Proposed Preferred Drug List Clinical Criteria Proposal for TennCare

Proposed
Preferred Drug List
with
Clinical Criteria
Proposal for TennCare
February 12, 2013
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February 12, 2013 Tennessee PAC
Responsibilities of the TennCare Pharmacy Advisory Committee
Source: Tennessee Code/Title 71 Welfare/Chapter 5 Programs and Services for Poor
Persons/Part 24 Tennessee TennCare Pharmacy Advisory Committee/71-5-2401 through 71-52404.
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
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Make recommendations regarding a preferred drug list (PDL) to govern all state expenditures
for prescription drugs for the TennCare program.
o The TennCare Pharmacy Advisory Committee shall submit to the bureau of
TennCare both specific and general recommendations for drugs to be included on
any state PDL adopted by the bureau. In making its recommendations, the
committee shall consider factors including, but not limited to, efficacy, the use of
generic drugs and therapeutic equivalent drugs, and cost information related to each
drug. The committee shall also submit recommendations to the bureau regarding
computerized, voice, and written prior authorization, including prior authorization
criteria and step therapy.
o The state TennCare pharmacy advisory committee shall include evidence-based
research in making its recommendations for drugs to be included on the PDL.
o The TennCare bureau shall consider the recommendations of the state TennCare
pharmacy advisory committee in amending or revising any PDL adopted by the
bureau to apply to pharmacy expenditures within the TennCare program. The
recommendations of the committee are advisory only and the bureau may adopt or
amend a PDL regardless of whether it has received any recommendations from the
committee. It is the legislative intent that, insofar as practical, the TennCare bureau
shall have the benefit of the committee’s recommendations prior to implementing a
PDL or portions thereof.
Keep minutes of all meetings including votes on all recommendations regarding drugs to be
included on the state preferred drug list
The chair may request that other physicians, pharmacists, faculty members of institutions of
higher learning, or medical experts who participate in various subspecialties act as
consultants to the committee as needed.
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February 12, 2013 Tennessee PAC
PDL Decision Process
 The primary clinical decision that needs to be made is determining if the drugs within the
therapeutic class of interest can be considered therapeutic alternatives.
 A Therapeutic Alternative is defined by the AMA as: “drug products with different chemical
structures but which are of the same pharmacological and/or therapeutic class, and usually
can be expected to have similar therapeutic effects and adverse reaction profiles when
1
administered to patients in therapeutically equivalent doses” .
 The Committee should not feel obligated to decide if every drug within the therapeutic class is
exactly equal to all other drugs within the class, nor should they feel obligated to decide if
every drug within the therapeutic class works equally well in every special patient population
or in every disease.
 In special situations (e.g., presence of comorbid conditions) and in special populations (e.g.,
pediatrics) use of a non-preferred drug might be the most appropriate therapy. These cases
can be handled through prior authorization (PA). PA serves as a “safety valve” in that it
facilitates use of the most appropriate agent regardless of PDL status.
LENGTH OF AUTHORIZATIONS:
Dependent upon diagnosis and length of therapy needed
to treat. (Most medications are used chronically, and thus would be approved for 1 year.)
1. Is there any reason the patient cannot be changed to a medication not requiring prior
approval within the same class?
Acceptable reasons include:
 Allergy to medications not requiring prior approval
 Contraindication to or drug-to-drug interaction with medications not requiring prior
approval
 History of unacceptable/toxic side effects to medications not requiring prior approval
2. The requested medication may be approved if both of the following are true:
 If there has been a therapeutic failure of at least two medications within the same
class not requiring prior approval (unless otherwise specified)
 The requested medication’s corresponding generic (if a generic is available and
preferred by the State) has been attempted and failed or is contraindicated
3. The requested medication may be approved if the following is true:
 An indication which is unique to a non-preferred agent and is supported by
peer-reviewed literature or an FDA approved indication exists.
--------------------------------------------------------------------------------------------------------------------------- ----The information provided for each drug class is organized into the following sections, when
applicable:
BACKGROUND:
 General overview
 Pharmacology
 Therapeutic effect(s)
 Adverse reactions
 Outcomes data
 Place in therapy according to current Treatment Guidelines
RECOMMENDATION:
 General recommendation regarding utility and therapeutic equivalence among the agents
in the class, as well as requirements for product availability (PDL placement)
1
AMA Policy H-125.991 Drug Formularies and Therapeutic Interchange
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February 12, 2013 Tennessee PAC
ENDOCRINE & METABOLIC AGENTS
RE-REVIEW: AGENTS FOR GOUT
BACKGROUND
 Gout is a complex inflammatory disease that occurs in response to the presence of
monosodium urate monohydrate crystals in the joints, bones and soft tissues. Treatment
of gout consists of rapid relief of pain and disability caused by acute gout attacks and the
reduction of serum urate levels.
 Colchicine is believed to exert a positive effect in gout by preventing the activation,
degranulation and migration of neutrophils, implicated in the pathogenesis of gout
symptoms. Allopurinol and febuxostat are both xanthine oxidase inhibitors. These agents
causes a decrease in urate levels through the inhibition of xanthine oxidase, the enzyme
responsible for the conversion of hypoxanthine to xanthine and then finally to uric acid.
Probenecid is a uricosuric agent that exerts its effects on serum urate by inhibiting the
reabsorption of uric acid at the proximal tubule which leads to uric acid excretion and a
decrease in overall serum urate levels.
Single Entity Agents
FDA- Approved Indications
Allopurinol
Management of patients w/ signs
& symptoms of primary or
secondary gout
Management of patients
receiving chemotherapy which
elevates uric acid levels
Management of patients w/
recurrent calcium oxalate calculi
Chronic management of
hyperuricemia in gout patients
Prophylaxis of gout flares
Treatment of gout flares
Treatment of Familial
Mediterranean Fever
Treatment of chronic gouty
arthritis complicated by frequent,
recurrent acute gout attacks
Treatment of hyperuricemia
associated w/ gout & gouty
arthritis
Adjuvant therapy w/ penicillins,
for elevation & prolongation of
plasma levels

Colchicine
Febuxostat
Probenecid
Combination
Products
Colchicine/Probenecid
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
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
The most common adverse reactions associated with allopurinol are dermatologic in
nature, including maculopapular eruption and pruritis. Use of colchicine is commonly
associated with gastrointestinal reactions, including diarrhea, nausea and vomiting and
febuxostat is commonly associated with abnormal liver enzymes.
o Colchicine is contraindicated in the presence of renal or hepatic impairment.
Probenecid is contraindicated in patients under the age of two, patients with
blood dyscrasias, uric acid kidney stones, and during an acute gout attack.
o A fluid intake sufficient to yield a daily urinary output of at least two liters and the
maintenance of neutral or slightly alkaline urine are recommended to prevent the
possible formation of xanthine calculi and to prevent renal precipitation of urates
in patients receiving concomitant uricosuric agents with administration of
allopurinol. Use caution in renal impairment as there may be an increased risk of
hypersensitivity reactions and dose adjustments may be needed. Some patients
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February 12, 2013 Tennessee PAC
ENDOCRINE & METABOLIC AGENTS
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with preexisting renal disease have shown a rise in blood urea nitrogen during
allopurinol use. Use caution in patients with preexisting hepatic impairment as
reversible hepatotoxicity has been reported with allopurinol.
o A higher rate of cardiovascular thromboembolic events were observed with
febuxostat compared to allopurinol; however a causal relationship with febuxostat
has not been established. Patients should be monitored for signs and symptoms
of myocardial infarction and stroke.
o An increase in gout flares is frequently observed during urate lowering therapy
initiation. Prophylactic therapy with either a nonsteroidal anti-inflammatory drug
or colchicine is recommended upon urate lowering therapy initiation with
allopurinol, febuxostat or probenecid.
o Blood dycrasias have been reported at therapeutic doses with use of colchicine.
Bone marrow depression has been reported with use of allopurinol. Caution
should be used with giving other medications with the potential for
myelosuppression.
o Neuromuscular toxicity and rhabdomyolysis have been reported with chronic
treatment in therapeutic doses of colchicine; concomitant use of statins, fibrates
or cyclosporine can potentiate these adverse events.
o Colchicine is contraindicated with concomitant administration of a P-glycoprotein
or a strong CYP3A4 inhibitor. Febuxostat is contraindicated in patients receiving
treatment with azathioprine or mercaptopurine. Concomitant administration of
probenecid and salicylates is contraindicated.
Available clinical evidence has demonstrated that colchicine is an effective agent in acute
gout attacks and as a prophylactic agent while patients initiate urate lowering therapy. No
available trials could be found that compared the efficacy of colchicine to either an NSAID
or a corticosteroid. Febuxostat, allopurinol and probenecid are effective in lowering serum
urate levels. Head to head studies that have evaluated febuxostat and allopurinol have
demonstrated that febuxostat is more effective in lowering serum urate levels; however in
these studies rates of gout flares were not significantly different between the two agents.
o The three major trials that were the basis for approval of febuxostat were the
FACT, APEX, and CONFIRMS trials. These studies were all randomized, doubleblind, controlled trials that compared the treatment of febuxostat, in doses
ranging from 40 to 240 mg/day, to allopurinol or placebo in patients with gout.
The FACT and APEX studies demonstrated that a significantly greater number of
patients treated with febuxostat 80, 120 and 240 mg were able to reach a serum
urate goal of less than six mg/dL. In the CONFIRMS trial patients in the 80 mg
group had similar outcomes to the FACT and APEX studies; however the
CONFIRMS trial also evaluated a 40 mg dose where the proportion of patients
with serum urate level <6.0 mg/dL was not found to be significantly different
between the febuxostat 40 mg and the allopurinol groups. However, in all three
studies there were no differences between any of the groups for the number of
patients who required treatment for acute gout flares. Regarding adverse events,
there were generally no significant differences in the incidence of adverse events
between the febuxostat and allopurinol groups and they were generally mild to
moderate in severity. There was also no statistically significant difference
between groups in the incidence of cardiovascular events.
The American College of Rheumatology (ACR) published updated guidelines for the
management of gout in 2012. The ACR, British Society of Rheumatology, and European
League Against Rheumatism (EULAR) treatment guidelines all recommend a
nonsteroidal anti-inflammatory drug (NSAID), colchicine, or a corticosteroid for the
treatment of an acute gout attack. According to the more recent ACR guidelines for the
management of gout, initiation of urate lowering therapy is recommended in patients with
an established diagnosis of gout and tophus or tophi, frequent attacks of acute gouty
arthritis (≥2 attacks/year), chronic kidney disease stage 2 or worse, and past urolithiasis.
The main goal of therapy is to promote monosodium urate monohydrate crystal
dissolution and prevent further crystal formation which will lead to a reduction in acute
gout flairs as well as the prevention of tophi development. In order to achieve this goal
serum urate levels must be reduced and maintained below the monosodium urate
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February 12, 2013 Tennessee PAC
ENDOCRINE & METABOLIC AGENTS
monohydrate crystal saturation point. Thus, the treatment serum urate goal
recommended in the ACR and EULAR guidelines is <6 mg/dL (360 mol/L) and slightly
less in the British Society of Rheumatology guideline (≤300 mol/L). Of note, the ACR
notes that serum urate lowering below 5 mg/dL may be needed to improve gout signs
and symptoms. Agents used to lower serum urate levels include allopurinol, probenecid,
and febuxostat. The main difference between these agents is that allopurinol and
febuxostat inhibit urate production and probenecid promotes urate excretion. The 2012
ACR guideline, which was published after FDA approval of febuxostat, recommends
either allopurinol or febuxostat as the first-line urate lowering therapy approach for the
management of gout, with no preference stated between the two. In comparison, older
guidelines, published prior to approval of febuxostat, recommend allopurinol first-line and
note febuxostat as a second-line option when allopurinol is not effective or not
appropriate. The ACR recommends probenecid as an alternative first-line urate lowering
therapy option in patients with a contraindication or intolerance to either allopurinol or
febuxostat. During initiation of urate lowering therapy the guidelines recommend
concurrent prophylaxis with either colchicine or an NSAID, although generally colchicine
is the preferred, to prevent acute attacks while starting therapy. Concomitant therapy is
generally recommended for up to six months at which point only the urate lowering agent
is continued. Treatment with the urate lowering agent has the potential to be lifelong.
RECOMMENDATION
The treatment of gout consists of rapid relief of pain and disability caused by acute gout attacks
and the reduction of serum urate levels. All current treatment guidelines recommend a NSAID,
colchicine, or a corticosteroid for the treatment of an acute gout attack; however the disease can
and often will continue to progress unless the serum urate level is normalized. Agents used for the
treatment of hyperuricemia are allopurinol, febuxostat, and probenecid. The 2012 ACR guideline
recommends either allopurinol or febuxostat as the first-line urate lowering therapy approach for
the management of gout, with no preference stated between the two agents. The ACR
recommends probenecid as an alternative first-line urate lowering therapy option in patients with a
contraindication or intolerance to either allopurinol or febuxostat. Available clinical evidence has
demonstrated that colchicine is an effective agent in acute gout attacks and as a prophylactic
agent while patients initiate urate lowering therapy. Head-to-head studies that have evaluated
febuxostat and allopurinol have demonstrated that febuxostat is more effective in lowering serum
urate levels; however in these studies, rates of gout flares were not significantly different between
the two agents. Probenecid also has utility as an adjunct to antibiotic therapy; therefore, it is
recommended at least colchicine, allopurinol and probenecid should be available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: AGENTS FOR GOUT
PREFERRED
NON-PREFERRED
®
®
allopurinol (compares to Zyloprim )
Uloric (febuxostat)
®
®
Colcrys (colchicine)
Zyloprim (allopurinol)
probenecid
probenecid/colchicine
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2012.
Accessed December, 2012.
2. Thompson MICROMEDEX on-line © 1974-2012. Accessed December, 2012.
3. Med Metrics. Agents for Gout Therapeutic Class Review. January 4, 2013.
4. Becker MA, Schumacher HR, Wortmann RL, MacDonald P, Eustace D, Palo W, et al.
Febuxostat compared to allopurinol in patients with hyperuricemia and gout. N Engl J
Med. 2005;353:1532-3.
5. Schumacher HR, Becker MA, Wortmann RL, MacDonald P, Hunt B, Streit J, et al. Effects
of febuxostat vs allopurinol and placebo in reducing serum urate in subjects with
Page 6 of 37
February 12, 2013 Tennessee PAC
ENDOCRINE & METABOLIC AGENTS
6.
7.
8.
9.
10.
11.
hyperuricemia and gout. A 28-week phase III, randomized, double-blind, parallel-group
trial. Arthritis Rheum. 2008;59(11):1540-8.
Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, et al. The
urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of
gout: the CONFIRMS trial. Arthritis Research and Therapy. 2010;12(R63):1-12.
Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American
College of Rheumatology guidelines for management of gout. Part 1: Systematic
nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis
Care & Research. 2012 Oct;64(10):1431-46.
Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T, et al. 2012 American
College of Rheumatology guidelines for management of gout. Part 2: therapy and
antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care & Research.
2012;64(10):1447-61.
Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British
Health Professionals in rheumatology guideline for the management of gout. The British
Society for Rheumatology (BSR). Rheumatology. 2007;46:13724;doi:10.1093/rheumatology/kem056a.
Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout.
Part II: Management. Report of a task force of the EULAR Standing Committee for
International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis.
2006;doi:10.1136/ard.2006.055269.
National Institute for Health and Clinical Excellence (NICE). Febuxostat for the
management of hyperuricemia in people with gout. NICE technology appraisal guidance
164. London (England): 2008. [cited 2012 June 27]. Available from:
http://guidance.nice.org.uk/TA164/Guidance/pdf/English.
RE-REVIEW: DISEASE MODIFYING ANTI-RHEUMATIC DRUGS
BACKGROUND
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


