay the accumulation of physical disability

0.5 mg cap QD

Gilenya®

Bradycardia after 1st dose Monitor!

risk of infection

pulmonary function

BP

Macular edema

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Gilenya® - Macular Edema

FAME (fingolimod-associated ME)

Usually 3-6 months after starting medication

OCT at baseline and 3-4 months after treatment begins

risk if diabetes and/or uveitis

Resolves/improves if d/c medication

FAME

Loss of sphingosine 1-phosphate receptor 1 signaling in endothelial cells

Downregulation of adhesion complexes

vascular permeability

http://www.aao.org/publications/eyenet/201204/pearls.cfm

Ocular Adverse Events from Systemic Medications

Report it!

MedWatch

www.fda.gov/safety/medwatch

OpenFDA

PAIN MANAGEMENTHydrocodone

Scripts ↑50% from 2000-2006

131 million scripts in 2010

Non-medical use 10th graders – 7.7%

12th graders – 8%

>12 YO – 9.3% Americans

#2 abused

FDA considered changing to Schedule 2 Safety and Risk Management Adv Cmt

19/10 (1/25/13)

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And then…

DEA published formal proposal Reschedule hydrocodone combination

products from Schedule III to II

February 27, 2014

Public comments until April 27, 2014

Final Ruling

October 6, 2014

Opioid CombinationsMany contain Acetaminophen

AKA N-acetyl-p-aminophenol (APAP)

APAP toxicity

more emergency room visits than any other drug

#1 cause of acute liver failure

25% of American adults weekly

63% overdoses - opioid-APAP combos

Acetaminophen Tylenol Regular Strength: 325 mg

1-2 q4-6h Tylenol Extra Strength: 500 mg

1-2 q4-6h Tylenol 8 hr: 625 mg

1-2 q8h Unavailable

Max of 1 g / 4 hoursMax of 4 g / day

More News on OpioidsFDA request – January 14, 2014

325 mg APAP limit

Voluntary

Over 50% compliance Vicodin 5/500 → 5/300

Vicodin ES 7.5/750 →7.5/300

Plans to withdraw approval of drugs with >325 mg

Hydrocodone Options (Former…)

Lortab hydrocodone + 500 mg acetaminophen 2.5, 5, 7.5 or 10 mg

Vicodin 500 mg acetaminophen + 5 mg hydrocodone

Vicodin ES 750/7.5

Vicodin HP 660/10

Vicoprofen hydrocodone 7.5 mg + ibuprofen 200 mg

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Trade Name FormulationFederal CS Schedule

Adult Dose

Lortab 5/325 Hydrocodone 5 mgAPAP 325 mg

C-II 1-2 q 4-6 h

Lortab 7.5/325 Hydrocodone 7.5 mgAPAP 325 mg

C-II 1 q 4-6 h

Lortab 10/325 Hydrocodone 10 mgAPAP 325 mg

C-II 1 q 4-6 h

Vicodin Hydrocodone 5 mgAPAP 300 mg

C-II 1-2 q 4-6 h

Vicodin ES Hydrocodone 7.5 mgAPAP 300 mg

C-II 1 q 4-6 h

Vicodin HP Hydrocodone 10 mgAPAP 300 mg

C-II 1 q 4-6 h

Vicoprofen Hydrocodone 7.5 mgIbuprofen 200

C-II 1 q 4-6 h

NSAIDs: Mechanism of Action

Inhibit cyclooxygenase

varying degreesCOX-1 “housekeeper enzyme”maintains normal gastric mucosa

COX-2 inducible by inflammation not present at baseline

Another Option: Tramadol

dual acting

mu opioid agonist

inhibits NE and serotonin reuptake

WAS non-scheduled opioid minimal abuse potential?

Aug 2014 – changed to Schedule IV

Avoid if opioid allergy

Tramadol Options

Ultram 50-100 mg q4-6 hr (max 400 mg/day)

Ultram ER 100-300 mg QD

Rybix ODT - 50 mg

Ryzold - 100-300 mg ER

ConZip – 100-300 mg ER

UltracetUltracet

37.5 mg tramadol

325 mg APAP

Short-term management of acute pain

5 days

2 tab q.4-6.h Max of 8 tabs/day

Also Schedule IV

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Alternative

Acetaminophen + Ibuprofen alternate dosages q4-6h analgesia comparable to Tylenol #3 in

dental and postoperative pain models

Ketoprofen Rx 50 mg q6-8h

Etc…

Cataract Surgery and

New Drugs

Omidria

Omeros Corp.

Approved 5/30/2014

Combination Phenylephrine 1%

Ketorolac 0.3%

Mixed in irrigation solution Used prn

OmidriaTo be used during cataract surgery or

IOL replacement Maintain pupil size

Reduce post-op pain

May BP

Caution NSAID hypersensitivity

Respiratory disease

Do not use during 3rd trimester

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ReSure Sealant

Ocular Therapeutix, Inc.

1/8/2014

Intraoperative management of CCI ( 3.5 mm) with wound leak

In situ formed PEG hydrogel crosslinking

Creates “soft and lubricious surface barrier to prevent leakage” of CCI

Off-Label Uses?

Monocular patients

Immunocompromised

Long-term steroid use

Complex cataract surgery

Enlarged incision

MRSA positive patients

Anti-Infective Update

Besivance™

Besifloxacin chloro-fluoroquinolone

0.6% ophthalmic suspension in Durasite

TID 7 days

preserved with BAK

>1 YO

no oral equivalent

Labeling change Sept 2012

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Besivance™

OK after cataract surgery?

