Coverage Policy Manual
Policy #: 2013049
Category: Pharmacy
Initiated: December 2013
Last Review: January 2019
  Ocriplasmin (Jetrea®) for Symptomatic Vitreomacular Adhesion

Description:
Ocriplasmin (Jetrea®, ThromboGenics Inc., Iselin, NJ) is a recombinant truncated form of human plasmin, a proteolytic enzyme that breaks down protein components at the vitreoretinal interface in the eye. Ocriplasmin is injected into the affected eye (intravitreal) as a single dose and can induce vitreous liquefaction and separation from the retina. Its proposed use is for the treatment of symptomatic vitreomacular adhesion.
 
Background
The vitreous is a gel-like fluid within the eye that adheres completely to the surface of the retina. The consistency of the vitreous and its adhesion to the retina are maintained by several proteins including collagen, laminin, and fibronectin. With aging, the proteins in the vitreous break down, resulting in liquefaction of the vitreous and eventual separation of the vitreous from the retina, a process called posterior vitreous detachment (PVD).
 
The process of vitreous detachment usually proceeds without incident, but sometimes the separation is not complete. The adhesion usually remains at sites where the bonds between the vitreous and retina are the strongest. Adhesion at the macula is called vitreomacular adhesion (VMA). In some cases vitreomacular adhesion can cause visual symptoms. The traction caused by the adherent vitreous can cause deformation of the retina, edema, and macular holes. The retina may tear or detach. Symptoms can be variable, but can include diminished visual acuity, distorted vision (metamorphopsia) and central field defect.
 
Patients are usually observed until resolution or worsening, in which case vitrectomy is the only treatment. Although it is believed that only 10% of cases resolve spontaneously, observation is usually indicated because vitrectomy has risks and an almost certain occurrence of cataract in the years following vitrectomy (Hikichi, 1995; Jackson, 2013).
 
Ocriplasmin is a recombinant product that is a shortened form of the protease plasmin. Early studies of ocriplasmin were conducted in patients who were scheduled to have vitrectomy and established doses that showed some effect in inducing PVD and the temporal course of the effect. Studies by Benz et al., de Smet et al., and Stalmans et al. led to the design and conduct of the pivotal clinical trials described in the Rationale section of this policy (Benz, 2010; de Smet, 2009; Stalmans, 2010).
 
Regulatory Status
Ocriplasmin (Jetrea®) received U.S. Food and Drug Administration (FDA) approval October 17, 2012 for the treatment of symptomatic vitreomacular adhesion. There were no contraindications noted. In the Warnings and Precautions section of the prescribing information, it was noted that a higher percentage of subjects treated with ocriplasmin in the clinical trials had worsening of visual acuity of 3 or more lines than subjects in the control group. Transient injection-associated effects such as inflammation occurred in a higher percentage of subjects treated with ocriplasmin than control subjects.
 

Policy/
Coverage:
Effective April 2019
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Ocriplasmin meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for:
    • A single intravitreal injection of ocriplasmin for treatment of an eye with symptomatic vitreomacular adhesion (VMA).
    • Treatment of the contralateral eye is not recommended within 7 days of the initial injection in order to monitor the post-injection course, including the potential for decreased vision in the injected eye.  
    • Repeat administration of ocriplasmin in the same eye is not approved.
    • Only 2 injections (1injection in each eye) are allowed per lifetime.
 
Dosing and administration
The recommended dose is 0.125 mg (0.1ml) administered by intravitreal injection to the affected eye once as a single dose.   Any other dosing outside of the recommended FDA guidelines will be denied.  
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of intravitreal ocriplasmin in all other situations, including use of repeat injections of ocriplasmin does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, the use of intravitreal ocriplasmin is considered investigational in all other situations, including use of repeat injections of ocriplasmin. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective prior to April 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
A single intravitreal injection of ocriplasmin for treatment of an eye with symptomatic vitreomacular adhesion (VMA) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of intravitreal ocriplasmin in all other situations, including use of repeat injections of ocriplasmin does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, the use of intravitreal ocriplasmin is considered investigational in all other situations, including use of repeat injections of ocriplasmin. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
The principal evidence supporting ocriplasmin for symptomatic vitreomacular adhesion (VMA) is the published study by Stalmans et al (Salmans, 2012.) The study presents pooled results of 2 identically designed double-blind placebo-controlled randomized trials. Patients enrolled in the study met strict inclusion and exclusion criteria listed in the policy statement. They were not currently scheduled to have vitrectomy, but according to assessment by their physician, 84% were expected to need vitrectomy if their condition did not improve. Overall, 652 eyes were treated; 464 with ocriplasmin and 188 with placebo. The principal endpoint of the study, resolution of vitreomacular adhesion at 28 days, occurred in 26.5% of ocriplasmin-treated patients and 10.1% of placebo-treated patients. Other 28-day secondary endpoints, posterior vitreal detachment and closure of macular holes, also favored ocriplasmin.
 
