BIMATOPROST: 14,752 Adverse Event Reports & Safety Profile

DURYSTA is a sterile intracameral implant containing 10 mcg of bimatoprost, a prostaglandin analog, in a solid polymer sustained-release drug delivery system (DDS). The drug delivery system consists of poly (D,L-lactide), poly (D,L-lactide-co-glycolide), poly (D,L-lactide) acid end, and polyethylene glycol 3350. DURYSTA is preloaded into a single-use, DDS applicator to facilitate injection of the rod-shaped implant directly into the anterior chamber of the eye. The chemical name for bimatoprost is ( Z )-7-[(1 R ,2 R ,3 R ,5 S )-3,5-dihydroxy-2-[(1 E ,3 S )-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]- N -ethyl-5-heptenamide, and its molecular weight is 415.57. Its molecular formula is C 25 H 37 NO 4 . Its structural formula is: Bimatoprost is a white to off-white powder, soluble in ethyl alcohol and methyl alcohol and slightly soluble in water. The polymer matrix slowly degrades to lactic acid and glycolic acid. The chemical name for bimatoprost is (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-N-ethyl-5-heptenamide, and its molecular weight is 415.57. Its molecular formula is C25H37NO4.

AND USAGE Bimatoprost ophthalmic solution, 0.03% is indicated to treat hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness. Bimatoprost ophthalmic solution, for topical ophthalmic use is a prostaglandin analog, indicated to treat hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness.

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

Figure

1 Figure 2 2. 1 General Information DURYSTA is an ophthalmic drug delivery system for a single intracameral administration of a biodegradable implant. DURYSTA should not be readministered to an eye that received a prior DURYSTA.

2.2 Administration The intracameral injection procedure must be performed under magnification that allows clear visualization of the anterior chamber structures and should be carried out using standard aseptic conditions for intracameral procedures, with the patient’s head in a stabilized position. The eye should not be dilated prior to the procedure. Remove the foil pouch from the carton and examine for damage. Then, open the foil pouch over a sterile field and gently drop the applicator on a sterile tray. Once the foil pouch is opened, use the applicator promptly.

Figure

1 Perform a detailed visual inspection of the applicator, including ensuring that the actuator button has not been depressed, and the safety tab is in place. Carefully remove the plastic safety cap taking care to avoid contacting the needle tip. Inspect the needle tip for damage under magnification prior to use; the implant retention plug may be visible in the bevel and should not be removed. Prior to use, remove the safety tab by pulling it out perpendicular to the long axis of the applicator (refer to Figure 1a above). Do not twist or bend the tab. Stabilize the eye as the needle is advanced through the cornea. Enter the anterior chamber with the needle bevel visible through clear cornea. Enter parallel to the iris plane, adjacent to the limbus through clear cornea in the superotemporal quadrant. The needle should be inserted approximately 2 bevel lengths with the bevel completely within the anterior chamber; avoid positioning the needle bevel directly over the pupil. Ensure the needle is not bent before depressing the actuator button.

See Figure

2.

Figure

2 Depress the back half of the actuator button (refer to Figure 1b above) firmly until an audible and/or palpable click is noted. Following the release of the implant, remove the needle via the same track in which it was inserted and tamponade the opening. The implant should not be left in the corneal injection track. Check the injection site for leaks; make sure that it is self-sealing and the anterior chamber is formed. After injection, do not recap the needle. Dispose of the used applicator in a sharps disposal container and in accordance with local requirements. Instruct the patient to remain upright for at least 1 hour after the procedure so the implant can settle. Some degree of eye redness and discomfort is expected following administration. However, it is recommended to instruct patients that if the eye becomes progressively red, sensitive to light, painful, or develops a change in vision, they should immediately contact the physician.

Ocular or periocular infections ( 4.1 ) Corneal endothelial cell dystrophy ( 4.2 ) Prior corneal transplantation ( 4.3 ) Absent or ruptured posterior lens capsule ( 4.4 ) Hypersensitivity ( 4.5 )

4.1 Ocular or Periocular Infections DURYSTA is contraindicated in patients with active or suspected ocular or periocular infections.

4.2 Corneal Endothelial Cell Dystrophy DURYSTA is contraindicated in patients with corneal endothelial cell dystrophy (e.g., Fuchs’ Dystrophy) [ see Warnings and Precautions ( 5.1 ) ] .

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

4.4 Absent or Ruptured Posterior Lens Capsule DURYSTA is contraindicated in patients whose posterior lens capsule is absent or ruptured, due to the risk of implant migration into the posterior segment. Laser posterior capsulotomy in pseudophakic patients is not a contraindication for DURYSTA use if the intraocular lens fully covers the opening in the posterior capsule.

4.5 Hypersensitivity DURYSTA is contraindicated in patients with hypersensitivity to bimatoprost or to any other components of the product [ see Adverse Reactions ( 6.1 ) ] .

REACTIONS The following adverse reactions are described elsewhere in the labeling:

• Pigmentation [see Warnings and Precautions (5.1) ]
• Eyelash Changes [see Warnings and Precautions (5.2) ]
• Intraocular Inflammation [see Warnings and Precautions (5.3) ]
• Macular Edema [see Warnings and Precautions (5.4) ]
• Hypersensitivity [see Contraindications (4) ] Most common adverse reaction (45%) is conjunctival hyperemia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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. In clinical trials, the most frequent events associated with the use of bimatoprost ophthalmic solution 0.03% occurring in approximately 15% to 45% of patients, in descending order of incidence, included conjunctival hyperemia, growth of eyelashes, and ocular pruritus.