Non-biological disease modifying anti-rheumatic medications (DMARDs) are used to treat
a variety of chronic inflammatory diseases.
The majority of non-biological DMARDs exert their effect by interfering with pathways in
the inflammatory cascade; the mechanism of action of auranofin or penicillamine in
rheumatoid arthritis is unknown. Hydroxychloroquine and sulfasalazine reduce
polymorphonuclear and lymphocyte responses. Leflunomide inhibits dihydroorotate
dehydrogenase thus reducing ribonucleic acid synthesis. Methotrexate is a cytotoxic
agent that impairs cell proliferation by inhibiting dihydrofolate reductase.
All DMARDs are approved by the FDA for the treatment of rheumatoid arthritis with the
exception of regular release sulfasalazine tablets, which are only approved for the
treatment of ulcerative colitis. Several DMARDs have other FDA approved indications in
addition to rheumatoid arthritis. Hydroxychloroquine is indicated for the treatment of
malaria and systemic lupus erythematosus. Methotrexate is indicated for poly-articular
course juvenile arthritis, severe psoriasis and various neoplastic disorders. Penicillamine
is indicated for the treatment of cystinuria and Wilson’s disease. Delayed release
sulfasalazine is also indicated for poly-articular course juvenile arthritis.
There are numerous common and serious adverse events associated with this class of
drugs. For a complete listing of adverse events, please refer to table 6 on pages 30-32 of
the complete therapeutic class review.
o Black box warnings:
 Auranofin carries a black box warning regarding gold toxicity, signs of
which include: fall in hemoglobin, leukopenia <4,000 white blood
3
3
cells/mm , granulocytes <1,500/mm , decrease in platelets
3
<150,000/mm , proteinuria, hematuria, pruritus, rash, stomatitis or
persistent diarrhea. Prescribers are advised to review lab results prior to
writing each auranofin prescription.
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February 12, 2013 Tennessee PAC
ENDOCRINE & METABOLIC AGENTS

Hydroxychloroquine carries a black box warning in which prescribers are
advised to familiarize themselves with the package insert prior to
prescribing.
 Leflunomide carries a black box warning regarding the risk of
teratogenicity as well as the risk of hepatotoxicity.
 Methotrexate has an extensive black box warning, including, but not
limited to: the risk of death, bone marrow depression, the importance of
compliance with monitoring, risks of liver toxicities, methotrexate-induced
lung-disease, teratogenic effects, use in impaired renal function, risk of
gastrointestinal toxicities, skin reactions and risk of severe toxic
reactions. For complete details, please refer to page 34-36 of the
complete therapeutic class review.
 Penicillamine carries a black box warning in which prescribers are
advised to familiarize themselves with the toxicities, special dosing
considerations and therapeutic benefits and that patients should remain
under close supervision of the physician.
o Contraindications:
 Hydroxychloroquine is contraindicated for long-term therapy for children
as well as for patients with the presence of retinal or visual field changes
attributable to any 4-aminoquinoline compound.
 Leflunomide is contraindicated in pregnant women and women of
childbearing potential who are not using reliable contraception.
 Methotrexate is contraindicated in nursing mothers, patients with
psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease
or other chronic liver disease, patients with psoriasis or rheumatoid
arthritis with overt or laboratory evidence of immunodeficiency
syndromes, patients with psoriasis or rheumatoid arthritis with preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia,
thrombocytopenia or significant anemia, and pregnant women with
psoriasis or rheumatoid arthritis.
 Penicillamine is contraindicated in nursing mothers, patients with
rheumatoid arthritis with a history or other evidence of renal insufficiency,
and during pregnancy, except for the treatment of Wilson’s disease and
certain cases of cystinuria.
 Sulfasalazine is contraindicated in intestinal or urinary obstruction and
porphyria.
o For a complete list of warning and precautions, please refer to table 8 on pages
37-42 of the complete therapeutic class review.
 Significant Drug Interactions
Generic
Interacting
Potential Result
Name
Medication or Disease
Auranofin
Penicillamine
Penicillamine can release gold previously bound to
tissue. Concurrent use of penicillamine and auranofin
may result in increased bone marrow depression and
rash. Monitor for bone marrow toxicity and discontinue
auranofin if necessary.
HydroxyDigoxin
Hydroxychloroquine may increase digoxin
chloroquine
concentrations (mechanism unknown). Concurrent use
of these agents should be avoided if possible.
Leflunomide
Cholestyramine
Cholestyramine may reduce leflunomide efficacy by
binding to lefunomide’s active metabolite. These agents
should not be administered together.
Live Vaccines
Immunosuppression by leflunomide may result in
interference with the immune response to live vaccines.
Live vaccines are not recommended during leflunomide
therapy. If necessary, consider interrupting therapy and
performing an elimination procedure.
Methotrexate
Concurrent use may result in increased hepatotoxicity
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February 12, 2013 Tennessee PAC
ENDOCRINE & METABOLIC AGENTS
Generic
Name
Interacting
Medication or Disease
Rifampin
Warfarin
Methotrexate
Amiodarone
Azathioprine, retinoids
Ciprofloxacin
Chloramphenicol,
cholestyramine, tetracycline
Cyclosporine
Live Vaccines
Mercaptopurine
Nonsteroidal antiinflammatory drugs,
salicylates, penicillins,
hydrochlorothiazide, proton
pump inhibitors
Phenylbutazone, phenytoin,
sulfonamides, doxycycline
Sulfasalazine
Theophylline
Trimethoprim/
sulfamethoxazole
Penicillamine
Iron, antacids
Penicillamine
Digoxin
Sulfasalazine
Cyclosporine
Digoxin
Riluzole
Sulfonylureas
Page 9 of 37
Potential Result
and bone marrow toxicity. Blood counts and liver
enzymes should be monitored monthly.
Enzyme induction by rifampin may increase the
clearance of leflunomide. Monitor plasma
concentrations of leflunomide and increase dose if
necessary.
Leflunomide may decrease the elimination of warfarin
through increased metabolism of CYP2C9. Monitor
International Normalized. Ratio levels, signs of
symptoms of bleeding and adjust warfarin dosage as
necessary.
Concurrent use may increase risk of methotrexate
toxicity.
Concurrent use may increase risk of hepatotoxicity.
Concurrent use may increase methotrexate levels.
Decreases methotrexate effectiveness by decreasing
enterohepatic recycling.
Cyclosporine may increase methotrexate levels.
Concurrent use of live vaccines and chemotherapeutic
agents may result in an increased risk of infection by
the live vaccines. Rotavirus vaccine is contraindicated
to be administered with chemotherapeutic agents.
May result in increased mercaptopurine toxicity due to
decreased xanthine oxidase metabolism.
These drugs may reduce renal clearance of
methotrexate. Consider decreasing methotrexate dose
and monitor for signs of toxicity. Do not administer
nonsteroidal anti-inflammatory drugs within 10 days of
high-dose methotrexate. Concomitant administration
with lower doses (7.5 to 15 mg/week) is usually well
tolerated.
Methotrexate toxicity may be increased by these drugs
due to protein binding displacement.
Concurrent use may result in increased risk of
hepatotoxicity.
Methotrexate may decrease the clearance of
theophylline. Theophylline levels should be monitored
when used concurrently with methotrexate.
Trimethoprim/sulfamethoxazole may increase bone
marrow suppression in patients receiving methotrexate.
Avoid concurrent administration if possible and monitor
for hematologic abnormalities.
Iron may decrease the absorption of penicillamine.
Separate administration by at least two hours.
Penicillamine may decrease digoxin effectiveness
through an unknown mechanism. Adjust digoxin dose
as necessary.
The action of cyclosporine may be reduced and oral
sulfonamides may increase the risk of nephrotoxicity.
Sulfasalazine may result in decreased absorption of
digoxin. Increase the digoxin dose as necessary.
Concurrent use may result in increased risk of
hepatotoxicity.
Concomitant use of sulfonamides and sulfonylureas
may increase the half-life of the sulfonylurea, increasing
February 12, 2013 Tennessee PAC
ENDOCRINE & METABOLIC AGENTS
Generic
Name
Interacting
Medication or Disease
the potential for hypoglycemia to occur.
The anticoagulant effect of warfarin may be enhanced,
increasing the potential for a hemorrhage.
Warfarin