Secondary outcomes measured beyond 28 days were also better in ocriplasmin-treated eyes. By 6 months, 17.7% of ocriplasmin-treated subjects had undergone vitrectomy versus 26.6% of placebo-treated subjects. Visual improvement results varied depending on how the data were analyzed, but generally favored ocriplasmin. Measured as categorical improvement of 3 or more lines on the Early Treatment of Diabetic Retinopathy (ETDRS) chart, ocriplasmin-treated subjects had higher success rates than placebo-treated subjects. Absolute gains in both groups were modest, particularly in the analysis where improvement was only counted in those who did not undergo vitrectomy (9.7% and 3.7%, respectively).
 
A higher proportion of patients in the ocriplasmin group had a clinically meaningful (≥5 point) improvement on 25-item National Eye Institute Visual Function Questionnaire scores (36.0% vs 27.2%, p=0.03), and fewer ocriplasmin-treated patients had a clinically meaningful worsening in their visual function compared with the placebo group (15.0% vs 24.3%, p=0.005) (Varma, 2015). Serious adverse events (SAEs) in ocriplasmin-injected eyes were not significantly different from placebo-injected eyes (7.7% ocriplasmin, 10.7% placebo) (Kaiser, 2015). The most common adverse effects reported in patients treated with ocriplasmin include eye floaters; bleeding of the conjunctiva, eye pain; flashes of light (photopsia); blurred vision; vision loss; retinal edema (swelling); and macular edema.
 
A phase 2 randomized, sham-controlled trial in 100 patients with age-related macular degeneration (AMD) was primarily intended to evaluate adverse effects, but also reported on efficacy results (Novack, 2015). Adverse events were higher in the ocriplasmin group, and SAEs in the study eye were observed in 10.7% of ocriplasmin-injected eyes compared with 0% sham-treated eyes. The efficacy in releasing VMAs was numerically similar to the MIVI-TRUST trial, but the difference was not statistically significant (24.3% vs 12.0%, p=0.26). Visual acuity was similar for the 2 groups.
A 2015 report for the American Society of Retina Specialists Therapeutic Surveillance Committee assessed adverse events from regulatory reports of 999 injections administered during clinical trials and voluntary reports of adverse events from 4387 doses administered postmarketing (Hahn, 2015). This publication described some reports, in a small percentage of patients, of significant and permanent vision loss, electroretinogram changes, dyschromatopsia, retinal tear/detachment, lens subluxation, impaired pupillary reflex, loss or disruption of the ellipsoid zone, vascular attenuation or vasoconstriction, and nyctalopia (night blindness). The rates of these adverse events cannot be determined with certainty due to the voluntary nature of reporting, raising the possibility of incomplete reporting.
 
2014 Update
A literature search conducted through August 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Ongoing and Unpublished Clinical Trials
As search of the online site clinicaltrials.gov in July 2014 identified the following study:
  • NCT02035748 is a distributor (Alcon)-sponsored Phase IV study to observe the anatomical and functional outcome of ocriplasmin injection over a 6-month period. The study has an estimated enrollment of 400 patients from 90 centers in Europe and Canada. The target completion date is June 2015.
 
In 2013, the National Institute for Health and Care Excellence (NICE) issued guidance on ocriplasmin for treating vitreomacular traction (NICE, 2013). NICE recommends ocriplasmin as an option for treating vitreomacular traction (VMT) in adults, only if:
  • an epiretinal membrane is not present and
  • they have a stage II full-thickness macular hole with a diameter of 400 micrometres or less and/or
  • they have severe symptoms.
 
2017 Update
A literature search conducted through January 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
The principal evidence supporting ocriplasmin for symptomatic vitreomacular adhesion (VMA) is the published study by Stalmans and colleagues for the MIVI-TRUST study group (Stalmans, 2010). The study presented pooled results of 2 identically designed, double-blind, placebo-controlled randomized trials. Patients enrolled in the trial met strict inclusion and exclusion criteria: they were not currently scheduled to have vitrectomy, but according to assessment by their physicians, 84% were expected to need vitrectomy if their conditions did not improve. Overall, 652 eyes were treated, 464 with ocriplasmin and 188 with placebo. The principal study end point, resolution of VMA at 28 days, was met by 26.5% of ocriplasmin-treated patients and by 10.1% of placebo-treated patients. Other 28-day secondary end points (posterior vitreal detachment, closure of macular holes) also favored ocriplasmin.
 
