____________________CONTRAINDICATIONS
____________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
JETREA safely and effectively. See full prescribing information for
JETREA
None. (4)
_______________WARNINGS AND PRECAUTIONS _______________
Decreases in vision due to progression of the condition with traction
may occur requiring surgical intervention. Patients should be monitored
and instructed to report any symptoms without delay. (5.1)
Intravitreal injection procedure associated effects (intraocular
inflammation/infection, intraocular hemorrhage and increased IOP)
may occur following an intravitreal injection. Patients should be
monitored and instructed to report any symptoms without delay.(5.2)
Potential for lens subluxation. (5.3)
•
•
JETREA (ocriplasmin) Intravitreal Injection, 2.5 mg/mL
®
For intravitreal injection
Initial U.S. Approval: 2012
__________________INDICATIONS AND USAGE
__________________
•
____________________ADVERSE REACTIONS
____________________
JETREA is a proteolytic enzyme indicated for the treatment of symptomatic
vitreomacular adhesion. (1)
The most commonly reported reactions (≥ 5%) in patients treated with
JETREA were vitreous floaters, conjunctival hemorrhage, eye pain, photopsia,
blurred vision, macular hole, reduced visual acuity, visual impairment, and
retinal edema. (6.1)
_______________DOSAGE AND ADMINISTRATION
Must dilute before use. (2.1)
_______________
•
•
•
For single use ophthalmic intravitreal injection only. (2.1)
The recommended dose is 0.125 mg (0.1 mL of the diluted solution)
administered by intravitreal injection to the affected eye once as a single
dose. (2.2)
To report SUSPECTED ADVERSE REACTIONS, contact
ThromboGenics Inc. at 1-855-253-7396 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
______________DOSAGE FORMS AND STRENGTHS
Single-use glass vial containing JETREA 0.5 mg in 0.2 mL solution for
intravitreal injection (2.5 mg/mL). (3)
______________
See 17 for PATIENT COUNSELING INFORMATION
Revised: 03/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
8
USE IN SPECIFIC POPULATIONS
8.1
8.3
8.4
8.5
OVERDOSAGE
DESCRIPTION
Pregnancy
1
2
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
Nursing Mothers
Pediatric Use
Geriatric Use
2.1
2.2
2.3
2.4
General Dosing Information
Dosing
Preparation for Administration
Administration and Monitoring
10
11
12
CLINICAL PHARMACOLOGY
3
4
5
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
12.1
12.3
NONCLINICAL TOXICOLOGY
Mechanism of Action
Pharmacokinetics
13
5.1
5.2
5.3
5.4
5.5
Decreased Vision
13.1
13.2
CLINICAL STUDIES
HOW SUPPLIED/STORAGE AND HANDLING
PATIENT COUNSELING INFORMATION
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal Toxicology and/or Pharmacology
Intravitreal Injection Procedure Associated Effects
Potential for Lens Subluxation
Retinal Breaks
14
16
17
Dyschromatopsia
6
ADVERSE REACTIONS
6.1
6.2
6.3
Clinical Trials Experience
Immunogenicity
Postmarketing Data
*Sections or subsections omitted from the full prescribing information
are not listed.
_____________________________________________________________________________________________________________________________
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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
JETREA
®
is a proteolytic enzyme indicated for the treatment of symptomatic vitreomacular adhesion.
2
DOSAGE AND ADMINISTRATION
General Dosing Information
2.1
Must be diluted before use. For single-use ophthalmic intravitreal injection only. JETREA must only be
administered by a qualified physician.
2.2
Dosing
The recommended dose is 0.125 mg (0.1 mL of the diluted solution) administered by intravitreal injection to the
affected eye once as a single dose.
2.3
Preparation for Administration
To prepare JETREA for intravitreal injection, adhere to the following instructions:
1. Remove the vial (2.5 mg/mL corresponding to 0.5 mg ocriplasmin) from the freezer and allow to thaw at
room temperature (within a few minutes).