Potential Result
All DMARDs, with the exception of leflunomide, have been used in clinical practice for
decades. The efficacy of DMARDs in treating rheumatoid arthritis has been well-studied
in placebo-controlled and head-to-head comparisons.
o The efficacy of auranofin, hydroxychloroquine, leflunomide, methotrexate,
penicillamine and sulfasalazine for rheumatoid arthritis were compared in
multiple meta-analyses. All DMARDs demonstrate efficacy in improving
American College of Rheumatology (ACR) criteria measures. There were no
significant difference in efficacy outcomes in any meta-analysis between
leflunomide, methotrexate, sulfasalazine and penicillamine. Auranofin was found
to be slightly less efficacious compared to other DMARDs in two studies and
hydroxychloroquine was found to be slightly less efficacious in one meta-analysis
regarding improvement in percentage of annual radiographic progression rate.
o A Cochrane review of penicillamine vs placebo found that although penicillamine
had a significant benefit in improving ACR criteria, 4.95 (95% confidence interval
[CI], 2.38 to 10.30) times as many patients taking more than 1,000 mg/day of
penicillamine and 2.60 (95% CI, 0.51 to 4.47) times as many patents taking 500
to 1,000 mg/day of penicillamine withdrew from therapy due to adverse reactions
compared to placebo.
Current guidelines from the ACR recommend that any patient diagnosed with rheumatoid
arthritis be offered treatment with DMARDs as either monotherapy or combination
therapy. The choice of a specific DMARD should be based on disease duration, activity
level, prognostic features, and specific patient characteristics. However, the ACR only
recommends methotrexate, leflunomide, sulfasalazine or hydroxychloroquine or certain
combinations of those drugs as initial therapy. The remaining DMARDs were not included
in the ACR recommendation due to either infrequent use or high incidence of adverse
effects. The National Institute for Health and Clinical Excellence guidelines for the
management and treatment of rheumatoid arthritis in adults does not favor any particular
DMARD as monotherapy, but recommends combination therapy with methotrexate and
at least one other DMARD as soon as possible.
RECOMMENDATION
Disease modifying anti-rheumatic drugs (DMARDs) are the primary initial treatment for rheumatoid
arthritis and should be offered as initial therapy to any patient diagnosed with rheumatoid arthritis.
The choice of initial agent or combination of agents should be based upon disease duration,
activity level, prognostic features and specific patient characteristics. Head-to-head comparisons
in medical literature have shown that, at the very least, methotrexate, leflunomide and
sulfasalazine have comparable efficacy, while auranofin, hydroxychloroquine and penicillamine
may be slightly less efficacious. Each individual DMARD is associated with dangerous adverse
effects and all, except sulfasalazine, have black box warnings. The only non-biological DMARDs
that the American College of Rheumatology recommends as initial therapy are methotrexate,
leflunomide, sulfasalazine or hydroxychloroquine or certain combinations of those drugs. The
National Institute for Health and Clinical Excellence guidelines for the management and treatment
of rheumatoid arthritis in adults does not favor any particular DMARD as monotherapy, but
recommends combination therapy with methotrexate and at least one other DMARD as soon as
possible. Due to their relative lower efficacy and lack of endorsement by current clinical guidelines,
penicillamine and auranofin can be considered inferior agents in this class. Therefore, it is
recommended at least methotrexate, leflunomide, sulfasalazine and hydroxychloroquine should be
available for use.
COMMITTEE VOTE:
APPROVED
Page 10 of 37
DISAPPROVED
APPROVED with MODIFICATION
February 12, 2013 Tennessee PAC
ENDOCRINE & METABOLIC AGENTS
RE-REVIEW: DMARDS
PREFERRED
NON-PREFERRED
®
®
hydroxychloroquine (compares to PLAQUENIL ) ARAVA (leflunomide)
®
® QL
leflunomide (compares to ARAVA )
AZULFIDINE
(sulfasalazine)
® QL
methotrexate
AZULFIDINE EN
(sulfasalazine EC)
®
®
RIDUARA (auranofin)
CUPRIMINE (penicillamine)
QL
®
®
Sulfasalazine (compares to AZULFIDINE )
DEPEN (penicillamine)
QL
®
sulfasalazine EC (compares to AZULFIDINE
PLAQUENIL (hydroxychloroquine)
®)
®
EN
RHEUMATREX (methotrexate)
®
TREXALL (methotrexate)
Quantity Limits
®
Azulfidine
®
Azulfidine EN
sulfasalazine
Sulfasalazine EC
8/day
8/day
8/day
8/day
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013.
Accessed January, 2013.
2. Thompson MICROMEDEX on-line © 1974-2012. Accessed January, 2013.
3. Med Metrics. Disease Modifying Anti-Rheumatic Medications Therapeutic Class Review.
November 9, 2012.
4. Osiri M, Shea B, Robinson V, Suarez-Almazor M, Strand V, Tugwell P, et al. Leflunomide
for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2003;(1):CD002047.
5. Gaujoux-Viala C, Smolen JS, Landewé R, Dougados M, Kvien TK, Mola EM, et al.
Current evidence for the management of rheumatoid arthritis with synthetic diseasemodifying antirheumatic drugs: a systematic literature review informing the EULAR
recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2010
Jun;69(6):1004-9.
6. Graudal N, Jürgens G. Similar effects of disease-modifying antirheumatic drugs,
glucocorticoids, and biologic agents on radiographic progression in rheumatoid arthritis:
Meta-analysis of 70 randomized placebo-controlled or drug-controlled studies, including
112 comparisons. Arthritis and Rheumatism. 2010 Oct;62(10):2852-63.
7. Maetzel A, Wong A, Strand V, Tugwell P, Wells G, Bombardier C. Meta-analysis of
treatment termination rates among rheumatoid arthritis patients receiving diseasemodifying anti-rheumatic drugs. Rheumatology (Oxford). 2000 Sep;39(9):975-81.
8. Suarez-Almazor M.E, Spooner C, Belseck E. Penicillamine for treating rheumatoid
arthritis. Cochrane Database Syst Rev. (Online) 2000(4):CD001460.
9. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. American College
of Rheumatology 2008 recommendations for the use of nonbiologic and biologic diseasemodifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008
Jun;15;59(6):762-84.
10. National Collaborating Centre for Chronic Conditions. Rheumatoid arthritis: the
management of rheumatoid arthritis in adults. London (UK): National Institute for Health
and Clinical Excellence (NICE); 2009 Feb;35 p.(NICE clinical guideline; no. 79).
Page 11 of 37
February 12, 2013 Tennessee PAC
ENDOCRINE & METABOLIC AGENTS
RE-REVIEW: ORAL MINERALOCORTICOIDS
BACKGROUND






Fludrocortisone is the only currently available mineralocorticoid.
Mineralocorticoids are steroid hormones that work within the distal renal tubule to
promote sodium resorption and hydrogen ion and potassium excretion.
Fludrocortisone is FDA- approved as partial replacement therapy for primary and
secondary adrenocortical insufficiency in Addison’s disease and for the treatment of saltlosing adrenogenital syndrome, also referred to as congenital adrenal hyperplasia.
Adverse events commonly associated with the use of fludrocortisone include edema,
abdominal distention, muscle weakness and electrolyte abnormalities. The majority of
adverse events occur as a result of the water and salt-retaining properties of the
mineralocorticoid. If used for a prolonged period of time, fludrocortisone therapy may also
be associated with glucocorticoid-related adverse events, such as osteoporosis and
impaired wound healing.
o Fludrocortisone is contraindicated in patients with systemic fungal infections.
o Fludrocortisone should be used cautiously in cases of diverticulitis, intestinal
anastomosis, ascites or latent peptic ulcers, renal insufficiency, hypertension,
osteoporosis, and myasthenia gravis. Fludrocortisone should be used cautiously
in patients with nonspecific ulcerative colitis if there is a likelihood of impending
abscess, perforation, or infection. Children on fludrocortisone are more
susceptible to infections than healthy children and may experience a more
serious or possibly fatal course of the disease. Use of fludrocortisone may lead to
increased susceptibility to infection and inability to localize infection. Additionally,
signs of infection may be masked and new infections may appear during use.
Fludrocortisone use may cause euphoria, insomnia, mood swings, changes in
personality, depression, psychotic tendencies; it may also aggravate existing
emotional instability or psychotic tendencies.
o Patients should not receive vaccines while taking fludrocortisone due to an
increased risk of infection from live vaccines and a lack of antibody response.
When use in combination, fludrocortisone use may enhance the hypokalemia
associated with potassium depleting diuretics. Fludrocortisone may increase the
risk of arrhythmia and digitalis toxicity associated with hypokalemia.
Clinical trials demonstrate that fludrocortisone effectively decreases plasma renin activity
and adrenocorticotropic hormone, improves sodium balance and improves overall
disease control according to patient-reported symptoms.
Current guidelines recommend mineralocorticoid use at diagnosis of congenital adrenal
hyperplasia and during infancy. The guidelines also suggest mineralocorticoid use in all
patients with the salt-losing form of congenital adrenal hyperplasia. Fludrocortisone has
also been used off-label for the treatment of orthostatic hypotension and as adjunct
therapy in septic shock if hydrocortisone is not available.
RECOMMENDATION
Fludrocortisone has been used in the treatment of salt-losing congenital adrenal hyperplasia and
as partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison’s
disease since 1955. Available data demonstrate the therapeutic benefit of utilizing this medication
for its sodium- and water-retaining properties. It has been shown to reduce plasma renin activity in
congenital adrenal hyperplasia and Addison’s disease. Fludrocortisone has also found utility in the
treatment of idiopathic orthostatic hypotension. It is recommended fludrocortisone should be
available for use.
COMMITTEE VOTE:
APPROVED
Page 12 of 37
DISAPPROVED
APPROVED with MODIFICATION
February 12, 2013 Tennessee PAC
ENDOCRINE & METABOLIC AGENTS
PREFERRED
fludrocortisone
RE-REVIEW: MINERALOCORTICOIDS
NON-PREFERRED
N/A
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2012.
Accessed December, 2012.
2. Thompson MICROMEDEX on-line © 1974-2012. Accessed December, 2012.
3. Med Metrics. Mineralocorticoids Therapeutic Class Review. August 9, 2012.
4. Clayton P, Miller W, Oberfield S, Ritzen M, Sippell W, Speiser P, et al. Consensus
statement on 21-hydroxylase deficiency from The Lawson Wilkins Pediatric Endocrine
Society and The European Society of Pediatric Endocrinology. J Clin Endocrinol Metab.
Sep 2002;87(9):4048-53.
5. Speiser P, Azziz R, Baskin L, Ghizzoni L, Hensle T, Merke D, et al. Congenital adrenal
hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society Clinical
Practice Guideline. Sep 2010;95(9):4133-60.
Page 13 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
RE-REVIEW: OPHTHALMIC ANTIHISTAMINES
BACKGROUND






Allergic conjunctivitis is the most common form of ocular allergy and may further be
classified into acute, seasonal or perennial allergic conjunctivitis. The symptoms from
any one of these forms, varies from ocular itching, redness, edema, photophobia and,
lacrimation as a result of type I immunoglobulin E (IgE)-mediated hypersensitivity.
This review will focus on the ophthalmic antihistamines which include alcaftadine,
azelastine, bepostastine, emedastine, epinastine, ketotifen, and olopatadine.
Following topical administration to the conjunctiva, ophthalmic antihistamines
competitively bind to histamine receptor sites to reduce itching and vasodilation. The
ophthalmic antihistamines also inhibit the degranulation of mast cells, thus limiting the
release of inflammatory mediators such as histamine and other chemical mediators
involved in allergic reactions. All of the ophthalmic antihistamines have demonstrated
both histamine type 1 (H1-antihistamine) and mast cell stabilizing properties with the
exception of emedastine.
FDA-Approved Indications:
alcaftadine, epinastine & ketotifen: for the prevention of ocular pruritus associated
with allergic conjunctivitis.
azelastine, bepostastine & olopatadine 0.2%: for the treatment of ocular itching
associated with allergic conjunctivitis.
emedastine & olopatadine 0.1%: for the treatment of signs and symptoms of
allergic conjunctivitis.
The most common adverse events associated with the use of the ophthalmic
antihistamines are ocular burning, stinging and headache.
o The ophthalmic antihistamines are all categorized as Pregnancy Category C,
with the exception of alcaftadine and emedastine, which is Pregnancy Category
B.
o Due to the topical administration of the ophthalmic antihistamines, systemic
absorption is minimal; therefore, clinically significant drug interactions are not
well defined.
As a result of the rapid onset of action of the ophthalmic antihistamines, many of the
studies comparing the ophthalmic antihistamines enrolled a small number of patients and
were conducted using single doses of the study medications with the conjunctival
allergen challenge (CAC) model. This study design attempts to induce an allergic
response to evaluate drug efficacy in a short-term study. Because of design limitations,
these studies give little information regarding long-term efficacy and safety with chronic
use of these agents.
o Greiner et al conducted a double-blind randomized controlled trial in patients
>18 years of age with a history of ocular allergies and/or a positive skin test
reaction to specified allergens within the last 24 months. This trial included 170
patients. All treatment groups (ophthalmic alcaftadine 0.05%, 0.10%, 0.25% and
ophthalmic olopatadine 0.1%) were associated with lower ocular itching scores
compared to placebo (P<0.05 for all comparisons). Compared to placebo, all
treatments significantly improved conjunctival redness scores at both 15 minutes
and 16 hours following administration (P<0.05 for all comparisons). A clinically
significant difference (≥1 unit difference from placebo) was only reported for the
ophthalmic alcaftadine 0.25% treatment group. At 16 hours following
administration, patients receiving ophthalmic alcaftadine 0.25% reported lower
ocular itching scores following allergen challenge compared to patients receiving
ophthalmic olopatadine (P=0.017).
o McCabe et al conducted a two-week trial (N=30), comparing ophthalmic
bepotastine to ophthalmic olopatadine 0.2%, there was a similar improvement in
the relief of morning ocular itch between treatments (P value not reported).
Page 14 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS

