ZOLYMBUS

5 WARNINGS AND PRECAUTIONS Pigmentation : Pigmentation of the iris, periorbital tissue (eyelid) and eyelashes can occur. Iris pigmentation is likely to be permanent. ( 5.1 ) Eyelash Changes : Gradual change to eyelashes including increased length, thickness and number of lashes. Usually, reversible. ( 5.2 ) 5.1 Pigmentation Bimatoprost has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is expected to increase as long as bimatoprost 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 bimatoprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. 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 ZOLYMBUS can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. 5.2 Eyelash Changes ZOLYMBUS may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, thickness, and number of lashes. Eyelash changes are usually reversible upon discontinuation of treatment. 5.3 Intraocular Inflammation Prostaglandin analogs, including bimatoprost, have been reported to cause intraocular inflammation. ZOLYMBUS should be used with caution in patients with active intraocular inflammation (e.g., iritis/uveitis) because inflammation may be exacerbated. 5.4 Macular Edema Macular edema, including cystoid macular edema, has been reported during treatment with bimatoprost ophthalmic products. ZOLYMBUS 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. 5.5 Contact Lens Use Contact lenses should be removed prior to the administration of ZOLYMBUS and may be reinserted 15 minutes after administration.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: Pigmentation including blepharal pigmentation and iris hyperpigmentation [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 reactions (≥10%) are conjunctival hyperemia (14%) and eye irritation (11%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Thea Pharma Inc. at 1-833-838-4028 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 the two clinical trials conducted with ZOLYMBUS (bimatoprost ophthalmic gel) 0.01% comparing it to preserved bimatoprost ophthalmic solution 0.01%, the most frequently reported ocular adverse reactions were conjunctival hyperemia (14%), eye irritation (11%), eye pruritus (9%) and foreign body sensation in eyes (8%). Other adverse drug reactions (reported in 1% to 6% of patients) with ZOLYMBUS in the studies included dry eye, abnormal sensation in eye, lacrimation increased, eye pain, and vision blurred. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of topical bimatoprost products. 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. These reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to bimatoprost, or a combination of these factors include: asthma-like symptoms, dizziness, dry eye, dyspnea, eye discharge, eye edema, foreign body sensation, headache, hypersensitivity including signs and symptoms of eye allergy and allergic dermatitis, hypertension, lacrimation increased, 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 photophobia.