2. Once completely thawed, remove the protective polypropylene flip-off cap from the vial (see Figure 1).
Figure 1:
3. The top of the vial should be disinfected with an alcohol wipe (see Figure 2).
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Reference ID: 3907134
Figure 2:
4. Using aseptic technique, add 0.2 mL of 0.9% w/v Sodium Chloride Injection, USP (sterile, preservative-free)
into the JETREA vial (see Figure 3) and gently swirl the vial until the solutions are mixed (see Figure 4).
Figure 3:
5
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Figure 4:
5. Visually inspect the vial for particulate matter. Only a clear, colorless solution without visible particles should
be used.
6. Using aseptic technique, withdraw all of the diluted solution using a sterile #19 gauge needle (slightly tilt the
vial to ease withdrawal) and discard the needle after withdrawal of the vial contents (see Figure 5). Do not
use this needle for the intravitreal injection.
Figure 5:
7. Replace the needle with a sterile #30 gauge needle, carefully expel the air bubbles and excess drug from the
syringe and adjust the dose to the 0.1 mL mark on the syringe (corresponding to 0.125 mg ocriplasmin) (see
Figure 6).
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Figure 6:
8. THE SOLUTION SHOULD BE USED IMMEDIATELY AS IT CONTAINS NO PRESERVATIVES.
9. Discard the vial and any unused portion of the diluted solution after single use.
2.4
Administration and Monitoring
The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include the
use of sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad
spectrum microbiocide should be administered according to standard medical practice.
The injection needle should be inserted 3.5 - 4.0 mm posterior to the limbus aiming towards the center of the
vitreous cavity, avoiding the horizontal meridian. The injection volume of 0.1 mL is then delivered into the
mid-vitreous.
Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular
pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If
required, a sterile paracentesis needle should be available.
Following intravitreal injection, patients should be instructed to report any symptoms suggestive of
endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurred or decreased
vision) without delay[seePatient Counseling Information (17)].
Each vial should only be used to provide a single injection for the treatment of a single eye. If the contralateral
eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum,
and injection needles should be changed before JETREA is administered to the other eye, however, treatment
with JETREA in the other 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.
Repeated administration of JETREA in the same eye is not recommended[seeNonclinical Toxicology (13.2)].
After injection, any unused product must be discarded.
No special dosage modification is required for any of the populations that have been studied (e.g. gender, elderly).
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3
DOSAGE FORMS AND STRENGTHS
Single-use glass vial containing JETREA 0.5 mg in 0.2 mL solution for intravitreal injection (2.5 mg/mL).
4
CONTRAINDICATIONS
None
5
WARNINGS AND PRECAUTIONS
Decreased Vision
5.1
A decrease of ≥ 3 line of best corrected visual acuity (BCVA) was experienced by 5.6% of patients treated with
JETREA and 3.2% of patients treated with vehicle in the controlled trials[seeClinical Studies (14)].
The majority of these decreases in vision were due to progression of the condition with traction and many
required surgical intervention. Patients should be monitored appropriately[seeDosage and Administration(2.4)].
5.2
Intravitreal Injection Procedure Associated Effects
Intravitreal injections are associated with intraocular inflammation / infection, intraocular hemorrhage and
increased intraocular pressure (IOP). In the controlled trials, intraocular inflammation occurred in 7.1% of
patients injected with JETREA vs. 3.7% of patients injected with vehicle. Most of the post-injection intraocular
inflammation events were mild and transient. Intraocular hemorrhage occurred in 2.4% vs. 3.7% of patients
injected with JETREA vs. vehicle, respectively. Increased intraocular pressure occurred in 4.1% vs. 5.3% of
patients injected with JETREA vs. vehicle, respectively.
5.3
Potential for Lens Subluxation
One case of lens subluxation was reported in a premature infant who received an intravitreal injection of
0.175 mg (1.4 times higher than the recommended dose)[seeUse in Specific Populations (8.4)]. Lens
subluxation was observed in three animal species (monkey, rabbit, minipig) following a single intravitreal
injection that achieved vitreous concentrations of ocriplasmin 1.4 times higher than achieved with the
recommended treatment dose. Administration of a second intravitreal dose in monkeys, 28 days apart, produced
lens subluxation in 100% of the treated eyes[seeNonclinical Toxicology (13.2)].