Patients treated with ophthalmic bepotastine reported a significantly greater relief
in evening ocular itch compared to patients receiving ophthalmic olopatadine
(P=0.011). With regard to patient preference, significantly more patients favored
treatment with ophthalmic bepotastine compared to ophthalmic olopatadine for
the all-day relief of ocular itching (63.3 vs 36.7%; P=0.04).
The American Academy of Ophthalmology (AAO) recommends an OTC ophthalmic
antihistamine/vasoconstrictor or ophthalmic antihistamine for the treatment of mild
allergic conjunctivitis. Ophthalmic allergy preparations with dual antihistamine and mastcell stabilizing properties may be used if the condition is recurrent or persistent. It should
be noted that current AAO guidelines do not give preference to one agent over another
within the class.
RECOMMENDATION
The ophthalmic antihistamines are FDA-approved for the treatment or prevention of the signs and
symptoms associated with allergic conjunctivitis. The American Academy of Ophthalmology
(AAO) recommends ophthalmic antihistamines as a treatment option for mild allergic conjunctivitis.
Additionally, guidelines state medications with dual antihistamine and mast-cell stabilizing
properties may be utilized for conditions that are recurrent or persistent, with no preference given
to one agent over another. Therefore it is recommended that at least 2 ophthalmic antihistamines
are available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: OPHTHALMIC ANTIHISTAMINES
PREFERRED
NON-PREFERRED
QL
® QL
Azelastine (compares to Optivar®)
BEPREVE
(Bepotastine)
® QL
® QL
BEPREVE
(Bepotastine)
ketotifen
® QL
® QL
ELESTAT
(epinastine)
PATADAY
(olopatadine)
® QL
EMADINE
(emedastine)
QL
Epinastine (compares to Elestat®)
® QL
LASTACAFT
(alcaftadine)
® QL
OPTIVAR
(azelastine)
® QL
PATANOL
(olopatadine)
® QL
ZADITOR
(ketotifen)
Quantity Limits
®
Bepreve / Bepotastine
®
Elestat / epinastine
®
Emadine /emedastine
®
Ketotifen/Zaditor
®
Lastacaft
®
Optivar /azelastine
®
PATADAY
®
PATANOL
10mL per Rx
5mL per Rx
5mL per Rx
10ml per RX
3mL per Rx
6mL per Rx
2.5mL per Rx
5mL per Rx
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013.
Accessed January, 2013.
2. Thompson MICROMEDEX on-line © 1974-2013. Accessed January, 2013.
Page 15 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
3. Med Metrics. Ophthalmic Antihistamines Therapeutic Class Review. December 11, 2012.
4. Greiner JV, Edwards-Swanson K, Ingerman A. Evaluation of alcaftadine 0.25%
ophthalmic solution in acute allergic conjunctivitis at 15 minutes and 16 hours after
instillation vs placebo and olopatadine 0.1%. Clin Ophthalmology. 2011;5:87-93.
5. McCabe CF, McCabe SE. Comparative efficacy of bepotastine besilate 1.5% ophthalmic
solution vs olopatadine hydrochloride 0.2% ophthalmic solution evaluated by patient
preference. Clin Ophthalmol. 2012;6:1731-8.
6. American Academy of Ophthalmology. Preferred Practice Pattern Guidelines.
Conjunctivitis [guideline on the Internet]. 2011 [cited 2012 Dec 10]. Available from:
http://one.aao.org/CE/PracticeGuidelines/PPP_Content.aspx?cid=79f4327d-6b7d-42e7bbf3-585e7c3852c7.
RE-REVIEW: OPHTHALMIC MAST CELL STABILIZERS
BACKGROUND




Allergic conjunctivitis is the most common form of ocular allergy and based on clinical
features may further be classified into acute, seasonal or perennial allergic conjunctivitis.
The symptoms from any one of these forms vary from ocular itching, redness, edema,
photophobia, and lacrimation as a result of type I immunoglobulin E (IgE)-mediated
hypersensitivity. Vernal conjunctivitis is a severe form of allergic conjunctivitis that may
involve the cornea and is more common in dry, warm climates. Vernal conjunctivitis may
be considered seasonal in moderate climates, with symptoms presenting in the spring.
The ophthalmic mast cell stabilizers, cromolyn, lodoxamide, nedocromil and pemirolast,
inhibit the degranulation of sensitized mast cells which occurs during the immediate
hypersensitivity reaction. In addition, mast cell stabilizers act by inhibiting the release of
histamine and other inflammatory mediators.
FDA approved indications are as follows:
o cromolyn sodium and lodoxamide: treatment of vernal keratoconjunctivitis,
vernal conjunctivitis and vernal keratitis
o nedocromil: treatment of ocular itching associated with allergic conjunctivitis
o pemirolast: prevention of ocular itching associated with allergic conjunctivitis
The most common adverse effects associated with ophthalmic use of the mast cell
stabilizers are burning/stinging sensation in the eye and headache. Other side effects
include:
 cromolyn sodium: taste perversion
 lodoxamide: blurred vision, burning sensation, and dry eye
 nedocromil: taste perversion and photophobia
 pemirolast: dry eyes and foreign body sensation
o



All of the ophthalmic mast cell stabilizers are Pregnancy Category B, with the
exception of pemirolast which is classified as Pregnancy Category C.
o Due to the topical administration of the ophthalmic mast cell stabilizers, systemic
absorption is minimal; therefore, clinically significant drug interactions are limited.
Caldwell et al evaluated cromolyn 4% QID versus lodoxamide 0.1% QID in 120 patients
over a 28 day duration. The clinical efficacy of lodoxamide was found to be more
effective than cromolyn 4% in improving clinical signs and symptoms of vernal
conjunctivitis (P values not reported).
Thirty-four patients (children 4 to 17 years of age) with VKC were randomized to receive
either nedocromil or cromolyn eye drops four times daily for 5 months. Nedocromil took
effect sooner and was superior to cromolyn in relief of itching, grittiness, hyperemia and
keratitis at 6 weeks (p<0.05) and of hyperemia (p<0.01), keratitis, papillae and
photophobia (p<0.05) at 22 weeks. Both treatments were well tolerated.
Shulman conducted a double-blind randomized controlled trial that evaluated nedocromil
2% BID versus pemirolast 0.1% BID in patients with seasonal allergic conjunctivitis over
Page 16 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS

an 8 week period. The trial included 78 patients where ophthalmic pemirolast was
reported to be as efficacious and safe as ophthalmic nedocromil for the treatment of
ragweed conjunctivitis; however, ophthalmic pemirolast was rated significantly more
comfortable than ophthalmic nedocromil.
The American Academy of Ophthalmology 2011 guidelines state treatment of allergic
conjunctivitis is based upon elimination of the offending allergens. The use of
pharmacological agents, including ophthalmic antihistamines and mast cell stabilizers,
may be useful in treating the associated symptoms. Clinical guidelines do not give
preference to one mast-cell stabilizer over another within the class. Additionally, the
guidelines recommend ophthalmic mast cell stabilizers if the patient’s condition is
recurrent or persistent.
RECOMMENDATION
The ophthalmic mast cell stabilizers are FDA (Food and Drug Administration) approved for the
management of signs and symptoms associated with allergic conjunctivitis. The American
Academy of Ophthalmology recommend that treatment of allergic conjunctivitis begin with removal
of the offending allergens and that pharmacological agents, including ophthalmic mast cell
stabilizers, may be useful in treating the associated symptoms. Ophthalmic mast cell stabilizers
are usually considered in patients with symptoms that are recurrent or persistent. Clinical
guidelines do not give preference to one mast-cell stabilizer over another within the class.
However, cromolyn and lodoxamide are the only agents within the class that are FDA approved for
the treatment of vernal conjunctivitis. Therefore it is recommended that at least 2 ophthalmic mast
stabilizers be available, one of which should be either cromolyn or lodoxamide for treatment of
vernal conjunctivitis.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: OPHTHALMIC MAST CELL STABILIZERS
PREFERRED
NON-PREFERRED
®
®
ALOCRIL (nedocromil)
ALAMAST (pemirolast)
®
cromolyn sodium
ALOMIDE (lodoxamide)
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013.
Accessed January, 2013.
2. Thompson MICROMEDEX on-line © 1974-2013. Accessed January, 2013.
3. Med Metrics. Ophthalmic Mast Cell Stabilizers Therapeutic Class Review. January 11,
2013.
4. Caldwell DR, Verin P, Hartwich-Young R, Meyer SM, Drake MM. Efficacy and safety of
lodoxamide 0.1% vs cromolyn sodium 4% in patients with vernal keratoconjunctivitis. Am
J Ophthalmol. 1992 Jun 15;113(6):632-7.
5. Verin PH, Dicker ID, Mortemousque B. Nedocromil sodium eye drops are more effective
than sodium cromoglycate eye drops for the long-term management of vernal
keratoconjunctivitis. Clin Exp Allergy. 1999 Apr;29(4):529-36.
6. Shulman DG. Two mast cell stabilizers, pemirolast potassium 0.1% and nedocromil
sodium 2%, in the treatment of seasonal allergic conjunctivitis: a comparative study. Adv
Ther. 2003 Jan-Feb;20(1):31-40.
Page 17 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
RE-REVIEW: OPHTHALMIC IMMUNOMODULATORS
BACKGROUND







Dry eye syndrome refers to a group of disorders of the tear film that are due to reduced
tear production or excessive tear evaporation. Disease and dysfunction on the ocular
surface results in an unstable and poorly maintained tear film that causes ocular irritation
symptoms and an epithelial disease known as keratoconjunctivitis sicca (KCS).
Decreased tear secretion and clearance initiates an inflammatory response on the ocular
surface which plays a role in the pathogenesis of KCS. Symptoms of KCS include, but
are not limited to: dryness, discomfort, irritation/pain, foreign body sensation,
photophobia, and blurred vision
The exact mechanism of action for cyclosporine ophthalmic emulsion is unknown;
however in patients whose tear production is presumed to be suppressed due to ocular
inflammation associated with KCS, cyclosporine ophthalmic emulsion is thought to act as
a partial immunomodulator.
Cyclosporine ophthalmic emulsion is FDA (Food and Drug Administration) approved to
increase tear production in patients whose tear production is thought to be suppressed
due to ocular inflammation associated with keratoconjunctivitis sicca.
The most common adverse effects of ophthalmic cyclosporine are ocular discharge,
ocular pain, ocular burning, conjunctival hyperemia, pruritus, and blurring.
o Cyclosporine ophthalmic emulsion is contraindicated in patients with active
ocular infections.
o Cyclosporine ophthalmic emulsion can be used concomitantly with artificial tears;
a fifteen minute interval should separate administration.
o Due to the limited systemic absorption of cyclosporine ophthalmic emulsion, no
drug interactions have been reported.
There are limited clinical trial data available to evaluate cyclosporine ophthalmic
emulsion. FDA approval was based on two randomized, placebo-controlled trials that
included 877 patients and an open-label, extension trial that included 412 patients. All
patients were diagnosed with moderate-to-severe KCS and decreased tear production
based on the Schirmer tear test. The combined results of the two placebo-controlled trials
demonstrated that cyclosporine ophthalmic emulsion 0.05% and 0.1% were associated
with significant improvements from baseline in corneal staining, Schirmer tear test
scores, Ocular Surface Disease Index (OSDI) scores, Subjective Facial Expression
Rating Scale scores, and various dry eye related symptoms.
One other trial compared cyclosporine to the use of punctal occlusion (of the lower lids)
and the combination of both therapies; both groups were also allowed to use concomitant
artificial tears throughout the study (n=30). Patients had moderate dry eye disease
defined as chronic symptoms of burning and scratchiness in both eyes; daily need for
multiple applications of artificial tears; and rose bengal staining of grade ≥2. The primary
endpoints were Schirmer scores (without anesthesia), corneal and conjunctival rose
bengal staining, and artificial tear use. The plug and combination groups demonstrated a
significant improvement relative to baseline (P≤0.005) and cyclosporine (P<0.001) in
mean Schirmer scores at the one and three month follow up visits. Initial response was
not seen in the cyclosporine group; these patients achieved a significant improvement
from baseline at the six month follow up visit (P≤0.005) which was indistinguishable from
the other groups (P values not reported). Mean artificial tear use declined significantly
from baseline in every treatment group at one and three months (P≤0.005 for all), except
for the cyclosporine group at one month. By the end of the study, the cyclosporine group
demonstrated a significant change from baseline in artificial tear use (P≤0.005) that was
statistically indistinguishable from other treatment groups.
Dry eye may be stratified by severity level into three categories based on the signs and
symptoms of disease, with treatment recommendations specific for disease severity.
Page 18 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS


