2.1 General Dosing Information

iDose TR is a travoprost delivery system consisting of a travoprost releasing implant pre-loaded in a sterile, single-dose inserter. iDose TR is administered intracamerally through a small, clear corneal incision and is anchored into the sclera at the iridocorneal angle. iDose TR should not be readministered to an eye that received a prior iDose TR.

2.2 Administration

1. The procedure must be carried out under aseptic conditions which include use of sterile gloves and a sterile drape.
2. The eye should be anesthetized using general, retrobulbar, peribulbar, or topical anesthesia per standard operating room procedures.
3. The iDose TR implantation procedure must be performed under magnification that allows clear visualization of the anterior chamber angle and angle structures including trabecular meshwork, with the patient’s head in a stabilized position. The pupil should not be dilated prior to the procedure.
4. An intracameral miotic can be injected to deepen the angle prior to insertion of the iDose TR.
5. It is recommended that the implant surgery be performed from the temporal side, using a temporal clear corneal incision. The implant will be implanted through the angle and the trabecular meshwork into the sclera on the nasal side.
6. Remove the barrier pouch from the carton and examine for damage. Open the barrier pouch, discard the oxygen scavenger packet, and remove the blister tray with Tyvek® lid. Open the Tyvek lid containing the iDose TR pre-loaded inserter and present to the surgeon. The iDose TR implant and single-dose inserter should be handled in the sterile field. Caution: Do not use the iDose TR if the Tyvek lid has been opened or the packaging appears damaged.
7. Prepare for gonioscopy by turning the patient’s head away from the surgeon by approximately 15° to 25° and tilt the scope toward the surgeon by approximately 35°. The total combined angle should be approximately 50° to 60°.
8. Place a small amount of viscoelastic on the cornea. Position the gonioprism on the cornea using light touch gonioscopy. Adjust the microscope to locate and focus on the trabecular meshwork.
9. Inspect the angle with a gonioprism to ensure that a good view of all angle structures is available at the nasal implant location.
10. Hold the single-dose inserter as shown in Figure 1 with your index finger comfortably on the implant release button.

Figure 1

11. Perform a detailed inspection of the tip of the sterile inserter under magnification to ensure that the iDose TR implant is present (Figure 2)

Figure 2

12. Create a clear corneal incision of approximately 2.4 mm at the temporal limbus location using an instrument of the surgeon’s choice.
13. Add a cohesive viscoelastic to the anterior chamber as needed to form the anterior chamber and improve visualization of the angle. Be careful not to overinflate.
14. Insertion of the implant:
a. When ready for implantation, remove the safety clip which holds the release button in place by squeezing and rocking the clip backwards (see Figure 2). Place finger on the release button to ensure it remains in the forward position and does not prematurely release the implant.
b. To smoothly enter the anterior chamber, slide the inserter tip with implant “side to side” in the incision.
c. Advance to the pupillary margin and ensure there is sufficient cohesive viscoelastic on the cornea before replacing the gonioprism onto the cornea.
d. Take care to avoid contact with the lens or cornea.
e. Advance to the anterior chamber angle and approach the trabecular meshwork (see Figure 3).

Figure 3

f. Press the implant directly through the trabecular meshwork, compressing the tissue until the implant anchor securely penetrates the sclera through the back wall of Schlemm’s canal. The base of the implant reservoir should be firmly in contact with and compressing the trabecular meshwork.
g. Once the anchor of the implant is securely embedded in sclera, pause for the tissue to relax. Carefully slide the implant release button backwards to open the inserter tip with grasper and release the implant from the inserter (Figure 4a). Ensuring the implant has released from the inserter grasper, slowly remove the inserter straight back (Figure 4b). Avoid pulling the implant out of position.

Figure 4a

Figure 4b

h. Apply slight pressure to the sides of the implant with the tip of the inserter to ensure the implant is fully anchored into scleral tissue. Note: If for any reason the implant appears loose or disengaged from the scleral tissue after the initial implantation, slide the implant release button back to fully open the graspers. Position the graspers between the ribs on the implant and regrasp the body of the implant between the ribs by pushing the release button forward and re-implant a minimum of ½ clock hour to either side. Do not re-implant at the same location.
i. Withdraw the inserter from the eye.

