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OPHTHALMICTHERAPEUTIC UPDATE
Tammy P. Than, MS, OD, FAAOUAB School of Optometry
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
2
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
3
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
4
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)
5
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
6
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
7
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
8
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
9
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
10
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
$$$
11
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
12
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
13
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