However, it is noted that use any of the recognized treatment options for dry eye
syndrome may be used to treat the disease regardless of the severity rating.
The 2011 American Academy of Ophthalmology (AAO) Practice Patterns for Dry Eye
syndrome recommend a step therapy approach to treating dry eyes based on
classifications of mild, moderate and severe disease as outlined below:
o Treatment of mild dry eyes should include environmental modifications,
discontinuation of any offending topical or systemic medications, aqueous
enhancement using artificial tear substitutes, gels or ointments, eye lid therapy
(warm compressions and good hygiene) and treatment of other contributing
ocular factors (blepharitis or meibomianitis).
o Treatment for moderate dry eyes should include treatments for mild dry eyes and
then additive therapy with anti-inflammatory agents (topical corticosteroids,
cyclosporine), systemic omega 3-fatty acid supplements, punctal plugs,
spectacle side shields, or moisture chambers.
o Treatment for severe dry eyes should include treatments for mild and moderate
dry eyes and additional therapy may include systemic anti-inflammatory agents,
cholinergic, mucolytic agents, autologous serum tears, contact lenses,
permanent punctal occlusion, and correction of any eyelid abnormalities
Clinical Practice guidelines for treatment of conjunctivitis from the American Optometric
Association (AOA) recommend the use of topical cyclosporine as an alternative to topical
corticosteroids for treatment of patients with severe atopic keratoconjunctivitis.
Additionally, these guidelines state topical cyclosporine may be beneficial in patients with
vernal keratoconjunctivitis who have failed conventional therapy.
RECOMMENDATION
Cyclosporine ophthalmic emulsion is FDA (Food and Drug Administration) approved to increase
tear production in patients with KCS (keratoconjunctivitis sicca). Clinical guidelines consider
cyclosporine ophthalmic emulsion to be an appropriate therapy option for patients with moderate
dry eye syndrome, treatment of severe atopic KCS, and for patients with atopic KCS who have
failed conventional therapy. Additionally, limited clinical trials demonstrate cyclosporine
ophthalmic emulsion showed a significant improvement in tear production and dry eye symptoms.
The American Academy of Ophthalmology (AAO) recommends treatment options based on
disease severity, but do not specifically indicate cyclosporine ophthalmic emulsion as a first-line
agent. The American Optometric Association (AOA) recommends use of topical cyclosporine as
an alternative to topical corticosteroids in severe atopic keratoconjunctivitis, and may be beneficial
in patients with vernal keratoconjunctivitis who have failed conventional therapy. Therefore it is
recommended that cyclosporine ophthalmic emulsion is available subject to clinical criteria to
ensure appropriate use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: OPHTHALMIC IMMUNOMODULATORS
PREFERRED
NON-PREFERRED
® PA
RESTASIS
(cyclosporine ophthalmic
N/A
emulsion)
Page 19 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
®
Prior Authorization Criteria for Restasis :
Restasis will be approved for:
 Treatment of moderate to severe keratoconjunctivitis sicca (KCS) in patients who have failed
at least ONE of the following therapies:
o Artificial tears drops or ointments administered at least four times daily
o Hydroxypropyl cellulose insert (Lacrisert®)
o Punctal plugs
 Treatment of dry eyes in recipients with Sjogren’s disease
 Recipients using the agent status post corneal transplant
 Treatment of severe atopic keratoconjunctivitis who have tried and failed at least TWO
ophthalmic steroids or have contraindication or intolerance to ophthalmic steroids.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013.
Accessed January, 2013.
2. Thompson MICROMEDEX on-line © 1974-2013. Accessed January, 2013.
3. Med Metrics. Ophthalmic Immunomodulators Therapeutic Class Review. January 21,
2013.
4. Sall K, Stevenson OD, Mundorf T, Reis B, et al. Two multicenter, randomized studies of
the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye
disease. Ophthalmology. 2000;107(4):631-9.
5. Barber L, Pflugfelder S, Tauber J, Foulks G. Phase III safety evaluation of cyclosporine
0.1% ophthalmic emulsion administered twice daily to dry eye disease patients for up to
three years. Ophthalmology. 2005;112:1790-4.
6. Roberts C, Carniglia P, Brazzo B. Comparison of topical cyclosporine, punctal occlusion
and a combination for the treatment of dry eye. Cornea. 2007;26:805-9.
7. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice
Patterns® Guidelines. Dry Eye Syndrome – Limited Revision. San Francisco (CA):
American Academy of Ophthalmology; 2011. Available at
http://one.aao.org/CE/PracticeGuidelines/PPP.aspx.
8. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice
Pattern Guidelines. Conjunctivitis [guideline on the Internet]. San Francisco (CA):
American Academy of Ophthalmology; 2011 [cited 2012 Nov 30]. Available from:
http://one.aao.org/CE/PracticeGuidelines/PPP_Content.aspx?cid=79f4327d-6b7d-42e7bbf3-585e7c3852c7.
Page 20 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
RE-REVIEW: OPHTHALMIC ANTIBIOTICS
BACKGROUND
Neomycin/
Polymyxin
B/Bacitracin
Neomycin/
Polymyxin B/
Gramicidin
Bacitracin/
Polymyxin B
Tobramycin
Sulfacetamide
Sodium
Ofloxacin
Moxifloxacin
Levofloxacin 0.5%
Gentamicin
Gatifloxacin
Erythromycin
Ciprofloxacin
Ointment
Ciprofloxacin
Solution











*
























*Solution only
Page 21 of 37
Polymyxin B/
Trimethoprim
Adjunctive treatment in systemic sulfonamide
therapy of trachoma
Prophylaxis of ophthalmia neonatorum due to
Neisseria gonorrhoeae or Chlamydia trachomatis
Treatment of acute meibomianitis
Treatment of bacterial conjunctivitis
Treatment of blepharitis
Treatment of blepharoconjunctivitis
Treatment of corneal ulcers
Treatment of dacryocystitis
Treatment of external infections of the eye and its
adnexa
Treatment of keratitis
Treatment of keratoconjunctivitis
Treatment of superficial ocular infections
Treatment of superficial ocular infections involving
the conjunctiva and/or cornea
Besifloxacin
Indication
Bacitracin

Ophthalmic antibiotics are used to treat several ocular infections including blepharitis, conjunctivitis, keratitis and others. Ophthalmic
antibiotics are available from many drug classes including aminoglycosides, macrolides, polypeptides, quinolones and sulfonamides. This
class review focuses on single-agent and combination ophthalmic antibiotic products.
Food and Drug Administration Approved Indications
Single Entity Agents
Combination Products
Azithromycin

February 12, 2013 Tennessee PAC



OPHTHALMIC AGENTS



Adverse events with the ophthalmic antibiotics are generally mild. Common adverse
events include burning, ocular discomfort, stinging, and tearing.
o Since ophthalmic medications have minimal systemic absorption, studies have
not been conducted to assess drug interactions associated with these
medications.
The results from head-to-head studies do not consistently show any one ophthalmic
antibiotic as significantly more effective than another with regard to bacterial eradication,
clinical resolution, clinical response, severity rating or symptom improvement for any
indication.
Guidelines published by the American Academy of Ophthalmology recommend that
blepharitis be treated with ophthalmic bacitracin or ophthalmic erythromycin and note that
macrolide antibiotics may have anti-inflammatory activity with regard to the treatment of
blepharitis. In addition, the guidelines state that keratitis should be treated with a broadspectrum ophthalmic antibiotic that may be selected based on the isolated organism, and
if no organism is identified, treatment with an ophthalmic fluoroquinolone is
recommended. The American Academy of Ophthalmology guideline also notes that fewer
gram-positive cocci are resistant to ophthalmic gatifloxacin and moxifloxacin
hydrochloride. For the treatment of conjunctivitis, it is recommended that the least
expensive or most convenient broad-spectrum antibiotic be selected for a five to seven
day course of treatment.
RECOMMENDATION
Ophthalmic antibiotics are used to treat several ocular infections including blepharitis,
conjunctivitis, keratitis and others. Ophthalmic antibiotics are available from many drug classes
including aminoglycosides, macrolides, polypeptides, quinolones and sulfonamides. Results from
head-to-head studies do not consistently show any one ophthalmic antibiotic as significantly more
effective than another with regard to bacterial eradication, clinical resolution, clinical response,
severity rating or symptom improvement for any indication. Guidelines published by the American
Academy of Ophthalmology recommend that blepharitis be treated with ophthalmic bacitracin or
ophthalmic erythromycin and note that macrolide antibiotics may have anti-inflammatory activity
with regard to the treatment of blepharitis. In addition, the guidelines state that keratitis should be
treated with a broad-spectrum ophthalmic antibiotic that may be selected based on the isolated
organism, and if no organism is identified, treatment with an ophthalmic fluoroquinolone is
recommended. The American Academy of Ophthalmology guideline also notes that fewer grampositive cocci are resistant to ophthalmic fourth generation fluroquinolones. Therefore, it is
recommended at least six ophthalmic antibiotics should be available for use, which should include
erythromycin and at least one fourth generation fluroquinolone.
COMMITTEE VOTE:
APPROVED
Page 22 of 37
DISAPPROVED
APPROVED with MODIFICATION
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
RE-REVIEW: OPHTHALMIC ANTIBIOTICS
PREFERRED
NON-PREFERRED
®
®
AK-Poly-Bac (bacitracin/polymyxin B)
AZASITE (azithromycin)
®
bacitracin
BESIVANCE (besifloxacin)
®
®
bacitracin/poly B (compares to POLYSPORIN )
BLEP-10 (sulfacetamide sodium)
®
ciprofloxacin (compares to CILOXAN®)
CILOXAN (ciprofloxacin)
®
®
erythromycin (compares to ROMYCIN )
GARAMYCIN (gentamicin)
®
Gentak (gentamicin)
levofloxacin 0.5% solution (compares to QUIXIN®)
®
gentamicin
MOXEZA (moxifloxacin)
®
neomycin/bacitracin/poly B(compares to
NEOSPORIN (neomycin/polymyxin B/gramicidin &
NEOSPORIN®)
neomycin/bacitracin/gramicidin (compares to
NEOSPORIN®)
ofloxacin (compares to OCUFLOX®)
polymyxin B/TMP (compares to POLYTRIM®)
®
Romycin (erythromycin)
sulfacetamide sodium (compares to BLEP-10®)
tobramycin (compares to TOBREX®)
®
TOBREX (tobramycin)
®
VIGAMOX (moxifloxacin)
neomycin/bacitracin/polymyxin B)
®
OCUFLOX (ofloxacin)
®
POLYSPORIN (bacitracin/polymyxin B)
®
POLYTRIM (polymyxin B/trimethoprim)
®
QUIXIN (levofloxacin)
®
ZYMAXID (gatifloxacin)
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013.
Accessed January, 2013.
2. Thompson MICROMEDEX on-line © 1974-2012. Accessed January, 2013.
3. Med Metrics. Ophthalmic Antibiotics Therapeutic Class Review. December 31, 2012.
4. American Academy of Ophthalmology Preferred Practice Patterns Committee. Preferred
Practice Pattern Guidelines. Blepharitis [guideline on the Internet]. San Francisco (CA):
American Academy of Ophthalmology; 2011 [cited 2012 Nov 30]. Available from:
http://one.aao.org/CE/PracticeGuidelines/PPP_Content.aspx?cid=500cd9ca-173c-4c31b6ea-a258e3549474.
5. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice
Pattern Guidelines. Conjunctivitis [guideline on the Internet]. San Francisco (CA):
American Academy of Ophthalmology; 2011 [cited 2012 Nov 30]. Available from:
http://one.aao.org/CE/PracticeGuidelines/PPP_Content.aspx?cid=79f4327d-6b7d-42e7bbf3-585e7c3852c7.
6. American Academy of Ophthalmology Preferred Practice Patterns Committee. Preferred
Practice Pattern Guidelines. Bacterial keratitis [guideline on the Internet]. San Francisco
(CA): American Academy of Ophthalmology; 2011 [cited 2012 Nov 30]. Available at:
http://one.aao.org/CE/PracticeGuidelines/PPP_Content.aspx?cid=0f20807f-bc61-4f11b570-01ae26990edb.
RE-REVIEW: OPHTHALMIC ANTIBIOTIC STERIOD COMBINATIONS
BACKGROUND


Ophthalmic antibiotic steroid combination products are indicated for the treatment of
steroid-responsive ocular inflammatory conditions where the presence or risk of a
superficial bacterial ocular infection exists.
Adverse events with the ophthalmic antibiotic steroid combinations are generally mild.
Common adverse events include burning, ocular discomfort, stinging, and tearing. Use,
particularly long-term, can result in an increase in intraocular pressure, glaucoma and
cataract formation.
o All products in this class are contraindicated with mycobacterial and fungal
infections of ocular structures as well as viral disease of the cornea and
conjunctiva.
o Corticosteroid use may mask or enhance acute purulent infections of the eye.
Page 23 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
o
o


