Pharmacology Update
Jimmy D. Bartlett, O.D.
eyedrug@uab.edu
Disclosure Statement
Alcon
Allergan Pharmaceuticals
Bausch & Lomb
Vision Service Plan
Vistakon
Therapeutic Update 2009
Jimmy D. Bartlett, O.D., Sc.D.
Professor of Optometry, School of Optometry
Professor of Pharmacology, School of Medicine
University of Alabama at Birmingham
The Famous Bartlett CE Guarantee!
What We Will Cover Today
New Drug Delivery Devices and Procedures
Helping Patients Afford Prescription Drugs
Topical NSAIDs in Post-op Cataract Care
A New Topical Ocular Anesthetic
Generic Drugs
Compounding of Special Formulations
New Anti-inflammatory and Antiallergy Drugs
New Strategies in Treating Blepharitis
Useful Websites for Drug Information
New Topical Ocular Anti-infective Drugs
New Drug Delivery Devices AND PROCEDURES
Punctal Plug Delivery of Glaucoma Medications
Punctal Plug Drug Delivery System
QLT Plug Delivery, Inc.
Phase II trial to evaluate the safety and efficacy of Latanoprost Punctal Plug Delivery System (L-PPDS) for the
treatment of open-angle glaucoma and ocular hypertension
Mean change in IOP from baseline at 12 weeks was -5.4 mmHg, -4.8 mmHg and -4.9 mmHg for the low (3.5 mcg),
medium (14 mcg), and high (21 mcg) concentrations of latanoprost, respectively
Bimatoprost 0.03% (Latisse)
Bimatoprost 0.03% (Latisse)
Indications and Usage
To treat hypotrichosis of the eyelashes by increasing their growth
Length
Thickness
Darkness
Mechanism of Action
Increases percentage of hairs in, and duration of anagen (growth) phase
Dosage and Administration
Clean face and remove makeup and contact lenses
Once nightly, apply one drop with supplied applicator evenly along skin of upper eyelid margin at base of eyelashes
Blot excess solution runoff
Repeat for fellow eyelid using new applicator
Do not use any other brush/applicator
Do not apply to lower eyelash line
Application
Patients with ≥ 1-Grade Increase
Changes in Length, Thickness, Darkness
Patient Advice
More than one application daily will not enhance the effect
Upon discontinuation of treatment, eyelash growth is expected to return to pretreatment levels
Effect on IOP
In patients with or without elevated IOP, Latisse will lower IOP, but the effect is not clinically significant or relevant
In patients using a topical prostaglandin as an ocular hypotensive, the concomitant use of Latisse may interfere
with the desired reduction in IOP
Monitor for changes in IOP
Pigmentary Changes
Potential for iris pigmentary changes, which are likely to be permanent
Eyelid or periorbital darkening is possible, which is reversible
Hair growth outside of treatment area
Iris Color Darkening
Eyelid/Periorbital Darkening
Contraindications
Intraocular inflammation
Macular edema, including CME
Use With Contact Lenses
Latisse contains BAK 0.005%
Remove lenses before applying Latisse
Can be reinserted 15 min after application
Special Populations
Pregnancy category C
Lactation
Excretion in breast milk is unknown
Use caution
Most Common Adverse Reactions
Eye itching
Conjunctival hyperemia
Skin hyperpigmentation
Frequently Asked Questions!
Does Latisse work on the scalp?
No
Does it work on eyebrows?
Maybe, but not as great as eyelashes
Can it be used on “chemo” patients?
Yes, but wait until hair growth starts to return
How long do patients need to use it?
Small changes can be seen in 2 months
Continual use is necessary to maintain effect
Can I use Lumigan in place of Latisse?