Secondary outcomes measured beyond 28 days were also better in ocriplasmin-treated eyes. By 6 months, 17.7% of ocriplasmin-treated subjects had undergone vitrectomy versus 26.6% of placebo-treated subjects. Visual improvement varied depending on how data were analyzed, but generally favored ocriplasmin. Measured as categorical improvement of 3 or more lines on the Early Treatment of Diabetic Retinopathy chart, ocriplasmin-treated subjects showed greater improvement than placebo-treated subjects. Absolute gains in both groups were modest, particularly in the analysis that only considered those who did not undergo vitrectomy (9.7% and 3.7%, respectively). A higher proportion of patients in the ocriplasmin group had a clinically meaningful (≥5 point) improvement on 25-item National Eye Institute Visual Function Questionnaire scores (36.0% vs 27.2%, p=0.03), and fewer ocriplasmin-treated patients had a clinically meaningful worsening in their visual function compared with the placebo group (15.0% vs 24.3%, p=0.005) (Varma, 2015). Resolution of VMA at 28 days, regardless of treatment group, was associated with greater improvement in visual acuity at all-time points (7.5-letter improvement vs 2.1-letter improvement, p<0.001) (Gandorfer, 2015).
 
Serious adverse events (SAEs) in ocriplasmin-injected eyes did not differ significantly from placebo-injected eyes (7.7% ocriplasmin vs 10.7% placebo) (Kaiser, 2015). The most common adverse effects reported in patients treated with ocriplasmin include eye floaters, bleeding of the conjunctiva, eye pain, flashes of light (photopsia), blurred vision, vision loss, retinal edema (swelling), and macular edema.
 
A phase 2, sham-controlled, randomized trial of 22 pediatric patients scheduled to undergo vitrectomy was intended to demonstrate whether ocriplasmin might permit a faster surgical procedure and fewer complications (Drenser, 2016). Use of ocriplasmin in pediatric patients is not currently recommended. The primary study outcome was the proportion of eyes with posterior vitreous detachment at the beginning of vitrectomy or after suction. This outcome might indicate a vitrectomy procedure that is easier to complete. The primary outcome was observed in 50% of the ocriplasmin group and 62.5% of the placebo group. This result does not reveal any potential benefit of ocriplasmin.
 
January 2018
 
A literature search conducted using the MEDLINE database through December 2017 did not reveal any new literature that would prompt a change in the coverage statement. The identified publications are summarized below.
 
Shah et al surveyed 2465 retinal physicians about ocriplasmin use and adverse events—270 (11%) completed questionnaires (reporting on 1056 treated eyes) (Shah, 2016). The most common adverse events reported included acute visual acuity decline (17.0%), retinal detachment or submacular fluid (10.2%), dyschromatopsia (9.1%), progression to macular hole (8.7%), retinal detachment (2.7%), retinal tear (2.0%), and afferent pupillary defect (1.8%). Reported adverse event rates were higher than those in clinical trial data (eg, incidence of decline in visual acuity in trials was 7.7%). However, the survey-based estimates would likely to be influenced by the high rate of physician nonresponse.
 
Chatziralli et al. conducted a meta-analysis ocriplasmin for vitreomacular traction (VMT) (Chatziralli, 2016). Results from 19 studies were pooled—randomized controlled trial, cohort, case-control, or cross-sectional designs were included. No study quality (risk of bias) appraisal was performed. Factors predictive for VMT release were adhesion diameter, age less than 65 years, female, and lack of a phakic lens. The pooled rate of macular hole closure was 33% (95% confidence interval, 326 to 39; I2=0%; 13 studies). Adverse event rates were summarized for 874 eyes, including acute decrease in visual acuity (17.4%), subretinal fluid (8.8%), dyschromatopsia (0.9%), progression to macular hole (5.0%), retinal detachment/tear (1.8%), and afferent pupillary defect (0.1%). Except for decreased acute visual acuity, adverse event rates were considerably lower than those from the Shah survey. While some factors were associated with response, implications are limited by the study-level nature of the meta-analysis.
 
American Academy of Ophthalmology
The American Academy of Ophthalmology’s 2016 preferred practice pattern on idiopathic epiretinal membrane and VMT offered the following recommendations:
 
“The treating physician should discuss the option of treating patients who have VMT with ocriplasmin and compare the treatment with observation, a gas bubble injected into the vitreous, or vitrectomy surgery. (good quality, strong recommendation) The discussion should include the relevant risks versus benefits for each of these options. (good quality, strong recommendation)” (Folk, 2016)
 
2019 Update
A literature search through December 2018 did not reveal any new literature that would prompt a change in policy coverage decision.  

CPT/HCPCS:
67028Intravitreal injection of a pharmacologic agent (separate procedure)
J7316Injection, ocriplasmin, 0.125 mg

References: Benz MS, Packo KH, Gonzalez V et al.(2010) A placebo-controlled trial of microplasmin intravitreous injection to facilitate posterior vitreous detachment before vitrectomy. Ophthalmology 2010; 117(4):791-7.