Ophthalmic ointments may slow corneal healing and cause blurred vision.
Since ophthalmic medications have minimal systemic absorption, studies have
not been conducted to assess drug interactions associated with these
medications
Clinical trials have demonstrated that ophthalmic antibiotic steroid combination products
are effective in treating and providing relief of in patients with external ocular infections,
including bacterial blepharitis, conjunctivitis and blepharokeratoconjunctivitis.
o In one study, the reduction in composite symptom scores in patients with
blepharokeratoconjunctivitis was similar between the tobramycin/dexamethasone
and tobramycin/loteprednol groups (-15.2±7.3 vs. -15.6±7.7); however, the
increase in intraocular pressure was significantly greater with
tobramycin/dexamethasone than tobramycin/loteprednol at day seven, day 15
and overall (0.6±2.3 vs -0.1±2.2 mm Hg; P=0.03, 1.0±3.0 vs -0.1±2.4 mm Hg;
P=0.01 and 2.3±2.3 vs 1.6±1.7 mm Hg; P=0.02, respectively).
Current clinical guidelines do not specifically address the ophthalmic antibiotic steroid
combination products; however, in their preferred practice pattern for the treatment of
bacterial keratitis, the American Academy of Ophthalmology states that ophthalmic
corticosteroid therapy may have a benficial role in treating some cases of infectious
keratitis due to the probable suppression of inflammation, which may reduce subsequent
corneal scarring and associated visual loss. The guidelines do not differentiate between
the available products.
RECOMMENDATION
Ophthalmic antibiotic steroid combination products are indicated for the treatment of steroidresponsive ocular inflammatory conditions where the presence or risk of a superficial bacterial
ocular infection exists. Results from head-to-head studies do not consistently show any one
ophthalmic antibiotic steroid combination product as significantly more effective than another with
regard to symptom improvement or reduction of postoperative inflammation. Clinical guidelines do
not differentiate between the available agents within this class. However, agents differ in their
FDA-approved ages with only tobramycin/dexamethasone and neomycin/polymyxin
B/dexamethasone approved for use in patients down to 2 years of age. Therefore, it is
recommended at least three ophthalmic antibiotic steroid combination products should be
available for use, with at least one of these being an ointment formulation and one approved for
use in patients down to 2 years of age. Additionally, given that loteprednol is associated with a
lower increase in IOP than other ophthalmic steroids, tobramycin/loteprednol should be available
for those patients in whom increased IOP is a concern.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: OPHTHALMIC ANTIBIOTIC STERIOD COMBINATIONS
PREFERRED
NON-PREFERRED
®
neomycin/bacitracin/polymyxin
BLEPHAMIDE (sulfacetamide/prednisolone)
®
B/hydrocortisone
MAXITROL (neomycin/polymyxin B/dexamethasone)
®
neomycin/polymyxin B/dexamethasone
POLYPRED (neomycin/polymyxin B/prednisolone)
(compares to MAXITROL®)
tobramycin/dexamethasone suspension (compares to
neomycin/polymyxin B/hydrocortisone
TobraDex®)
®
sulfacetamide/prednisolone (compares to
TOBRADEX Ointment (tobramycin/dexamethasone)
®
®
BLEPHAMIDE )
TOBRADEX ST suspension (tobramycin/dexamethasone)
®
® PA
PREDG (gentamicin/prednisolone)
ZYLET
(tobramycin/loteprednol)
®
TobraDex suspension
(tobramycin/dexamethasone)
Page 24 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
Prior Authorization Criteria for Zylet
®
Zylet® will be approved if the recipient has a contraindication or intolerance to any two of the
preferred ophthalmic antibiotic/steroid combination products, OR if there are concerns over a
potential increase in intra-ocular pressure (IOP) with other steroids (i.e. glaucoma, recipient is pre
or post cataract surgery and a known steroid-responder, etc.).
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013.
Accessed January, 2013.
2. Thompson MICROMEDEX on-line © 1974-2013. Accessed January, 2013.
3. Med Metrics. Ophthalmic Antibiotic Steroid Combinations Therapeutic Class Review.
December 31, 2012.
4. White EM, Macy JI, Bateman KM, Comstock TL. Comparison of the safety and efficacy of
loteprednol 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the
treatment of blepharokeratoconjunctivitis. Curr Med Res Opin. 2008;24(1):287-96.
5. American Academy of Ophthalmology Preferred Practice Patterns Committee. Preferred
Practice Pattern Guidelines. Bacterial keratitis [guideline on the Internet]. San Francisco
(CA): American Academy of Ophthalmology; 2011 [cited 2012 Nov 30]. Available at:
http://one.aao.org/CE/PracticeGuidelines/PPP_Content.aspx?cid=0f20807f-bc61-4f11b570-01ae26990edb.
RE-REVIEW: OPHTHALMIC ANTIVIRALS
BACKGROUND






Keratitis, or corneal infection and inflammation, caused by herpes simplex virus (HSV) is
a common and major cause of blindness. The HSV types associated with keratitis are
HSV-1 and -2. The HSV-1 subtype is responsible for the majority of ocular lesions. There
are four types of HSV keratitis and include infectious epithelial keratitis, stromal keratitis,
endotheliitis and neurotrophic keratopathy. Ocular herpes simplex virus (HSV) infections
are characterized by a primary outbreak and subsequent recurrences. After the primary
infection, HSV becomes latent in the trigeminal ganglion or the cornea and conditions
such as stress, ultraviolet radiation, hormonal changes and use of topical ophthalmic
medications can reactivate the virus. Lesions are common in immunosuppressed patients
such as those with a recent organ transplant or with human immunodeficiency virus.
Ophthalmic antiviral agents are one treatment option for ocular HSV; currently available
agents include trifluridine and ophthalmic ganciclovir.
Ophthalmic ganciclovir works as an antiviral agent by competitively inhibiting viral DNA
polymerases and by incorporation into viral DNA resulting in chain termination.
Trifluridine is incorporated in place of thymidine into viral DNA, resulting in faulty DNA
and the inability to reproduce or to infect or destroy tissue.
Ophthalmic ganciclovir is FDA approved for the treatment of acute herpetic keratitis
(approved for patients 2 years and older).
Trifluridine is FDA approved for primary keratoconjunctivitis and recurrent epithelial
keratitis due to HSV-1 and -2 (approved for patients 6 years and older).
The most common adverse reactions seen with ophthalmic ganciclovir include blurred
vision, conjunctival hyperemia, eye irritation, and punctuate keratitis. The most common
adverse reactions seen with trifluridine include burning and stinging upon instillation,
palpebral edema, and hyperemia.
o Patients should not wear contact lenses if they have signs or symptoms of
herpetic keratitis or during the course of therapy with ophthalmic ganciclovir.
o Administration of ophthalmic trifluridine may cause mild local irritation of the
conjunctiva and cornea when instilled, but these effects are usually transient.
Page 25 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
o



There are no significant drug-drug interactions identified with the ophthalmic
antivirals.
Currently there are no head-to-head clinical trials of ophthalmic ganciclovir and
ophthalmic trifluridine. As the older agent in the class, ophthalmic trifluridine has
established safety and efficacy in the treatment of keratitis. When compared to acyclovir,
which is not available as an ophthalmic dosage form, no significant difference between
the two treatments in cure rates was found (90% vs 75%; P value not reported).
Additionally, both treatments were well tolerated. Ophthalmic ganciclovir has also
demonstrated safety and efficacy in the treatment of keratitis, and when compared to
acyclovir, no significant differences in healing rates were observed; however, treatment
with ophthalmic ganciclovir did appear to be better tolerated.
In addition, a Cochrane review (N=5,363) found that the use of ophthalmic vidarabine
(discontinued), ophthalmic trifluridine, ophthalmic ganciclovir, or acyclovir resulted in
improvement in most patients with keratitis within one week of treatment, with no
treatment being significantly better than another.
According to the current American Academy of Ophthalmology treatment guideline,
ophthalmic trifluridine, ophthalmic ganciclovir, and oral acyclovir are potential treatment
options for the management of herpes simplex virus conjunctivitis. The guidelines does
not differentiate between the available treatment options.
RECOMMENDATION
Keratitis, or corneal infection and inflammation, caused by herpes simplex virus (HSV) is a
common and major cause of blindness. Ophthalmic antiviral agents are one treatment option for
ocular HSV; currently available agents include trifluridine and ophthalmic ganciclovir. Currently
there are no head-to-head clinical trials of ophthalmic ganciclovir and ophthalmic trifluridine.
However, both agents have established safety and efficacy in the treatment of keratitis. The
current clinical guidelines from the American Academy of Ophthalmology for the treatment of HSV
conjunctivitis state that ophthalmic trifluridine, ophthalmic ganciclovir and oral acyclovir are
potential treatment options, the guidelines do not give preference to one agent over another.
Therefore it is recommended that at least one ophthalmic antiviral agent be available for use.
Additionally, ophthalmic ganciclovir should be available for patients less than 6 years of age.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: OPHTHALMIC ANTIVIRALS
PREFERRED
NON-PREFERRED
®
®
trifluridine (compares to VIROPTIC )
VIROPTIC (trifluridine)
® PA
ZIRGAN
(ganciclovir)
Clinical Criteria for Zirgan
o
®
Prior Authorization not required for patients less than 6 years of age.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013.
Accessed January, 2013.
2. Thompson MICROMEDEX on-line © 1974-2012. Accessed January, 2013.
3. Med Metrics. Ophthalmic Antivirals Therapeutic Class Review. January 21, 2013.
4. Kessler HA, Hurwitz S, Farthing C, Benson CA, Feinberg J, Kuritzkes DR et al. Pilot study
of topical trifluridine for the treatment of acyclovir-resisitant mucocutaneous herpes
simplex disease in patients with AIDS (ACTG 172). AIDS Clinical Trials Group. J Acquir
Immune Defic Syndr Hum Retrovirol. 1996;12(2):147-52.
Page 26 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
5. La Lau C, Oosterhuis JA, Versteeg J, Van G, Renardel de Lavalette JGC, Craankijk A et
al. Multicenter trial of acyclovir and trifluorothymidine in herpetic keratitis. Am J Med.
1982;73(1A):305-6.
6. Hoh HB, Hurley C, Claoue C, Viswalingham M, Easty DL, Goldschmidt P et al.
Randomised trial of ganciclovir and acyclovir in the treatment of herpes simplex dendritic
keratitis: a multecentre study. Br J Ophthalmol. 1996;80:140-3.
7. Colin J, Hoh HB, Easty DL, Herbort CP, Resnikoff S, Rigal D et al. Ganciclovir ophthalmic
gel (Vigran; 0.15%) in the treatment of herpes simplex keratitis [abstract]. Cornea.
1997;16(4):393-9.
8. Wilhelmus K. Therapeutic interventions for herpes simplex virus epithelial keratitis.
Cochrane Database of Systematic Reviews. 2008, Issue 1. Art. No.: CD002898.
DOI:10.1002/14651858.CD002898.pub3.
9. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice
Pattern Guidelines. Conjunctivitis [guideline on the Internet]. San Francisco (CA):
American Academy of Ophthalmology; 2011 [cited 2013 Jan 11]. Available from:
http://one.aao.org/CE/PracticeGuidelines/PPP_Content.aspx?cid=79f4327d-6b7d-42e7bbf3-585e7c3852c7.
RE-REVIEW: OPHTHALMIC BETA BLOCKERS
BACKGROUND





Glaucoma is an optic neuropathy that causes gradual degeneration of the cells making
up the optic nerve. Glaucoma manifests initially as visual field loss and may progress to
blindness. Glaucoma is the leading cause of irreversible blindness and the second
leading cause of vision loss in the world.
Intraocular pressure (IOP) is the one major risk factor for glaucoma that is treatable.
Clinical evidence suggests that lowering IOP inhibits or reduces the progression of optic
nerve damage. The current treatment of glaucoma focuses on decreasing IOP by one of
three methods: laser therapy, surgery or pharmacological intervention. Treatment may
be initiated in patients with a raised IOP even in the absence of visual field loss or optic
nerve damage. Generally, an IOP greater than 22 mm Hg is considered to be elevated
and would be treated by most clinicians. The target IOP should be individualized based
on the patient’s response to therapy and disease progression; as there is no consensus
target IOP below which further visual loss and optic nerve damage will be prevented.
Pharmacological intervention is generally used as initial therapy prior to laser or surgical
treatment. Ophthalmic beta blockers are a primary treatment option for the management
of glaucoma and act to decrease aqueous humor production.
This class review consists of the following single-entity ophthalmic beta-blockers and
their FDA (Food and Drug Administration) approved indications:
o betaxolol hydrochloride- treatment of chronic open angle glaucoma or
ocular hypertension
o carteolol hydrochloride- treatment of chronic open angle glaucoma or
ocular hypertension either alone or in combination with other IOP lowering
therapies
o levobunolol- treatment of chronic open angle glaucoma or ocular
hypertension
o metipranolol- reduction of IOP in patients with open angle glaucoma or
ocular hypertension
o timolol hemihydrates/timolol maleate- treatment of elevated IOP in
patients with glaucoma or ocular hypertension
The most common adverse effects seen with ophthalmic beta blockers are primarily
ocular in nature and are similar between the agents; adverse effects include blurred
vision, eye erythema, transient ocular discomfort, burning sensation, and tearing.
o Due to timolol’s potential cardiac and pulmonary effects, timolol is
contraindicated in patients with bronchial asthma, a history of bronchial asthma,
severe chronic obstructive pulmonary disease, sinus bradycardia, second or third
degree atrioventricular block, overt cardiac failure, or cardiogenic shock.
Page 27 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
o


