TRAVOPROST: 6,455 Adverse Event Reports & Safety Profile

Travoprost is a synthetic prostaglandin F analog. Its chemical name is [1R-[1α(Z),2β(1E,3R*),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethylester. It has a molecular formula of C 26 H 35 F 3 O 6 and a molecular weight of 500.55 g/mol. The chemical structure of travoprost is: Travoprost USP, is a clear, colorless, viscous oil that is very soluble in acetonitrile, methanol, octanol, and chloroform. It is insoluble in water. Travoprost ophthalmic solution USP, 0.004% (ionic buffered solution) is supplied as clear, colorless sterile, buffered aqueous solution of travoprost, free from foreign visible particles with a pH of approximately 5.7 and an osmolality of approximately 290 mOsmol/kg. Travoprost ophthalmic solution USP, 0.004% (ionic buffered solution) contains Active : travoprost USP, 0.04 mg/mL; Inactives : polyoxyl 40 hydrogenated castor oil, boric acid, propylene glycol, sorbitol, zinc chloride, sodium hydroxide and/or hydrochloric acid (to adjust pH), and water for injection, USP. Preserved in the bottle with an ionic buffered system. travo-structure

AND USAGE Travoprost ophthalmic solution (ionic buffered solution) 0.004% is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open angle glaucoma or ocular hypertension. Travoprost ophthalmic solution (ionic buffered solution) 0.004% is a prostaglandin analog indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. (1)

AND ADMINISTRATION For ophthalmic intracameral administration ( 2.1 ) The intracameral administration should be carried out under standard aseptic conditions ( 2.2 )

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.

2.2 Administration Instructions 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 with your index finger comfortably on the implant release button (see Figure 1 )

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 (see 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 (see Figure 4a ). Ensuring the implant has released from the inserter grasper, slowly remove the inserter straight back (see 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. Figure-01 Figure-02 Figure-03 Figure-04 Figure-05 Figure-06

2.3 Evaluation and Testing Before Readministering iDose TR Perform specular microscopy to evaluate the corneal endothelium and establish pre-implantation baseline corneal endothelial cell density prior to the initial administration of iDose TR and prior to each readministration <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> .

Table

1 describes readministration modifications if specific adverse reactions have occurred [see Contraindications (4) , Warnings and Precautions (5.2 , 5.5) ].

Table

1: Dosage (Readministration) Modifications for Adverse Reactions Adverse Reactions Dosage Modification Ocular or periocular infections Withhold dose (readministration) Prior iDose TR device dislocation Withhold dose (readministration) Central corneal endothelial cell loss of 10% or greater from pre-administration baseline (adjusted for age-related 1% loss per year and for a 10% loss following an anterior segment surgical procedure [e.g., cataract surgery]) Withhold dose (readministration)

2.4 Readministration Instructions Note: When readministering an iDose TR implant, always remove the previous iDose TR implant AFTER implantation of the new implant. Follow &quot;Administration Instructions&quot; Steps 1 to 13 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . Assure the anterior chamber is fully formed with a cohesive viscoelastic. If you notice a soft eye, or a shallow anterior chamber, re-inflate. If needed, apply cohesive viscoelastic directly on the previous implant while inflating to remove any loose tissue, iris strands, or debris. Insert the new iDose TR implant following &quot;Administration Instructions&quot; Step 14a through 14h <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . With the iDose TR inserter or viscoelastic cannula, perform a procedural check on the previous implant by gently touching it left to right, right to left, and bottom to top (iris up). Movement of the iris is suggestive of adhesions to the implant. If the previous iDose TR is adhered to the iris, slide the release button on the inserter 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. Slowly rotate the grasped implant 10° clockwise and counterclockwise. Any movement of the iris is suggestive of adhesions. Gently twist and separate the implant from any adhesions while slowly removing the implant. When satisfied that the previous iDose TR is free and clear of the iris, slowly pull the previous implant back from the trabecular meshwork avoiding tension on adjacent ocular structures and withdraw the inserter from the eye. Follow &quot;Administration Instructions&quot; Step 15 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> .

2.5 Frequency of Readministration It is not recommended to readminister an iDose TR more than once per year.

Ocular or periocular infections ( 4.1 ) Corneal endothelial dystrophy ( 4.2 ) Prior corneal transplantation ( 4.3 ) Hypersensitivity ( 4.4 )

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&apos;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&apos;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 .