15. Location of iDose TR in Trabecular Meshwork
a. Perform a high-magnification examination to confirm that the implant is in proper position (i.e., the proximal end rests in the anterior chamber with an unobstructed membrane) (see Figure 5) and securely attached with the anchor thoroughly embedded in the sclera.

Figure 5

b. It is normal for an edge of the implant to make contact with the iris. Note: In a normal iris (no viscoelastic in the anterior chamber and non-constricted pupil), the iris may obstruct the view of a portion of the cap of the implant.
c. Irrigate and aspirate the anterior chamber with balanced salt solution to remove all viscoelastic. Press down on the posterior edge of the incision as needed to facilitate complete removal of viscoelastic.
d. Inflate the anterior chamber with saline solution as needed to achieve physiologic pressure.

4.1 Ocular or Periocular Infections

iDose TR (travoprost intracameral implant) is contraindicated in patients with active or suspected ocular or periocular infections.

4.2 Corneal Endothelial Dystrophy

iDose TR is contraindicated in patients with corneal endothelial cell dystrophy (e.g., Fuch’s Dystrophy, corneal guttatae).

4.3 Prior Corneal Transplantation

iDose TR is contraindicated in patients with prior corneal transplantation, or endothelial cell transplants (e.g., Descemet’s Stripping Automated Endothelial Keratoplasty [DSAEK]).

4.4 Hypersensitivity

iDose TR is contraindicated in patients with hypersensitivity to travoprost or to any other components of the product.

5.1 Iridocorneal Angles

iDose TR should be used with caution in patients with narrow iridocorneal angles (Shaffer grade < 3) or other angle abnormalities (e.g., peripheral anterior synechia, rubeosis iridis) that could impair proper placement of iDose TR at the planned implantation site.

5.2 Device Dislocation

Dislocation of the iDose TR has been observed in clinical trials. Patients should be monitored routinely to confirm the location of the iDose TR at the site of administration. If the iDose TR implant becomes dislocated, it should be surgically removed.

5.3 Macular Edema

Macular edema, including cystoid macular edema, has been reported during treatment with ophthalmic travoprost, including iDose TR intracameral implant. iDose TR should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.

5.4 Intraocular Inflammation

Prostaglandin analogs, including iDose TR, have been reported to cause intraocular inflammation. iDose TR should be used with caution in patients with active intraocular inflammation (e.g., uveitis) because the inflammation may be exacerbated.

5.5 Pigmentation

Topical ophthalmic travoprost has been reported to cause increased pigmentation to pigmented tissues. Pigmentation is expected to increase as long as travoprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of travoprost, pigmentation of the iris is likely to be permanent. The long-term effects of increased pigmentation are not known.

Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with travoprost can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly.

5.6 Endophthalmitis

Intraocular surgical procedures and injections have been associated with endophthalmitis. Proper aseptic technique must always be used with administering iDose TR, and patients should be monitored following the administration.

5.7 Magnetic Resonance Imaging (MRI) Conditional

iDose TR is MR Conditional. Patients should be informed that the implant is MR Conditional (as noted on their Patient ID card). If the patient requires magnetic resonance imaging (MRI), they should inform their healthcare provider that they have an iDose TR implanted in their eye.

A patient with the iDose TR may be safely scanned under the following conditions. Failure to follow these conditions may result in injury to the patient.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse events rates are derived from three randomized, double-masked clinical trials in which 868 patients with open angle glaucoma (OAG) or ocular hypertension (OHT) received an iDose TR and were followed for one year. The most commonly reported ocular adverse reactions (2% to 6%) were increases in intraocular pressure, iritis, dry eye, visual field defects, eye pain, ocular hyperaemia, and reduced visual acuity. Ocular adverse reactions reported in less than 2% of patients were conjunctival hemorrhage, photophobia, punctate keratitis, blepharitis, eye irritation, corneal abrasion, device dislocation, vitreous detachment, and foreign body sensation in eyes.

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies of iDose TR (travoprost intracameral implant) administration in pregnant women to inform a drug-associated risk. Subcutaneous administration of travoprost to pregnant mice and rats throughout the period of organogenesis produced embryo-fetal lethality, spontaneous abortion, and premature delivery at potentially clinically relevant doses.