Not advisable! Medicolegal and insurance issues
Latisse.com
Helping Patients Afford Prescription Drugs
Helping Patients Afford Prescription Drugs
Patient assistance programs
Ocular
Systemic
Discount drug cards
Obtaining low-cost generic drugs
Patient Assistance Programs
www.NeedyMeds.org
Patients search for programs, download applications, search for help based on location or disease
Partnership for Prescription Assistance (www.pparx.org, 1-888-477-2669)
Matches patients to more than 475 private and public programs
Offers help with copayments
Glaucoma (and other!) Drug Costs
Patient Assistance Programs
www.RxAssist.org
Patients search database of programs by medication
Tip sheets on free or low cost medication
Information on copays and generic drugs
Discount Drug Cards
www.TogetherRxAccess.com
1-800-444-4106
Sponsored by nine major drug companies
Free card offers 20% to 40% discounts on retail prices for > 300 drugs
Merck and Pfizer
Discounts range from 15% to 50%
www.merckhelps.com/uninsured
www.pfizerhelpfulanswers.com
Obtaining Low-Cost Generic Drugs
www.RxOutreach.com
1-800-769-3880
Offers more than 350 generic medications at $20 to $95 for 180-day supplies
Xubex Pharmaceutical Services (www.xubex.com, 1-866-699-8239)
Offers more than 250 generics at $20 to $30 for most 90-day supplies
Obtaining Low-Cost Generic Drugs
Wal-Mart, Target, Safeway
Many generics are $4 for 30-day supply with no eligibility restrictions
Some offer 90-day supplies for $10 to $15
Assistance Programs for Glaucoma Patients
Alcon Cares: (800) 222-8103
Allergan: (800) 553-6783
Merck: (800) 727-5400
Pfizer Connection to Care: (866) 776-3700
Vistakon Pharmaceuticals: (866) 815-6874
Patient Assistance Programs
Should a Topical NSAID be a Routine Post-op Cataract Med?
Ketorolac Tromethamine
Commercially available as 0.5 % & 0.4% solution (Acular LS)
Approved for treatment of seasonal allergic conjunctivitis
Inhibits postoperative inflammation after cataract surgery (as effective as dexamethasone)
Effective for prophylaxis and treatment of CME following cataract surgery
Prevention of CME
CME is the most frequent cause of visual decline following uncomplicated cataract surgery
Late onset (4 to 6 weeks post-operatively)
Estimated to occur in 12% of low-risk cataract cases
CME development is due in part to prostaglandin-mediated breach of blood-retinal barrier
Steroids Work “Upstream”, NSAIDs “Downstream”
Comparison of Topical Ketorolac 0.4% 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 ketorolac 1 hr before surgery
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 postop PA significantly reduces incidence of CME and macular thickening in low
risk cataract patients
Ketorolac 0.45% (Acuvail)
Current formulations of ketorolac
0.5 % multidose (Acular)
0.5% single-use vial (Acular PF)
0.4% multidose (Acular LS)
New ketorolac 0.45 % (single-use vial, PF)
Indicated for pain and inflammation following cataract surgery
Dosage: BID x 2 weeks
Potential cross-sensitivity with other NSAIDs
Packaging: 6 foil pouches, 5 vials per pouch
A novel Topical Ocular Anesthetic
New Topical Ocular Anesthetic
Akten Ophthalmic Gel 3.5%
Unit-dose (5 ml)
Preservative-free
Lidocaine gel
Indicated for any ocular procedure requiring a topical anesthetic
Indicated for patients allergic to ester anesthetics
Classification of Local Anesthetics
Generic Drugs
Therapeutic Equivalency
Bioequivalency Standards
Must contain the same active ingredient
In same concentration
Same dosage form
Administered by same route
Must have comparable bioavailability
Rate and extent of drug absorption and delivery to site of action
Bioavailability Serum-Concentration Time Curve
FDA “Orange Book”
Approved Drug Products with Therapeutic Equivalence Evaluations
Lists 10,000 drug products, 80% of which are generic
Of the 8,000 generics, >90% are therapeutically equivalent to innovator product
Difference in cost between average generic prescription and average brand name drug now exceeds $90!
Prescribe only “A” or “AT” rated drug products
Therapeutic Equivalence Ratings
A-rated
Therapeutically equivalent
B-rated
Has not demonstrated bioequivalence
AB-rated
May be bioequivalent
AT-rated
Topical product with probable bioequivalence
What About Generic Glaucoma Drugs?
Generic brimonidine 0.15% and 0.2% are AT-rated
Timolol GFS 0.5% (Falcon) is generic version of Timoptic XE 0.5% and is AB-rated
Istalol (ISTA), preserved with potasium sorbate, is equivalent to timolol maleate solution
Generic acetazolamide is equivalent to Diamox and 37% less expensive
Generic Versus Brand Name Steroids
Avoid generic Pred Forte (drug clogs bottle tip)
What About Econopred Plus?
Econopred Plus is Now Omnipred
New milling process that standardizes particle size to < 1 µm
Head-to-head comparison with Pred Forte
Post-op Day 1
Post-op Day 12
Post-op Day 28
Compounding of Special Formulations
Have You Ever Needed….