5.4
Retinal Breaks
In the controlled trials, the incidence of retinal detachment was 0.9% in the JETREA group and 1.6% in the
vehicle group, while the incidence of retinal tear (without detachment) was 1.1% in the JETREA group and 2.7%
in the vehicle group. Most of these events occurred during or after vitrectomy in both groups. The incidence of
retinal detachment that occurred pre-vitrectomy was 0.4% in the JETREA group and none in the vehicle group,
while the incidence of retinal tear (without detachment) that occurred pre-vitrectomy was none in the JETREA
group and 0.5% in the vehicle group.
5.5
Dyschromatopsia
Dyschromatopsia (generally described as yellowish vision) was reported in 2% of all patients injected with
JETREA. In approximately half of these dyschromatopsia cases there were also electroretinographic (ERG)
changes reported (a- and b-wave amplitude decrease).
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6
ADVERSE REACTIONS
The following adverse reactions are described below and elsewhere in the labeling:
· Decreased Vision[seeWarnings and Precautions (5.1)]
· Intravitreal Injection Procedure Associated Effects[seeWarnings and Precautions (5.2)andDosage and
Administration (2.4)]
· Potential for Lens Subluxation[seeWarnings and Precautions (5.3)]
· Retinal Breaks[seeWarnings and Precautions (5.4) and Dosage and Administration (2.4)]
· Dyschromatopsia[seeWarnings and Precautions (5.5)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates in one clinical trial
of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not
reflect the rates observed in practice.
Approximately 800 patients have been treated with an intravitreal injection of JETREA. Of these, 465 patients
received an intravitreal injection of ocriplasmin 0.125 mg (187 patients received vehicle) in the 2 vehicle-
controlled studies (Study 1 and Study 2).
The most common adverse reactions (incidence 5% - 20% listed in descending order of frequency) in the vehicle-
controlled clinical studies were: vitreous floaters, conjunctival hemorrhage, eye pain, photopsia, blurred vision,
macular hole, reduced visual acuity, visual impairment, and retinal edema.
Less common adverse reactions observed in the studies at a frequency of < 5% in patients treated with JETREA
included macular edema, increased intraocular pressure, anterior chamber cell, photophobia, vitreous detachment,
ocular discomfort, iritis, cataract, dry eye, metamorphopsia, pupillary reflex impaired, conjunctival hyperemia,
retinal degeneration, and visual symptoms perceived in the contralateral eye. .
Dyschromatopsia was reported in 2% of patients injected with JETREA, with the majority of cases reported from
two uncontrolled clinical studies. In approximately half of these dyschromatopsia cases there were also
electroretinographic (ERG) changes reported (a- and b-wave amplitude decrease).
6.2
Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. Immunogenicity for this product has not
been evaluated.
6.3
Postmarketing Experience
Night blindness has been identified during post-approval use of JETREA. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
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8
USE IN SPECIFIC POPULATIONS
Pregnancy
8.1
Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with ocriplasmin. There are no
adequate and well-controlled studies of ocriplasmin in pregnant women. It is not known whether ocriplasmin can
cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. The systemic
exposure to ocriplasmin is expected to be low after intravitreal injection of a single 0.125 mg dose. Assuming
100% systemic absorption (and a plasma volume of 2700 mL), the estimated plasma concentration is 46 ng/mL.
JETREA should be given to a pregnant woman only if clearly needed.
8.3
Nursing Mothers
It is not known whether ocriplasmin is excreted in human milk. Because many drugs are excreted in human milk,
and because the potential for absorption and harm to infant growth and development exists, caution should be
exercised when JETREA is administered to a nursing woman.
8.4
Pediatric Use
The use of JETREA in pediatric patients is not recommended. A single center, randomized, placebo controlled,
double masked clinical study to investigate the safety and efficacy of a single intravitreal injection of 0.175 mg
ocriplasmin in pediatric subjects as an adjunct to vitrectomy was conducted in 24 eyes of 22 patients. There were
no statistical or clinical differences between groups for the induction of total macular PVD, any of the secondary
endpoints or adverse events.
