NDC 24856-002 Jetrea

Ocriplasmin

NDC Product Code 24856-002

NDC 24856-002-01

Package Description: 1 VIAL, SINGLE-USE in 1 CARTON > .3 mL in 1 VIAL, SINGLE-USE

NDC Product Information

Jetrea with NDC 24856-002 is a a human prescription drug product labeled by Thrombogenics Inc.. The generic name of Jetrea is ocriplasmin. The product's dosage form is injection, solution and is administered via intravitreal form.

Labeler Name: Thrombogenics Inc.

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Jetrea Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • OCRIPLASMIN 1.25 mg/mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • CITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP)
  • MANNITOL (UNII: 3OWL53L36A)
  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • HYDROCHLORIC ACID (UNII: QTT17582CB)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravitreal - Administration within the vitreous body of the eye.
  • Intravitreal - Administration within the vitreous body of the eye.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Proteolytic Enzyme - [EPC] (Established Pharmacologic Class)
  • Peptide Hydrolases - [CS]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Thrombogenics Inc.
Labeler Code: 24856
FDA Application Number: BLA125422 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: BLA - A product marketed under an approved Biologic License Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 09-18-2017 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

End Marketing Date: 01-31-2021 What is the End Marketing Date?
This is the date the product will no longer be available on the market. If a product is no longer being manufactured, in most cases, the FDA recommends firms use the expiration date of the last lot produced as the EndMarketingDate, to reflect the potential for drug product to remain available after manufacturing has ceased. Products that are the subject of ongoing manufacturing will not ordinarily have any EndMarketingDate. Products with a value in the EndMarketingDate will be removed from the NDC Directory when the EndMarketingDate is reached.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Jetrea Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

JETREA® is a proteolytic enzyme indicated for the treatment of symptomatic vitreomacular adhesion.

2.1 General Dosing Information

For single-use ophthalmic intravitreal injection only. JETREA must only be administered by a qualified physician.This formulation of JETREA does not require dilution.

2.2 Dosing

The recommended dose is 0.125 mg (0.1 mL of the 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:Remove the vial (1.25 mg/mL corresponding to 0.375 mg ocriplasmin) from the freezer and allow to thaw at room temperature (within a few minutes). Use JETREA immediately after thawing. Unopened vials in the original carton protected from light can be stored up to 8 hours when stored below 77°F (25°C). Do not refreeze a vial once it has been thawed.Once completely thawed, remove the protective polypropylene blue flip-off cap from the vial (see Figure 1).Figure 1:The top of the vial should be disinfected with an alcohol wipe (see Figure 2).Figure 2:Visually inspect the vial for particulate matter. Only a clear, colorless solution without visible particles should be used.Using aseptic technique, withdraw all of the 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 3). Do not use this needle for the intravitreal injection.Figure 3: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 4).Figure 4:THE SOLUTION SHOULD BE USED IMMEDIATELY AS IT CONTAINS NO PRESERVATIVES.Discard the vial and any unused portion of the 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 [see Patient 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 [see Nonclinical 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).

3 Dosage Forms And Strengths

Injection: Single-use glass vial containing JETREA 0.375 mg in 0.3 mL solution for intravitreal injection (1.25 mg/mL).

4 Contraindications

None

5.1 Decreased Vision

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 [see Clinical 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 [see Dosage 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) [see Use 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 [see Nonclinical 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).

6 Adverse Reactions

  • The following adverse reactions are described below and elsewhere in the labeling:Decreased Vision [see Warnings and Precautions (5.1)]Intravitreal Injection Procedure Associated Effects [see Warnings and Precautions (5.2) and Dosage And Administration (2.4)]Potential for Lens Subluxation [see Warnings and Precautions (5.3)]Retinal Breaks [see Warnings and Precautions (5.4) and Dosage And Administration (2.4)]Dyschromatopsia [see Warnings 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.

8.1 Pregnancy

Teratogenic EffectsPregnancy 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 posterior vitreous detachment (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 a Pichia pastoris expression system.JETREA is a sterile, clear and colorless solution with no preservatives in a single-use glass vial containing 0.375 mg ocriplasmin in 0.3 mL solution for intravitreal injection.Each vial contains 0.375 mg ocriplasmin (active), 0.16 mg citric acid, 0.56 mg mannitol, 1.35 mg sodium chloride, sodium hydroxide and hydrochloric acid (for pH adjustment), and water for injection (q.s.). The pH of the solution is 3.1.

12.1 Mechanism Of Action

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 Ocriplasmina 2 subjects below lower limit of detection, other 2 subjects at 0.88 and 0.57 mcg/mLb Lower limit of detectionTime post-injection(subjects)5-30min(n=8)31-60min(n=8)2-4hours(n=8)24hr ± 2hr(n=4)7days ± 1day(n=4)Mean ± SDOcriplasmin levels (mcg/mL)12 ±7.68.1 ±5.22.6 ±1.60.5 ±0.3a<0.27bOcriplasmin enters the endogenous protein catabolism pathway through which it is rapidly inactivated via its interactions with protease inhibitor α2-antiplasmin or α2-macroglobulin.

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 (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 5).Table 2: Proportion of Patients with VMA Resolution in the Study Eye (Study 1, Study 2: Full Analysis Set)Study 1Study 2Vehicle N=107JETREAN=219Difference (95% CI)VehicleN=81 JETREA N=245 Difference(95% CI)n (%)n (%)n (%)n (%)Day 78 (7.5)54 (24.7)17.2 (9.6, 24.8)1 (1.2)36 (14.7)13.5 (8.4, 18.5)Day 1412 (11.2)57 (26.0)14.8 (6.5, 23.2)1 (1.2)44 (18.0)16.7 (11.4, 22.1)Day 2814 (13.1)61 (27.9)14.8 (6.0, 23.5)5 (6.2)62 (25.3)19.1 (11.6, 26.7)Month 316 (15.0)58 (26.5)11.5 (2.6, 20.5)7 (8.6)62 (25.3)16.7 (8.5, 24.9)Month 615 (14.0)60 (27.4)13.4 (4.5, 22.2)10 (12.3)65 (26.5)14.2 (5.1, 23.2)Figure 5: 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 6).Table 3: Categorical Change from Baseline in BCVA at Month 6, Irrespective of Vitrectomy (Study 1 and Study 2)Study 1Study 2JETREAVehicleDifferenceJETREAVehicleDifferenceN=219N=107(95% CI)N=245N=81(95% CI)≥3 line Improvement in BCVAMonth 628 (12.8%)9 (8.4%)4.4 (-2.5, 11.2)29 (11.8%)3 (3.8%)8.1 (2.3, 13.9)>3 line Worsening in BCVAMonth 616 (7.3%)2 (1.9%)5.4 (1.1, 9.7)10 (4.1%)4 (5.0%)-0.9 (-6.3, 4.5)Figure 6: 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 0.375 mg ocriplasmin in 0.3 mL preservative-free, citric-buffered solution (1.25 mg/mL). JETREA is supplied in a 2 mL glass vial with a blue polypropylene flip-off cap. The vial stopper is not made with natural rubber latex. Vials are for single use only.NDC 24856-002-01StorageStore 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 [see Warnings 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.Manufactured by:ThromboGenics, Inc.101 Wood Avenue South, Suite 610Iselin, NJ 08830U.S. License Number: 1866©2012, ThromboGenics, Inc. All rights reserved.Revised February 2017Initial U.S. Approval: 2012ThromboGenics U.S. patents: 7,445,775; 7,547,435; 7,914,783 and other pending patents.

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