Asthmatic attacks and pulmonary distress have been reported with the use of
some beta-blocking agents. Caution should be exercised in the treatment of
glaucoma in patients with excessive restriction of pulmonary function.
o Ophthalmic beta blockers have low incidence of systemic absorption and no
significant drug-drug interactions have been identified.
Head-to-head trials in the ophthalmic beta-blockers class involving patients with openangle glaucoma or ocular hypertension show that all treatments are efficacious in
decreasing IOP from baseline; however, various results were seen when groups were
compared to each other.
o Evans et al compared betaxolol to timolol in patients with primary open angle
glaucoma (n=26). The study was conducted over a 16 week period with
alternating 4 week treatment periods & 4 week washout periods. The primary
endpoint was change in IOP from baseline/washout period. The timolol group
had a significant reduction in IOP when compared to baseline (22.2 mmHg vs
17.7 mmHg; P=0.007). However, the betaxolol group did not show a significant
change in IOP (21.7 mmHg vs 20.0 mmHg; P=0.09). Neither drug produced
significant changes with regards to heart rate, blood pressure, and visual field
sensitivity.
o Krieglstein et al compared levobunolol versus metipranolol in patients with open
angle glaucoma or ocular hypertension (N=46). Primary endpoint was change in
mean IOP from baseline. At each visit both groups had significant decreases
from baseline in mean IOP. However no significant between group differences
were seen at any visit or for overall mean change (P values not reported).
o Shedden et al compared timolol gel forming solution (GFS) versus timolol
solution in patients with open angle glaucoma or ocular hypertension (N=286).
The primary endpoint was change in IOP from baseline. Secondary endpoints
were adverse events, change in heart rate and blood pressure. No statistically
significant differences between the two treatment groups were seen with regard
to decreases in IOP. There were significantly more reports of blurred vision in the
timolol GFS group than the timolol solution (soln.) group (29% vs 18%; P=0.04)
as well as the incidence of tearing (7% vs 1%; P=0.04). Burning and/or stinging
was reported at a significantly higher rate in the timolol soln. group when
compared to the timolol GFS group (22% vs 12%; P=0.04). At week 12, the
decrease in mean heart rate was significantly less in the timolol GFS group when
compared to the timolol soln. group (-1.1 vs -4.2 beats per minute; P=0.024). At
week 24 the decrease in mean heart rate was less for the timolol GFS group,
however this was not found to be significant (-1.1 vs -3.6 beats per minute;
P=0.051).The mean change in blood pressure in both groups ranged from -4.1
mmHg to 0.8 mmHg and was not found to be statistically significant between the
two groups (P>0.05).
The American Academy of Ophthalmology and American Optometric Association clinical
guidelines recommend ophthalmic β adrenergic antagonists and prostaglandin analogues
as first-line pharmacologic therapy in patients with elevated IOP. Combination or
monotherapy with agents from an alternative pharmacologic class is recommended for
patients that experience intolerable adverse events or who do not achieve the optimal
IOP reduction with first-line agents.
RECOMMENDATION
Glaucoma manifests initially as visual field loss and may progress to blindness. Intraocular
Pressure (IOP) is the one major risk factor for glaucoma that is treatable. Clinical evidence
suggests that lowering IOP inhibits or reduces the progression of optic nerve damage. Head-tohead trials in the ophthalmic beta-blocker class involving patients with open-angle glaucoma or
ocular hypertension show that all treatments are efficacious in decreasing IOP from baseline.
However, various results were seen when groups were compared to each other. The American
Academy of Ophthalmology and American Optometric Association clinical guidelines recommend
ophthalmic beta blockers and prostaglandin analogues as first-line therapy agents in patients with
elevated IOP. Combination or monotherapy with agents from an alternative pharmacologic class
is recommended for patients that experience intolerable adverse events or who do not achieve the
Page 28 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
optimal IOP reduction with first-line agents. Additionally, guidelines do not specifically differentiate
between the agents. Therefore, it is recommended that at least 2 ophthalmic beta blockers are
available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: OPHTHALMIC BETA BLOCKERS
PREFERRED
NON-PREFERRED
®
carteolol
BETAGAN (levobunolol)
®
levobunolol (compares to Betagan )
betaxolol (compares to Betoptic S®)
®
®
metipranolol (compares to Optipranolol )
BETOPTIC-S (betaxolol)
®
®
timolol maleate (compares to Istalol ,
BETIMOL (timolol hemihydrates)
®
®
Timoptic )
ISTALOL (timolol maleate)
®
OPTIPRANOLOL (metipranolol)
®
TIMOPTIC (timolol maleate)
®
TIMOPTIC OCUDOSE (timolol maleate PF)
®
TIMOPTIC XE (timolol maleate gel)
timolol maleate gel forming soln (compares to
®
Timoptic XE )
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013.
Accessed January, 2013.
2. Thompson MICROMEDEX on-line © 1974-2013. Accessed January, 2013.
3. Med Metrics. Ophthalmic Beta Blockers Therapeutic Class Review. December 12, 2012.
4. Evans DW, Harris A, Cantor LB. Primary open-angle glaucoma patients characterized by
ocular vasospasm demonstrate a different ocular vascular response to timolol verses
betaxolol. J Ocul Pharmacol Ther. 1999:15(6):479-87.
5. Krieglstein GK, Novack GD, Voepel E, Schwarzback G, Lange U, Schunck KP, et al.
Levobunolol and metipranolol: comparative ocular hypotensive efficacy, safety, and
comfort. Br J Opthalmol. 1987;71:250-3.
6. Shedden A, Laurence J, Tipping R, Timoptic-XE 0.5% study group. Efficacy and
tolerability of timolol maleate ophthalmic gel-forming solution vs timolol ophthalmic
solution in adults with open-angle glaucoma or ocular hypertension: a six-month, doublemasked, multicenter study. Clin Ther. 2001;23(3):440-50.
RE-REVIEW: O PHTHALMIC CARBONIC ANHYDRASE INHIBITORS
BACKGROUND



Glaucoma is an optic neuropathy that causes gradual degeneration of the cells making
up the optic nerve. Glaucoma can be categorized into 4 distinct types which include
primary open-angle, acute angle-closure, secondary and congenital. Patients with openangle glaucoma initially experience peripheral visual field loss, followed by central field
loss, which may progress to irreversible blindness if left untreated.
Treatment of glaucoma focuses on decreasing intraocular pressure (IOP) by one of three
methods: laser therapy, surgery or pharmacological intervention. Pharmacological
intervention is generally used as initial therapy prior to laser or surgical treatment. There
are five classes of ophthalmic drugs used for the long-term management of glaucoma:
alpha-2 adrenergic agonists, β adrenergic antagonists, carbonic anhydrase inhibitors,
parasympathomimetics and prostaglandin analogues.
This class review will focus on the carbonic anhydrase inhibitors (CAI) which decreases
aqueous humor production. Brinzolamide, dorzolamide hydrochloride, and the fixed
Page 29 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS





dose combination product dorzolamide hydrochloride/timolol maleate comprise the CAI
drug class.
Brinzolamide and dorzolamide hydrochloride are Food and Drug Administration (FDA)
approved for the treatment of elevated IOP in patients with ocular hypertension or openangle glaucoma. The combination product, dorzolamide hydrochloride/timolol maleate is
indicated for the treatment of elevated IOP in patients with ocular hypertension or openangle glaucoma who inadequately respond to ophthalmic beta blockers.
A few common adverse reactions observed with the use of ophthalmic CAI include
blepharitis, a burning sensation in the eye, blurred vision, visual discomfort, ocular
pruritus, and ocular discharge.
Currently available trials support the FDA-approved indications for ophthalmic CAI and
have demonstrated these agents are a viable treatment option for the management of
intraocular pressure (IOP). However, the efficacy of ophthalmic carbonic anhydrase
inhibitors in reducing vision loss due to glaucoma has not been established in clinical
trials.
o A double-blind randomized controlled trial performed by March et al observed
brinzolamide 1% [1 drop into affected eye(s) BID] versus brinzolamide 1% [1
drop into affected eye(s) TID] versus timolol 0.5% [1 drop into affected eye(s)
BID]. This trial included 378 patients who were 21 years of age or older with
primary open-angle glaucoma or ocular hypertension. All three groups
demonstrated a statistically significant reduction in IOP from baseline
(P<0.0001). When timolol was compared to both brinzolamide groups, timolol
demonstrated a statistically significant reduction in IOP (P=0.0002, both groups).
o Strahlman et al conducted a double-blind randomized controlled trial in 523
patients between 21 to 85 years of age with open-angle glaucoma or ocular
hypertension. This trial reviewed Dorzolamide 2% [1 drop into affected eye(s)
TID] versus betaxolol 0.5% [1 drop into affected eye(s) BID] versus timolol 0.5%
[1 drop into affected eye(s) BID]. Over one year, dorzolamide reduced IOP by
approximately 23%, while timolol and betaxolol reduced the IOP by 25 and 21%,
respectively. When dorzolamide was compared to betaxolol, the percentage
decrease in IOP was not statistically significant (P values not reported).
o Two large meta-analyses evaluated the relative efficacy of ophthalmic
formulations of prostaglandin analogues, beta blockers, alpha agonists, and
carbonic anhydrous inhibitors in reducing IOP. These trials concluded that the
largest reduction in IOP occurred with ophthalmic prostaglandin analogues and
ophthalmic timolol maleate. Ophthalmic carbonic anhydrase inhibitors were
associated with a lower relative reduction in IOP; though, the changes from
baseline were statistically significant among patients receiving ophthalmic
carbonic anhydrase inhibitors.
The American Academy of Ophthalmology, American Optometric Association and
National Institute for Clinical Excellence recommend ophthalmic prostaglandin analogues
and ophthalmic beta blockers as first-line medication agents in patients with elevated
IOP. Ophthalmic carbonic anhydrase inhibitors are recommended as a second line agent
in patients who have not achieved a target IOP reduction or developed an intolerable
adverse event with an ophthalmic beta-blocker or an ophthalmic prostaglandin analogue.
Clinical studies do not show that one single agent within the class is safer or more
effective than the other. However, ophthalmic brinzolamide may be associated with less
burning and stinging compared to ophthalmic dorzolamide hydrochloride; while, taste
disturbance may be less common with ophthalmic dorzolamide hydrochloride.
RECOMMENDATION
All ophthalmic carbonic anhydrase inhibitors are indicated for use in the treatment of increased
IOP due to open-angle glaucoma or ocular hypertension. The combination product, dorzolamide
hydrochloride/timolol maleate, is indicated for use in patients with ocular hypertension or openangle glaucoma who had insufficient response to ophthalmic beta-blocker monotherapy.
Ophthalmic carbonic anhydrase inhibitors are recommended as a second line therapy option in
patients who have not achieved a target IOP reduction or developed an intolerable adverse event
with an ophthalmic beta-blocker or an ophthalmic prostaglandin analogue. Clinical trials
Page 30 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
demonstrate that ophthalmic carbonic anhydrase inhibitors are a viable treatment option for the
management of intraocular pressure (IOP), therefore it is recommended that at least one carbonic
anhydrase inhibitor is available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: O PHTHALMIC CARBONIC ANHYDRASE INHIBITORS
PREFERRED
NON-PREFERRED
® QL
® QL
AZOPT
(brinzolamide)
COSOPT
(dorzolamide HCL/timolol maleate)
QL
® QL
dorzolamide HCL (compares to
COSOPT PF
(dorzolamide HCL/timolol maleate
®
Trusopt )
PF)
QL
® QL
dorzolamide HCL/timolol maleate
TRUSOPT
( dorzolamide HCL)
®
(Compares to Cosopt )
Quantity Limits
®
AZOPT
Dorzolamide
®
Trusopt
dorzolamide HCL/timolol maleate
®
COSOPT
COSOPT® PF
3/month(billing units of 5)
2/month (billing units of 10 & 15) 15ml/month
30 mL/month 10ml/month
20 mL/month 10ml/month
60 vials
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2012.
Accessed January, 2013.
2. Thompson MICROMEDEX on-line © 1974-2013. Accessed January, 2013.
3. Med Metrics. Carbonic Anhydrase Inhibitors Therapeutic Class Review. December 31,
2012.
4. March W, Ochsner K, Brinzolamide Long-Term Therapy Study Group. The long-term
safety and efficacy of brinzolamide 1.0% (Azopt®) in patients with primary open-angle
glaucoma or ocular hypertension. Am J of Ophthalmol. 2000;129:136-43.
5. Strahlman E, Tipping R, Vogel R, International Dorzolamide Study Group. A doublemasked, randomized 1-year study comparing dorzolamide (Trusopt®), timolol, and
betaxolol. Arch Ophthalmol. 1995;113:1009-16.
RE-REVIEW: OPHTHALMIC MYDRIATICS & MYDRIATIC COMBOS
BACKGROUND


Mydriasis requires either paralysis of the pupillary constrictor muscles, achieved with the
use of anticholinergic agents, or stimulation of the dilator muscles, as produced by
sympathomimetics. Cycloplegia results from paralysis of the ciliary muscles, which is
also produced by the use of anticholinergics.
The anticholinergic agents, atropine, cyclopentolate, homatropine, scopolamine and
tropicamide dilate the pupil and paralyze accommodation. Therefore, these agents are
known as ophthalmic mydriatics and cylcoplegics and are most commonly used topically
in the examination of the eye and during ophthalmic procedures. They also may be used
in the management of inflammatory conditions of the eye to treat or prevent the formation
of adhesions between the lens and the iris (e.g., uveitis) and in strabismus.
Page 31 of 37
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS




Ophthalmic anticholinergics, atropine sulfate, cyclopentolate, homatropine, scopolamine
and tropicamide are FDA approved for the induction of mydriasis and cycloplegia.
Ophthalmic homatropine and atropine sulfate are also FDA approved for the
management of uveitis and ophthalmic scopolamine is also FDA approved for the
treatment of iridocyclitis, a type of uveitis. The combination cyclopentolate/phenylephrine
product is approved for producing mydriasis.
Adverse events commonly associated with the ophthalmic mydriatics are blurred vision,
burning sensation, eye irritation and light intolerance. Additionally, use of these agents
can be associated with a transient increase in intraocular pressure.
o All of the agents in this class are contraindicated in narrow-angle glaucoma.
Atropine is also contraindicated in patients with adhesions between the iris and
lens. Ophthalmic scopolamine is also contraindicated in patients with acute
hemorrhage, paralytic ileus, tachycardia secondary to cardiac insufficiency, or
myasthenia gravis. The combination product, cyclopentolate/phenylephrine is
contraindicated in patients with hypertension and ventricular arrhythmias as a
result of the sympathomimetic and anti-cholinergic effects from both components
contained within the product.
o Use of ophthalmic mydriatic containing products may cause central nervous
system disturbances, which is of greater concern in pediatric patients, but may
occur at any age, especially with higher strength solutions.
o Ophthalmic mydriatic preparations may contain benzalkonium chloride which
may be absorbed by contact lenses; therefore, contacts should be removed prior
to administration.
o There are no clinically significant and/or reported drug interactions associated
with the majority of the ophthalmic mydriatics.
There is limited clinical trial data regarding the efficacy and safety of the ophthalmic
mydriatics; however, these agents have been available for several years and are
established treatment options.
o Hofmeister, et al compared tropicamide to cyclopentolate in 30 myopic adult
patients undergoing refractive surgery. No statistically significant difference was
found between the two treatments’ cycloplegic refractions (tropicamide; P=0.10
and cyclopentolate; P=0.14).
The ophthalmic mydriatics vary in onset and duration of action; with cyclopentolate,
homatropine and tropicamide being preferred for ophthalmic procedures due to a more
rapid onset of action and a shorter duration of action compared to atropine sulfate and
scopolamine. The combination mydriatic agent is typically used to enhance mydriasis,
especially in patients who might respond poorly to anticholinergics alone, such as those
with dark irides or diabetes or for patients who are receiving prolonged miotic therapy. It
is also important to note, there are no pertinent clinical guidelines associated with these
agents in the clinical literature.
RECOMMENDATION
Atropine sulfate, cyclopentolate, homatropine, scopolamine and tropicamide are ophthalmic
mydriatics FDA approved for the induction of cycloplegia and mydriasis. These agents are most
commonly used topically in the examination of the eye and during ophthalmic procedures. They
also may be used in the management of inflammatory conditions of the eye to treat uveitis and in
strabismus. There is limited clinical trial data regarding the safety and efficacy of the ophthalmic
mydriatics; however, these agents are established treatment options. The combination mydriatic
agent is typically reserved to enhance mydriasis in patients who respond poorly to single entity
agents. Therefore, it is recommended that at least 2 ophthalmic mydriatic agents are available for
use.
COMMITTEE VOTE:
APPROVED
Page 32 of 37
DISAPPROVED
APPROVED with MODIFICATION
February 12, 2013 Tennessee PAC
OPHTHALMIC AGENTS
RE-REVIEW: MYDRIATICS & MYDRIATIC COMBOS
PREFERRED
NON-PREFERRED
®
®
Atropine-Care (atropine)
AK-PENTOLATE (cyclopentolate)
®
®
atropine (compares to Isopto Atropine )
CYCLOGYL (cyclopentolate)
®
cyclopentolate (compares to Cyclogyl®
CYCLOMYDRIL (cyclopentolate/phenylephrine)
®
®
1%, AK-pentolate )
ISOPTO ATROPINE (atropine)
®
®
tropicamide (compares to Tropicacyl ,
ISOPTO HOMATROPINE (homatropine)
®
®
Mydriacyl )
ISOPTO HYOSCINE (scopolamine)
®
MYDRIACYL (tropicamide)
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013.
Accessed January, 2013.
2. Thompson MICROMEDEX on-line © 1974-2013. Accessed January, 2013.
3. Med Metrics. Ophthalmic Mydriatics Therapeutic Class Review. January 4, 2013.
4. Hofmeister EM, Kaupp SE, Schallhorn SC. Comparison of tropicamide and cyclopentolate
for cycloplegic refractions in myopic adult refractive surgery patients [abstract]. J Cataract
Refract Surg. 2005;31(4):694-700.
Page 33 of 37
February 12, 2013 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: MISCELLANEOUS AGENTS FOR IBS
BACKGROUND






Constipation is a common gastrointestinal complaint. Constipation can be a symptom of
many different types of conditions. Common causes of constipation include low
fiber/poorly balanced diet, medications, hormonal and metabolic changes, irritable bowel
syndrome and some neurological diseases. Initial treatment options for constipation
include dietary changes, lifestyle modifications, and mild laxatives. This class review
consists of the miscellaneous IBS agents, which includes linaclotide and lubiprostone.
Lubiprostone works by activating chloride channel-2, a normal constituent of the apical
membrane of the human intestine. By increasing intestinal fluid secretion, lubiprostone
increases motility of the intestine, thereby increasing the passage of stool and alleviating
symptoms associated with constipation. Linaclotide is a minimally absorbed agonist of
the guanylate cyclase-C receptor. Linaclotide and its active metabolite bind to guanylate
cyclase-C and act locally on the luminal surface of the intestinal epithelium. Activation of
guanylate cyclase-C results in an increase in both intracellular and extracellular
concentrations of cyclic guanosine monophosphate. Elevation in intracellular cyclic
guanosine monophosphate stimulates secretion of chloride and bicarbonate into the
intestinal lumen, resulting in increased intestinal fluid and accelerated transit.
Lupriprostone and linaclotide are both FDA-approved for the treatment of chronic
idiopathic constipation. Linaclotide is also FDA-approved for the treatment of
constipation predominant irritable bowel syndrome (IBS-C) in adults while lubiprostone is
FDA-approved for the treatment of IBS-C only in females who are at least 18 years of
age.
Commonly reported side effects of lubiprostone include nausea, diarrhea and headache.
The most commonly reported side effects of linaclotide are gastrointestinal and include
diarrhea, nausea and abdominal pain.
o Linaclotide and lubiprostone are both contraindicated with known or suspected
mechanical gastrointestinal obstruction. Linaclotide is also contraindicated in
pediatric patients up to 6 years of age and use should be avoided in patients
aged 6 to 17 years of age.
o Linaclotide and lubiprostone both carry a warning regarding the risk of
development of diarrhea and that use should be stopped if severe diarrhea
develops. Lubiprostone carries a warning that nausea may develop; however
concomitant administration with food may lessen the development of nausea.
Lubiprostone also carries a warning of the risk of dyspnea which may resolve
within three hours although cases of recurrence have been reported. Dosage
adjustment of lubiprostone is required in patients with moderate to severe hepatic
impairment.
o There are no known drug interactions with linaclotide or lubiprostone.
Placebo controlled clinical trials have demonstrated the efficacy of both linaclotide and
lubiprostone for their FDA-approved indications. Currently, there are no head to head
clinical trials comparing these agents to one another or to other available therapies for
the treatment of constipation.
The American College of Gastroenterology 2009 guideline on the management of IBS
notes lubiprostone as more effective compared to placebo in alleviating global IBS
symptoms in women with constipation-predominant IBS; however, its role in comparison
to treatment alternatives is not discussed. The place in therapy of linaclotide is not
currently addressed in consensus guidelines on IBS. According to the World
Gastroenterology Organization guidelines, issued in 2011, osmotic laxatives, linaclotide,
or lubiprostone, may be used for chronic constipation relief after failure of lifestyle
modification, stopping or reducing constipation-inducing medications, and fiber
supplementation or bulking agents.
Page 34 of 37
February 12, 2013 Tennessee PAC
GASTROINTESTINAL AGENTS
RECOMMENDATION
Lubiprostone and linaclotide are FDA-approved for the treatment of chronic idiopathic constipation
as well as constipation-predominant IBS. Both agents have demonstrated efficacy for their FDAapproved indications in placebo controlled trials. To date, these agents have not been directly
compared to therapies which are recognized as first-line treatment strategies for constipation;
therefore they are typically reserved for patients in whom other approaches have been
unsuccessful. Current clinical guidelines include lubiprostone and linaclotide as treatment options
when therapy with dietary management, stopping or reducing constipation-inducing medications,
and treatment with laxatives have been unsuccessful. Due to the number of other treatment
options available for the management of constipation that have established safety profiles and are
recognized as first-line agents, it is recommended that agents in this class are subject to prior
authorization.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: MISCELLANEOUS AGENTS FOR IBS
NON-PREFERRED
®
PA,QL
AMITIZA (lubiprostone)
®
PA,QL
LINZESS (linaclotide)
PREFERRED
N/A
Prior Authorization Criteria for Amitiza
®
®
Approval for Amitiza will be granted upon documentation of:
 Diagnosis of idiopathic chronic constipation or constipation predominate irritable bowel
syndrome (IBS), AND
o Trial and failure of at least TWO other laxatives (bulk, osmotic, or stimulant)
ONE agent from TWO of the following classes:
o Osmotic laxatives
o Bulk-forming laxatives
o Stimulant laxatives
OR
 Diagnosis of constipation predominate irritable bowel syndrome (IBS) in female, AND
o Trial and failure of at least TWO other laxatives (bulk, osmotic, or stimulant)
ONE agent from TWO of the following classes:
o Osmotic laxatives
o Bulk-forming laxatives
o Stimulant laxatives
COMMITTEE VOTE:
APPROVED
DISAPPROVED
Prior Authorization Criteria for Linzess
APPROVED with MODIFICATION
®
®
Approval for Linzess will be granted upon documentation of:
 Diagnosis of idiopathic chronic constipation or constipation predominate irritable bowel
syndrome (IBS), AND
 Trial and failure of at least TWO other laxatives (bulk, osmotic, or stimulant) ONE agent
from TWO of the following classes:
o Osmotic laxatives
o Bulk-forming laxatives
o Stimulant laxatives
Page 35 of 37
February 12, 2013 Tennessee PAC
GASTROINTESTINAL AGENTS
COMMITTEE VOTE:
APPROVED
DISAPPROVED
Quantity Limits
®
Amitiza
®
Linzess
APPROVED with MODIFICATION
2/day
1/day
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2012.
Accessed January, 2013.
2. Thompson MICROMEDEX on-line © 1974-2012. Accessed January, 2013.
3. Med Metrics. Miscellaneous Irritable Bowel Syndrome Agents Therapeutic Class Review.
January 11, 2013.
4. American College of Gastroenterology. American College of Gastroenterology Task Force
on Irritable Bowel Syndrome: An Evidence-Based Systematic Review on the Management
of Irritable Bowel Syndrome. Am J Gastroenterol. 2009;104(Suppl 1):S1-S35.
5. World Gastroenterology Organization (WGO). Constipation: A global perspective. J Clin
Gastroenterol. 2011;45(6):483-7.
Page 36 of 37
February 12, 2013 Tennessee PAC
CRITERIA FOR REVIEW
Prior Authorization Criteria for Promacta®:
Approval will be granted if ALL of ONE the following criteria are met:
 Diagnosis of idiopathic thrombocytopenia purpura (ITP), AND
 Documentation of failure or insufficient response to adequate treatment
with corticosteroids AND immunoglobulins, OR ITP-related splenectomy,
AND
 Documentation that patient’s thrombocytopenia and clinical condition puts
the patient at increased risk of bleeding.
 Diagnosis of thrombocytopenia in patient with chronic hepatitis C, AND
o Patient receiving (or planning to initiate) interferon-based anti-viral
therapy
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for Exjade®
Exjade® will be approved for recipients two years of age and older who meet ALL of the
following criteria:
 Diagnosis of chronic iron overload due to blood transfusions, AND
o Serum ferritin > 1,000 mcg/L, OR
o Liver iron concentration between 3.2 and 7 mg Fe/g dw L
 Diagnosis of non-transfusion-dependent thalassemia (NTDT) in patients aged 10
& older, AND
o Serum ferritin > 1,000 mcg/L, OR
o Liver iron concentration between 3.2 and 7 mg Fe/g dw L
®
Exjade will not be approved for recipients with creatinine clearance less than 40 mL/min
or for recipients with platelet count less than 50x109/L.
Note: It is recommended that if the serum ferritin is consistently < 500mcg/L therapy
should be stopped; however, this may be up to the prescriber’s discretion in his/her
experience of treating patients with iron-overload.
COMMITTEE VOTE:
APPROVED
Page 37 of 37
DISAPPROVED
APPROVED with MODIFICATION
February 12, 2013 Tennessee PAC
`