Acetylcysteine 5%, preservative-free
Cyclopentolate 0.5-1%, PF
Cyclopentolate/phenylephrine combo
Fortified cephazolin, gentamicin, tobramycin, PF
Phenylephrine 2.5%, PF
PHMB 0.01%, 0.02%
Prednisolone acetate, PF
Proparacaine, PF
Tropicamide, cyclopentolate, phenylephrine spray
Vancomycin 20 mg/ml, 25 mg/ml, 50 mg/ml
Leiter’s Rx Ophthalmic Compounding
1700 Park Ave., Suite 30
San Jose, CA 95126
877-EYE-DROP
www.leiterrx.com
The Prescription Center
1907 West Avenue South
Preservative-Free Tetracaine
The Solution (1980s)
Mydriatic-Cycloplegic Solution
La Crosse, WI 54601
800-292-6773
(800) 203-9066
3.75 ml cyclopentolate 2.0%
3.75 ml phenylephrine 10%
7.5 ml tropicamide 1.0%
Final concentration is:
Cyclopentolate 0.5%
Phenylephrine 2.5%
Tropicamide 0.5%
Mydriatic/Cycloplegic Spray
Mydriatic/Cycloplegic Combo Eyedrops
Dapiprazole is Back!
Dapiprazole 0.5%, formerly Rev-Eyes
Now available as compounded product (NuRev)
Focus Laboratories, Inc. (866-752-6006)
25 mg powder/5 ml diluent
21-day shelf life
$42, with volume discounts
NuRev
NEW ANTI-INFLAMMATORY AND
ANTIALLERGY DRUGS
Difluprednate (Durezol) 0.05%
Difluprednate (Durezol) 0.05%
(Sirion Therapeutics)
New ophthalmic steroid
Emulsion vehicle
FDA approved for inflammation and pain associated with ocular surgery
Dosage
QID beginning 24 h after surgery x 2 wk
BID x 1 wk
Taper
Drug Development History
Developed by Mitsubishi as a dermatologic preparation
Categorized as a “very strong” steroid in dermatology
Developed by Senju as an ophthalmic emulsion
Licensed in June 2006 by Sirion Therapeutics
NDA submitted in December 2007, granted priority review
DurezolTM (difluprednate ophthalmic emulsion) 0.05% was approved for the treatment of inflammation and pain
associated with ocular surgery on June 23, 2008
Benefits of the Durezol Emulsion
Since Durezol is an emulsion, it solves some of the problems of steroid suspensions
Durezol does not require
shaking
Durezol has excellent
drop-to-drop dose
uniformity compared
to prednisolone
Results from a Pivotal Trial of Durezol™ and Pred Forte® in Anterior Uveitis
Study Design
Percent Reduction in Mean Pain Scores
Conclusions
Durezol dosed QID was not inferior to Pred Forte dosed eight times a day
Durezol may offer increased patient compliance and satisfaction
QID dosing
Emulsion formulation
BAK free
Sirion has submitted a supplemental NDA for the treatment of anterior uveitis
Bepotastine Besilate 1.5% (Bepreve)
Bepotastine besilate (Bepreve) 1.5% (Ista Pharmaceuticals)
Antihistamine and mast cell stabilizer
Inhibits eosinophil chemotaxis
Indication: Allergic conjunctivitis (itching)
Bepotastine besilate (Bepreve) 1.5%
Preservative: BAK 0.005%
Dosage: BID
Approved for children ≥ 2 years
Pregnancy category C
ADRs: Headaches; mild taste (25%)
Three bottle sizes: 2.5, 5, 10 ml
About half the cost of most Rx allergy meds
OTC Ketotifen 0.025% Products
Zaditor (Novartis)
Alaway (Bausch & Lomb)
Refresh Eye Itch Relief (Allergan)
Ketotifen (Alcon, Apotex, Akorn)
Claritin Eye Allergy
Relief
New Strategies for Treating Blepharitis
DuraSite®: The AzaSite Vehicle
DuraSite® contains
Polycarbophil USP
Sodium chloride, edetate disodium (EDTA), benzalkonium chloride (BAK 0.003%), purified water and
sodium hydroxide to adjust pH
DuraSite is a synthetic polymeric mucoadhesive matrix that stabilizes small molecules like azithromycin
Increases the bioavailability of azithromycin in tissue
Advantages of DuraSite®
Mucoadhesive Properties
AzaSite as an Anti-inflammatory
Like tetracycline, azithromycin has anti-inflammatory properties independent of its antibiotic action
May be effective with once-daily topical application
Could be component of comprehensive lid management regimen for MGD
Use first line, before oral doxycycline?