Chatziralli I, Theodossiadis G, Xanthopoulou P, et al.(2016) Ocriplasmin use for vitreomacular traction and macular hole: A meta-analysis and comprehensive review on predictive factors for vitreous release and potential complications. Graefes Arch Clin Exp Ophthalmol. Jul 2016;254(7):1247-1256. PMID 27137631

de Smet MD, Gandorfer A, Stalmans P et al.(2009) Microplasmin intravitreal administration in patients with vitreomacular traction scheduled for vitrectomy: the MIVI I trial. Ophthalmology 2009; 116(7):1349-55, 55 e1-2.

Drenser K, Girach A, Capone A, Jr.(2016) A randomized, placebo-controlled study of intravitreal ocriplasmin in pediatric patients scheduled for vitrectomy. Retina. Mar 2016;36(3):565-575. PMID 26398685

Drenser K, Girach A, Capone A, Jr.(2016) A randomized, placebo-controlled study of intravitreal ocriplasmin in pediatric patients scheduled for vitrectomy. Retina. Mar 2016;36(3):565-575. PMID 26398685

Duker JS, Kaiser PK, Binder S, et al.(2013) The International Vitreomacular Traction Study Group classification of vitreomacular adhesion, traction, and macular hole. Ophthalmology. Dec 2013;120(12):2611-2619. PMID 24053995

Folk JC, Adelman RA, Flaxel CJ, et al.(2016) Idiopathic epiretinal membrane and vitreomacular traction Preferred Practice Pattern® guidelines. Ophthalmology. Jan 2016;123(1):P152-181. PMID 26578445

Gandorfer A, Benz MS, Haller JA, et al.(2015) Association between anatomical resolution and functional outcomes in the mivi-trust studies using ocriplasmin to treat symptomatic vitreomacular adhesion/vitreomacular traction, including when associated with macular hole. Retina. Jun 2015;35(6):1151-1157. PMID 25741816

Gandorfer A, Benz MS, Haller JA, et al.(2015) Association between anatomical resolution and functional outcomes in the mivi-trust studies using ocriplasmin to treat symptomatic vitreomacular adhesion/vitreomacular traction, including when associated with macular hole. Retina. Jun 2015;35(6):1151-1157. PMID 25741816

Hahn P, Chung MM, Flynn HW, Jr., et al.(2015) Safety profile of ocriplasmin for symptomatic vitreomacular adhesion: A comprehensive analysis of premarketing and postmarketing experiences. Retina. Jun 2015;35(6):1128-1134. PMID 25635575

Hikichi T, Yoshida A, Trempe CL.(1995) Course of vitreomacular traction syndrome. Am J Ophthalmol 1995; 119(1):55-61.

Jackson TL, Donachie PH, Sparrow JM et al.(2013) United Kingdom National Ophthalmology Database Study of Vitreoretinal Surgery: Report 1; Case mix, complications, and cataract. Eye (Lond) 2013; 27(5):644-51.

Kaiser PK, Kampik A, Kuppermann BD, et al.(2015) Safety profile of ocriplasmin for the pharmacologic treatment of symptomatic vitreomacular adhesion/traction. Retina. Jun 2015;35(6):1111-1127. PMID 25635577

National Institute of Health and Care Excellence (NICE).(2013) Ocriplasmin for treating vitreomacular traction. 2013; TA297:http://publications.nice.org.uk/ocriplasmin-for-treating-vitreomacular-traction-ta297/guidance. Accessed June, 2014.

Novack RL, Staurenghi G, Girach A, et al.(2015) Safety of intravitreal ocriplasmin for focal vitreomacular adhesion in patients with exudative age-related macular degeneration. Ophthalmology. Apr 2015;122(4):796-802. PMID 25435217

Shah SP, Jeng-Miller KW, Fine HF, et al.(2016) Post-marketing survey of adverse events following ocriplasmin. Ophthalmic Surg Lasers Imaging Retina. Feb 2016;47(2):156-160. PMID 26878449

Stalmans P, Benz MS, Gandorfer A et al.(2012) Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med 2012; 367(7):606-15.

Stalmans P, Delaey C, de Smet MD et al.(2010) . Intravitreal injection of microplasmin for treatment of vitreomacular adhesion: results of a prospective, randomized, sham-controlled phase II trial (the MIVI-IIT trial). Retina 2010; 30(7):1122-7.

Varma R, Haller JA, Kaiser PK.(2015) Improvement in Patient-Reported Visual Function After Ocriplasmin for Vitreomacular Adhesion: Results of the Microplasmin for Intravitreous Injection-Traction Release Without Surgical Treatment (MIVI-TRUST) Trials. JAMA Ophthalmol. Jun 11 2015.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.