8.5
Geriatric Use
In the clinical studies, 384 and 145 patients were ≥ 65 years and of these 192 and 73 patients were ≥ 75 years in
the JETREA and vehicle groups respectively. No significant differences in efficacy or safety were seen with
increasing age in these studies.
10
OVERDOSAGE
The clinical data on the effects of JETREA overdose are limited. One case of accidental overdose of 0.250 mg
ocriplasmin (twice the recommended dose) was reported to be associated with inflammation and a decrease in
visual acuity.
11
DESCRIPTION
Ocriplasmin is a recombinant truncated form of human plasmin with a molecular weight of 27.2 kDa produced by
recombinant DNA technology in aPichia pastorisexpression system.
JETREA is a sterile, clear and colorless solution with no preservatives in a single-use glass vial containing 0.5 mg
ocriplasmin in 0.2 mL solution for intravitreal injection after dilution.
Each vial contains 0.5 mg ocriplasmin (active) and 0.21 mg citric acid, 0.75 mg mannitol, sodium hydroxide (for
pH adjustment) and water for injection. The pH of the solution is 3.1.
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12
CLINICAL PHARMACOLOGY
Mechanism of Action
12.1
Ocriplasmin has proteolytic activity against protein components of the vitreous body and the vitreoretinal
interface (VRI) (e.g. laminin, fibronectin and collagen), thereby dissolving the protein matrix responsible for the
vitreomacular adhesion (VMA).
12.3
Pharmacokinetics
The intravitreal pharmacokinetics of ocriplasmin were determined in a clinical study in patients scheduled for
vitrectomy where 0.125 mg ocriplasmin (corresponding to an average concentration of 29 mcg ocriplasmin per
mL vitreous volume [approximately 4.3 mL/eye]) was administered as a single intravitreal dose at different time
points prior to vitrectomy. The mean ocriplasmin activity levels decreased with time from injection to time of
sampling as illustrated in Table 1, according to a second-order kinetic process. At 24 hours post-injection the
levels in the vitreous were below 3% of the theoretical concentration reached immediately after injection.
Because of the small dose administered (0.125 mg), detectable levels of ocriplasmin in systemic circulation are
not expected after intravitreal injection.
Table 1:
Mean Ocriplasmin Activity Levels in Vitreous Samples after Intravitreal Injection of
0.125 mg Ocriplasmin
Time post-injection
(subjects)
5-30min
(n=8)
31-60min
(n=8)
2-4hours
(n=8)
24hr ± 2hr
(n=4)
7days ± 1day
(n=4)
Mean ± SD
Ocriplasmin levels
(mcg/mL)
12 ±7.6
8.1 ±5.2
2.6 ±1.6
0.5 ±0.3a
< 0.27b
a 2 subjects below lower limit of detection, other 2 subjects at 0.88 and 0.57 mcg/mL
b Lower limit of detection
Ocriplasmin enters the endogenous protein catabolism pathway through which it is rapidly inactivated via its
interactions with protease inhibitor α2-antiplasmin or α2-macroglobulin.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity, mutagenicity or reproductive and developmental toxicity studies were conducted with
ocriplasmin.
13.2
Animal Toxicology and/or Pharmacology
The ocular toxicity of ocriplasmin after a single intravitreal dose has been evaluated in rabbits, monkeys and
minipigs. Ocriplasmin induced an inflammatory response and transient ERG changes in rabbits and monkeys,
which tended to resolve over time. Lens subluxation was observed in the 3 species at ocriplasmin concentrations
in the vitreous at or above 41 mcg/mL, a concentration 1.4-fold above the intended clinical concentration in the
vitreous of 29 mcg/mL. Intraocular hemorrhage was observed in rabbits and monkeys.