New Treatment Algorithm for Anterior Blepharitis
New Treatment Algorithm for Posterior Blepharitis
ADVERSE OCULAR EFFECTS OF SYSTEMIC mEDICATIONS
Drugs Affecting Retinal Function
Thioridazine
Talc
Cardiac glycosides
Clomiphene
Sildenafil
Tamoxifen
Hydroxychloroquine
Hydroxychloroquine
Plaquenil Retinopathy
Subtle relative visual field defects
Macular pigmentary mottling
Classic “bull’s eye” maculopathy
Rarely, attenuated arterioles, optic atrophy, macular edema
Pseudoretinitis pigmentosa
Visual field loss correlates with retinopathy
Risk of Plaquenil Retinopathy
Incidence is 4% with daily dosage of 400 mg for 1 year
Prudent daily dosages (400 mg/day or 6.5 mg/kg/day, whichever is less) present little risk
Management
Baseline ophthalmic examinations are mandatory
Monitor every 4-6 months?
Current Screening Recommendations (and codes)
Clinical Procedures
Visual acuity
Color vision
Pseudoiso Plates
AO HRR
Amsler grid
Visual fields (Humphrey 10-2)
Slit lamp exam
Dilated ophthalmoscopy (BIO and precorneal)
ICD Codes
V67.51 (Monitor completed drug therapy)
V58.69 (Monitor long-term current medication)
Glaucoma Therapeutic
Option Timeline
Mainstays of Contemporary Treatment
Prostaglandin
Topical CAI
-blocker
2 agonist
The “New” 0.1% Alphagan P
Allergic Dermatoconjunctivitis
Generic Alphagan
Brimonidine 0.2%/Timolol 0.5% (Combigan)
“Nice-to-Know” Things About Combigan
When used twice daily, ocular hypotensive efficacy is similar to dorzolamide/timolol (Cosopt) in patients with
POAG or OHT
Combigan is significantly more comfortable than Cosopt, which could translate into better patient compliance
(adherence) with medical therapy
Allergic Conjunctivitis Is Less Frequent Than With Brimonidine 0.2%
Adrenergic agonists reduce ocular cell volume, leading to increases in intercellular space
Permits potential allergens to reach subepithelial tissues
Ocular Epithelial Cells Without Timolol
Ocular Epithelial Cells With Timolol
When added to an AA, timolol maintains normal ocular cell size and intercellular spaces
Inflammatory mediators are blocked
Ocular Epithelial Cells With Timolol
Allergic Dermatoconjunctivitis
New information on ocular anti-infectives
Ocular TRUST
The only longitudinal nationwide antimicrobial susceptibility surveillance program specific to ocular isolates
S. aureus
Coagulase-negative staphylococci
S. pneumoniae
H. influenzae
Susceptibility Testing
In vitro susceptibility testing to nine antimicrobials
Ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin
Azithromycin
Trimethoprim
Tobramycin
Polymyxin B
Penicillin
Staphylococcus aureus
Staphylococcus aureus
Practical Take-Home Points
Methicillin resistance in staphylococci is a marker of multi-drug resistance
MRSA is susceptible only to trimethoprim and, to a lesser extent, tobramycin
New anti-infective drugs
Besifloxacin (Besivance) Suspension
New chemical entity: An 8-chloro fluoroquinolone
NOT used systemically – only available in U.S.
Relative resistance-proof: No oral counterpart
FDA-approved only for bacterial conjunctivitis
FDA-approved dosage: TID for 7 days
Pediatric approval: ages 1 and older
Preserved with 0.01% BAK
Durasite vehicle for long retention time at site of infection (ocular surface)
Unique Features of Besifloxacin
The first chloro-fluoroquinolone
Never used systemically
Reduced risk of resistance
Durasite vehicle
Equivalent to moxifloxacin (Vigamox) for treatment of bacterial conjunctivitis*
Ganciclovir 0.15% Ophthalmic Gel (Zirgan)
(Sirion Therapeutics)
First new topical ophthalmic antiviral since 1980
Indicated for acute HSV epithelial keratitis
Dosage: 1 drop 5x/day (~ q3h while awake) until healed, then TID x 7 days
Side effects: blurred vision, SPK, conj injection
Pregnancy Category C
Pediatric use ≥ 2 years
Targets only virus-infected cells, thus less corneal toxicity
Clinical Studies
Randomized trial of 164 patients showed equivalent to acyclovir 3% ophthalmic ointment; clinical resolution at Day
7 was 77% for Zirgan and 72% for acyclovir
In three randomized, controlled trials of 213 patients, clinical resolution at Day 7 was 72% for Zirgan and 69% for
acyclovir
Placebo-controlled, double-masked, randomized study of adenoviral keratoconjunctivitis showed significantly
shorter time to recovery (7.7 vs 18.5 days; p<0.05)
Commercial Availability
Packaging: 5 gm tube
Expected availability: Early 2010
Corneal Healing Following Zirgan Use