REACTIONS Most common adverse reaction (30% to 50%) is conjunctival hyperemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc. at 1-855-839-8195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 most common adverse reaction observed in controlled clinical trials with travoprost ophthalmic solution 0.004% and travoprost ophthalmic solution 0.004% (ionic buffered solution) was ocular hyperemia, which was reported in 30% to 50% of patients. Up to 3% of patients discontinued therapy due to conjunctival hyperemia. Ocular adverse reactions reported at an incidence of 5% to 10% in these clinical trials included decreased visual acuity, eye discomfort, foreign body sensation, pain, and pruritus. Ocular adverse reactions reported at an incidence of 1% to 4% in clinical trials with travoprost ophthalmic solution 0.004% or travoprost ophthalmic solution 0.004% (ionic buffered solution) included abnormal vision, blepharitis, blurred vision, cataract, conjunctivitis, corneal staining, dry eye, iris discoloration, keratitis, lid margin crusting, ocular inflammation, photophobia, subconjunctival hemorrhage, and tearing. Non-ocular adverse reactions reported at an incidence of 1% to 5% in these clinical studies were allergy, angina pectoris, anxiety, arthritis, back pain, bradycardia, bronchitis, chest pain, cold/flu syndrome, depression, dyspepsia, gastrointestinal disorder, headache, hypercholesterolemia, hypertension, hypotension, infection, pain, prostate disorder, sinusitis, urinary incontinence, and urinary tract infections.

6.2 Postmarketing Experience Additional adverse reactions have been identified during post approval use of travoprost ophthalmic solution 0.004% or travoprost ophthalmic solution 0.004% (ionic buffered solution) in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to travoprost ophthalmic solution 0.004% or travoprost ophthalmic solution 0.004% (ionic buffered solution), or a combination of these factors, include: arrhythmia, vomiting, epistaxis, tachycardia, and insomnia. In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the eyelid sulcus have been observed.

AND PRECAUTIONS Iridocorneal Angles : iDose TR should be used with caution in patients with narrow angles or other angle abnormalities ( 5.1 )

Device

Dislocation : Monitor patients routinely to confirm the location of the iDose TR at the site of administration ( 5.2 ) Pigmentation : Increased pigmentation of the iris can occur. Iris pigmentation is likely to be permanent ( 5.8 )

5.1 Iridocorneal Angles iDose TR should be used with caution in patients with narrow iridocorneal angles (Shaffer grade &lt; 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3 , 2.4) ]</span> .

5.3 Patients without Baseline Corneal Endothelial Cell Density Prior to Initial Administration It is not recommended to readminister iDose TR if baseline central corneal endothelial cell density was not established prior to initial administration of iDose TR <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4 , 5.5) ]</span> .

5.4 Recommended Minimum Corneal Endothelial Cell Density for Readministration Central corneal endothelial cell density should not be less than the recommended minimum listed in Table 2 prior to the initial administration of iDose TR and prior to each readministration. If corneal endothelial cell density was not established prior to the initial administration of iDose TR and only a single eye was implanted, corneal endothelial cell density in the un-implanted contralateral eye meeting the recommended minimum density may be used for eligibility determination for readministration of iDose TR (see Table 2 ).

Table

2: Recommended Minimum Central Corneal Endothelial Cell Density Central Corneal Endothelial Cell Density Age Phakic Eyes Pseudophakic Eyes ≤ 45 years 2,200 (cells/mm 2 ) 1,540 (cells/mm 2 ) 46 to 55 years 2,000 (cells/mm 2 ) 1,400 (cells/mm 2 ) 56 to 65 years 1,800 (cells/mm 2 ) 1,260 (cells/mm 2 ) > 65 years 1,600 (cells/mm 2 ) 1,120 (cells/mm 2 )

5.5 Corneal Endothelial Cell Loss iDose TR should be readministered with caution in eyes with 10% or greater loss in central corneal endothelial cell density from pre-administration baseline (adjusted for age-related 1% loss per year and for a 10% loss following an anterior segment surgical procedure [e.g., cataract surgery]). If baseline corneal endothelial cell density was not established prior to the initial administration of iDose TR and only a single eye is implanted, a 10% threshold level of endothelial cell density loss as a difference of the implanted eye versus un-implanted contralateral eye should be considered before readministering iDose TR.

5.6 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.

5.7 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.

5.8 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.

5.9 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.

5.10 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.

Parameter

Condition of Use / Information Nominal Values of Static Magnetic Field (T) 3.0 T or less Maximum Spatial Field Gradient (T/m and gauss/cm) 40-T/m (4,000-gauss/cm) Type of RF Excitation Circularly Polarized (CP) (i.e., Quadrature-Transmission) Transmit RF Coil Information Any transmit RF coil may be used Operating Mode of MR System Normal Operating Mode Maximum Whole Body Averaged SAR 2-W/kg (Normal Operating Mode)

Maximum

Head SAR 3.2-W/kg (Normal Operating Mode) Limits on Scan Duration Whole body averaged SAR of 2-W/kg for 60 minutes of continuous RF exposure (i.e., per pulse sequence or back-to-back sequences/series without breaks) MR Image Artifact The presence of this implant produces an imaging artifact. Therefore, carefully select pulse sequence parameters if the implant is located in the area of interest.