Advise pregnant women of a potential risk to a fetus. iDose TR should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Data

Animal Data

An embryo-fetal development study was conducted in pregnant rats administered travoprost once daily at doses up to 10 mcg/kg by subcutaneous injection from gestation day (GD) 6 to 17, to target the period of organogenesis. At 10 mcg/kg, 116 times the maximum human ocular dose (MHOD) of 1 implant per eye, based on body surface area (BSA), assuming sustained travoprost release from the implant for 6 months or 0.0139 mcg/kg/day, travoprost was teratogenic in rats, evidenced by an increase in the incidence of skeletal malformations as well as external and visceral malformations, including fused sternebrae, domed head and hydrocephaly. Travoprost caused post-implantation loss at 10 mcg/kg. The fetal no observed adverse effect level (NOAEL) was 3 mcg/kg (34.5 times the maximum human ocular dose (MHOD) of 1 implant per eye, based on BSA).

An embryo-fetal development study was conducted in pregnant mice administered travoprost once daily by subcutaneous injection at doses up to 1 mcg/kg from GD 6 to 16, to target the period of organogenesis. Travoprost induced an increase in post-implantation losses and a decrease in fetal viability in mice at subcutaneous doses > 0.3 mcg/kg. The fetal NOAEL was 0.3 mcg/kg (1.7 times the MHOD based on BSA). The maternal NOAEL was 1 mcg/kg (5.8 times the MHOD based on BSA).

Pre/postnatal development studies were conducted in rats administered travoprost once daily by subcutaneous injection from GD 7 (early embryonic period) to postnatal Day 21 (end of lactation period). At doses of greater than or equal to 0.12 mcg/kg/day (1.4 times the MHOD based on BSA), the incidence of post-natal mortality was increased, and neonatal body weight was decreased. Neonatal development was also affected, evidenced by delayed eye opening, pinna detachment and preputial separation, and by decreased motor activity.

8.2 Lactation

Risk Summary

There are no data on the effects of travoprost on the breastfed child or milk production. It is not known if travoprost is present in human milk following ophthalmic administration.

The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for iDose TR and any potential adverse effects on the breast-fed child from iDose TR.

8.4 Pediatric Use

The safety and effectiveness of iDose TR have not been established in pediatric patients.

8.5 Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

12.1 Mechanism of Action

Travoprost free acid, a prostaglandin analog is a selective FP prostanoid receptor agonist, which is believed to reduce IOP by increasing uveoscleral outflow. The exact mechanism of action is unknown at this time.

12.3 Pharmacokinetics

Travoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea and other intraocular tissues to its biologically active free acid. Systemically, travoprost free acid is metabolized to inactive metabolites via beta-oxidation of the α (carboxylic acid) chain to give the 1,2-dinor and 1,2,3,4-tetranor analogs, via oxidation of the 15-hydroxyl moiety, as well as via reduction of the 13, 14 double bond.

Data from a pharmacokinetic study of 105 subjects evaluating two models of the travoprost intracameral implant with different elution rates have shown that the plasma concentrations of travoprost free acid are below 10 pg/mL (the quantitation limit of the assay, LLOQ) in all subjects at day 10, week 12 and month 12 following administration of iDose TR.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies in mice and rats at subcutaneous doses of 10, 30, or 100 mcg/kg/day did not show any evidence of carcinogenic potential. However, at 100 mcg/kg/day, male rats were only treated for 82 weeks, and the maximum tolerated dose (MTD) was not reached in the mouse study. The high dose (100 mcg/kg) represents > 500 times the MHOD based on BSA.

Mutagenesis

Travoprost was not mutagenic in the Ames test, mouse micronucleus test or rat chromosome aberration assay. A slight increase in the mutant frequency was observed in one of two mouse lymphoma assays in the presence of rat S-9 activation enzymes.

Fertility

Travoprost did not affect mating or fertility indices in male or female rats at subcutaneous doses up to 10 mcg/kg/day (116 times the MHOD based on BSA). At 10 mcg/kg/day (116 times the MHOD based on BSA), the mean number of corpora lutea was reduced, and the post-implantation losses were increased. These effects were not observed at 3 mcg/kg/day (34.5 times the MHOD based on BSA).