A second intravitreal administration of ocriplasmin (28 days apart) in monkeys at doses of 75 mcg/eye
(41 mcg/mL vitreous) or 125 mcg/eye (68 mcg/mL vitreous) was associated with lens subluxation in all
ocriplasmin treated eyes. Sustained increases in IOP occurred in two animals with lens subluxation. Microscopic
findings in the eye included vitreous liquefaction, degeneration/disruption of the hyaloideocapsular ligament
11
Reference ID: 3907134
(with loss of ciliary zonular fibers), lens degeneration, mononuclear cell infiltration of the vitreous, and
vacuolation of the retinal inner nuclear cell layer. These doses are
1.4-fold and 2.3-fold the intended clinical concentration in the vitreous of 29 mcg/mL, respectively.
14
CLINICAL STUDIES
The efficacy and safety of JETREA was demonstrated in two multicenter, randomized, double masked, vehicle-
controlled, 6 month studies in patients with symptomatic vitreomacular adhesion (VMA). A total of 652 patients
(JETREA 464, vehicle 188) were randomized in these 2 studies. Randomization was 2:1 (JETREA:vehicle) in
Study 1 and 3:1 in Study 2.
Patients were treated with a single injection of JETREA or vehicle. In both of the studies, the proportion of
patients who achieved VMA resolution at Day 28 (i.e., achieved success on the primary endpoint) was
significantly higher in the ocriplasmin group compared with the vehicle group through Month 6 (
Table 2 and Figure 7).
Table 2:
Proportion of Patients with VMA Resolution in the Study Eye (Study 1, Study 2: Full
Analysis Set)
Figure 7:
Proportion of Patients with VMA Resolution in the Study Eye (Study 1 and Study 2)
Total posterior vitreous detachment (PVD) induction in symptomatic vitreomacular adhesion patients was
evaluated by B-scan ultrasound. A statistically significantly higher percentage of JETREA treated patients
achieved total PVD at Day 28 compared to vehicle treated patients in Study 1 (16% vs. 6%; p=0.014) and in
Study 2 (11% vs. 0%; p<0.01).
The number of patients with at least 3 lines increase in visual acuity was numerically higher in the ocriplasmin
group compared to vehicle in both trials, however, the number of patients with at least a 3 lines decrease in visual
acuity was also higher in the ocriplasmin group in one of the studies (
Table 3 and Figure 8).
Table 3:
Categorical Change from Baseline in BCVA at Month 6, Irrespective of Vitrectomy (Study 1
and Study 2)
Figure 8:
Percentage of Patients with Gain or Loss of ≥ 3 Lines of BCVA at Protocol- Specified Visits
16
HOW SUPPLIED/STORAGE AND HANDLING
Each vial of JETREA contains 0.5 mg ocriplasmin in 0.2 mL citric-buffered solution (2.5 mg/mL). JETREA is
supplied in a 2 mL glass vial with a latex free rubber stopper. Vials are for single use only.
NDC 24856-001-00
Storage
Store frozen at or below -4˚F (-20˚C). Protect the vials from light by storing in the original package until time of
use.
17
PATIENT COUNSELING INFORMATION
In the days following JETREA administration, patients are at risk of developing intraocular
inflammation/infection. Advise patients to seek immediate care from an ophthalmologist if the eye becomes red,
sensitive to light, painful, or develops a change in vision[seeWarnings and Precautions (5.2)].
Patients may experience temporary visual impairment after receiving an intravitreal injection of JETREA [see
Warnings and Precautions (5.1)].Advise patients to not drive or operate heavy machinery until this visual
impairment has resolved. If visual impairment persists or decreases further, advise patients to seek care from an
ophthalmologist.
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Reference ID: 3907134
Manufactured for:
ThromboGenics, Inc.
101 Wood Avenue South, Suite 610
Iselin, NJ 08830
U.S. License Number: 1866
©2012, ThromboGenics, Inc. All rights reserved.
Revised March 2016
Initial U.S. Approval: 2012
ThromboGenics U.S. patents: 7,445,775; 7,547,435; 7,914,783 and other pending patents.
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Reference ID: 3907134