Approximately

3% of patients discontinued therapy due to conjunctival hyperemia. Ocular adverse events occurring in approximately 3 to 10% of patients, in descending order of incidence, included ocular dryness, visual disturbance, ocular burning, foreign body sensation, eye pain, pigmentation of the periocular skin, blepharitis, cataract, superficial punctate keratitis, periorbital erythema, ocular irritation, and eyelash darkening. The following ocular adverse events reported in approximately 1 to 3% of patients, in descending order of incidence, included: eye discharge, tearing, photophobia, allergic conjunctivitis, asthenopia, increases in iris pigmentation, and conjunctival edema. In less than 1% of patients, intraocular inflammation was reported as iritis. Systemic adverse events reported in approximately 10% of patients were infections (primarily colds and upper respiratory tract infections). The following systemic adverse events reported in approximately 1 to 5% of patients, in descending order of incidence, included headaches, abnormal liver function tests, asthenia and hirsutism.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of bimatoprost ophthalmic solution 0.03%. 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. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to bimatoprost ophthalmic solution, or a combination of these factors, include: abnormal hair growth, asthma-like symptoms, dizziness, dyspnea, eyelid edema, hypersensitivity reaction including signs and symptoms of eye allergy and allergic dermatitis, hypertension, nausea, and periorbital and lid changes associated with periorbital fat atrophy leading to skin tightness, deepening of the eyelid sulcus, eyelid ptosis, enophthalmos and eyelid retraction; and skin discoloration (non-periocular).

AND PRECAUTIONS Concurrent administration of Bimatoprost ophthalmic solution, for topical ophthalmic use and intraocular pressure (IOP)-lowering prostaglandin analogs in ocular hypertensive patients may decrease the IOP-lowering effect. Patients using these products concomitantly should be closely monitored for changes to their IOP. ( 5.1 ) Pigmentation of the eyelids and iris may occur. Iris pigmentation is likely to be permanent. ( 5.2, 5.3 )

5.1 Effects on Intraocular Pressure Bimatoprost ophthalmic solution (LUMIGAN ® ) lowers intraocular pressure (IOP) when instilled directly to the eye in patients with elevated IOP. In clinical trials, in patients with or without elevated IOP, bimatoprost ophthalmic solution 0.03% lowered IOP, however, the magnitude of the reduction was not cause for clinical concern. In ocular hypertension studies with LUMIGAN ® , it has been shown that exposure of the eye to more than one dose of bimatoprost daily may decrease the intraocular pressure lowering effect. In patients using LUMIGAN ® or other prostaglandin analogs for the treatment of elevated intraocular pressure, the concomitant use of bimatoprost ophthalmic solution 0.03% may interfere with the desired reduction in IOP. Patients using prostaglandin analogs including LUMIGAN ® for IOP reduction should only use bimatoprost ophthalmic solution 0.03% after consulting with their physician and should be monitored for changes to their intraocular pressure.

5.2 Iris Pigmentation Increased iris pigmentation has occurred when bimatoprost solution was administered. Patients should be advised about the potential for increased brown iris pigmentation which is likely to be permanent <span class="opacity-50 text-xs">[see Adverse Reactions (6.2]</span> . The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. The long term effects of increased pigmentation are not known. Iris color changes seen with administration of bimatoprost ophthalmic solution 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. Treatment with bimatoprost ophthalmic solution 0.03% can be continued in patients who develop noticeably increased iris pigmentation.

5.3 Lid Pigmentation Bimatoprost has been reported to cause pigment changes (darkening) to periorbital pigmented tissues and eyelashes. The pigmentation is expected to increase as long as bimatoprost is administered, but has been reported to be reversible upon discontinuation of bimatoprost in most patients.

5.4 Hair Growth Outside the Treatment Area There is the potential for hair growth to occur in areas where bimatoprost ophthalmic solution 0.03% comes in repeated contact with the skin surface. It is important to apply bimatoprost ophthalmic solution 0.03% only to the skin of the upper eyelid margin at the base of the eyelashes using the accompanying sterile applicators, and to carefully blot any excess bimatoprost ophthalmic solution 0.03% from the eyelid margin to avoid it running onto the cheek or other skin areas.

5.5 Intraocular Inflammation Bimatoprost ophthalmic solution 0.03% should be used with caution in patients with active intraocular inflammation (e.g., uveitis) because the inflammation may be exacerbated.

5.6 Macular Edema Macular edema, including cystoid macular edema, has been reported during treatment with bimatoprost ophthalmic solution (LUMIGAN®) for elevated IOP. Bimatoprost ophthalmic solution 0.03% 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 Contamination of bimatoprost ophthalmic solution 0.03% or Applicator The Bimatoprost ophthalmic solution 0.03% bottle must be kept intact during use. It is important to use bimatoprost ophthalmic solution 0.03% as instructed, by placing one drop on the single-use- per-eye applicator. The bottle tip should not be allowed to contact any other surface since it could become contaminated. The accompanying sterile applicators should only be used on one eye and then discarded since reuse of applicators increases the potential for contamination and infections. There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products <span class="opacity-50 text-xs">[see Patient Counseling Information (17)]</span>.

5.8 Use with Contact Lenses Bimatoprost ophthalmic solution 0.03% contains benzalkonium chloride, which may be absorbed by and cause discoloration of soft contact lenses. Contact lenses should be removed prior to application of solution and may be reinserted 15 minutes following its administration.