Animal study Am J Ophthalmol 2010;150(4):498-504

Injected into anterior chamber

Block TMW

Damage corneal endothelium

Besivance™

Malhotra et al. Clinical Ophthalmology2012:6;855-63

Besivance or Vigamox QID

Study Conclusion

Besivance was well tolerated when used prophylactically after suturelesscataract surgery Similar to Vigamox

n = 60

Larger studies needed to confirm these findings

MGD

Azithromycin versus Doxycycline for MGD

Br J Ophthalmol 2015 Feb;99(2):199-204 Kashkouli MB et al

Study Conclusion: 5-day oral azithromycin is recommended

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Azithromycin (Zithromax™)

2nd generation MacrolideWell tolerated

Recent change to labeling…

MRSA – Not in My Office…

Screening and Characterization of Staphylococcus aureus from Ophthalmology Clinic Surfaces: A Proposed Surveillance Tool Reem et al; Am J Ophth 2014 Sampled various surfaces

Quarterly for one year

MSSA 24%

MRSA 4% (1-10%)

MRSA

MRSA most likely found: Slit Lamp (head and chin rests)

Keyboards

MRSA isolates 80% multi-drug resistant (≥ 3 classes)

No infection with devices directly touching eye

Clinical Implication?

Antibiotic Resistance

The CDC estimated last year that 2,049,422 illnesses due to antibiotic-resistant infections occur annually in the US

23,000 deaths

Economic burden is estimated at ~$20 billion due to direct effects of drug-resistant infections

http://www.forbes.com/sites/davidkroll/2014/06/20/antibiotic-pipeline-revival-fda-approves-cubist-pharmaceuticals-sivextro-for-mrsa-other-serious-skin-infections/

Sivextro®

Tedizolid phosphate

oxazolidinone

Prodrug

Inhibits protein synthesis (50S)

IND: acute skin infections including MRSA

Oral and IV

200 mg QD x 6 d

$$$

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Dalvance®

Dalbavancin

Durata Therapeutics

5/23/2014

Cell wall synthesis inhibitor

Acute bacterial skin infections

IV admin only

Pazeo®

0.7% olopatadine

Approved 1/30/15

BAK

QD

2.5 mL

Available now

Allergy Immunotherapy

Treatment of pollen-induced allergic rhinitis ± conjunctivitis Confirmed with + skin test or in vitro testing

for specific IgE antibodies

2014 – three drugs Sublingual

“Precise mechanisms are not known”

Allergic Immunotherapy

Ragwitek (Merck) Pollen extract from short ragweed

Grastek (Merck) Extract from Timothy grass

Oralair (Greer Labs) 5 pollens: sweet vernal, orchard, perennial

rye, timothy and kentucky blue grass

Allergic Immunotherapy

Dose #1 In-office

Observation for 30-45 minutes

EpiPen Rx

One tablet daily

Begin 3 months before pollen season

Nasal and ocular symptoms Compared to placebo

Bromfenac 0.09%

Bromday® d/c

QD Begin day before cat sx and continue for 2

weeks

BAK

CI: sulfite allergy

2.5 mL

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Prolensa

Approved 4/5/2013

ISTA B+L

0.07% bromfenac

new formulation

added tyloxapol

ocular inflammation and pain following cataract surgery

QD

1.6 and 3 mL

CI: Sulfite allergy

Comparison of Topical Ketorolac0.4% Plus Steroid vs Steroid Alone

Patients with no CME risks (diabetic retinopathy, retinal vascular disease, macular abnormality) received PA 1% QID alone OR PA 1% + ketorolac 0.4% QID x 4 weeks

Both groups received 4 doses of ketorolac1 hr before surgery

n = 546

Results

No patients in NSAID/steroid group and 5 patients in steroid group had clinically apparent CME

Based on OCT, no NSAID/steroid patient had definite or probable CME compared with 6 steroid patients

Adding perioperative ketorolac to postopPA significantly reduces incidence of CME and macular thickening in low risk cataract patients

Wittpenn JR, et al. A randomized, masked comparison of topical ketorolac 0.4% plus steroid vs steroid alone in low-risk cataract surgery patients. Am J Ophthalmol 2008; 146; 554-560.

But… Almeida et al. J Cat & Ref Surg 2012; Sept:

1537-43.

n = 54 per group

nepafenac or ketorolac or placebo

QID x 1 month

Conclusions: No difference in macular volume between 3 groups. Thus for patients without risk factors having routine surgery, prophylactic topical NSAIDS are not recommended

Retinal Drugs

Ozurdex®

70% dexamethasone + 30% polymer delivery system (Allergan)

Bioerodible (Novadur)

Delivers drug for ~ 6 weeks

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Ozurdex®

IND Macular edema after RVO

Chronic noninfectious posterior uveitis (6/2010)

Diabetic macular edema (9/26/14)

Ozurdex®

MEAD (Macular Edema: Assessment of Implantable Dexamethasone in Diabetes) Study

Demonstrated long-term efficacy without the need for monthly injections

two multi-center 3-year sham-controlled, masked, randomized clinical studies

Side Effects

IOP Peak at week 8

Cataract 68% vs 21% (sham)

Iluvien®

Fluocinolone acetonide

Alimera Sciences

Intravitreal Implant Non-bioerodible

0.19 mg 0.25 microgram/day (initial rate)

36 months

Approved 9/26/2014

Iluvien®

Indication Diabetic macular edema in patients who

have previously been treated with a course of corticosteroids and did not have a clinically significant rise in IOP

Eylea

Neovascular AMD

Macular Edema Following RVO

DME

Diabetic Retinopathy in Patients with DME Added 3/2015