UPNEEQ

1 INDICATIONS AND USAGE UPNEEQ is indicated for the treatment of acquired blepharoptosis in adults. UPNEEQ is indicated for the treatment of acquired blepharoptosis in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Instill one drop of UPNEEQ into one or both ptotic eye(s) once daily. Discard the single patient-use container immediately after dosing. Contact lenses should be removed prior to instillation of UPNEEQ and may be reinserted 15 minutes following its administration. If more than one topical ophthalmic drug is being used, the drugs should be administered at least 15 minutes between applications. Instill one drop into one or both ptotic eye(s) once daily. ( 2 )

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Ptosis may be associated with neurologic or orbital diseases such as stroke and/or cerebral aneurysm, Horner syndrome, myasthenia gravis, external ophthalmoplegia, orbital infection and orbital masses. Consideration should be given to these conditions in the presence of ptosis with decreased levator muscle function and/or other neurologic signs. ( 5.1 ) Alpha-adrenergic agonists as a class may impact blood pressure. Advise patients with cardiovascular disease, orthostatic hypotension, and/or uncontrolled hypertension or hypotension to seek medical care if their condition worsens. ( 5.2 ) Use with caution in patients with cerebral or coronary insufficiency or Sjögren’s syndrome and advise patients to seek medical care if signs and symptoms of potentiation of vascular insufficiency develop. ( 5.3 ) Advise patients to seek immediate medical care if pain, redness, blurred vision and photophobia occur (signs and symptoms of acute angle closure). ( 5.4 ) 5.1 Ptosis as Presenting Sign of Serious Neurologic Disease Ptosis may be associated with neurologic or orbital diseases such as stroke and/or cerebral aneurysm, Horner syndrome, myasthenia gravis, external ophthalmoplegia, orbital infection and orbital masses. Consideration should be given to these conditions in the presence of ptosis with decreased levator muscle function and/or other neurologic signs. 5.2 Potential Impacts on Cardiovascular Disease Alpha-adrenergic agonists may impact blood pressure. UPNEEQ should be used with caution in patients with severe or unstable cardiovascular disease, orthostatic hypotension, and uncontrolled hypertension or hypotension. Advise patients with cardiovascular disease, orthostatic hypotension, and/or uncontrolled hypertension/hypotension to seek immediate medical care if their condition worsens. 5.3 Potentiation of Vascular Insufficiency UPNEEQ should be used with caution in patients with cerebral or coronary insufficiency, or Sjögren’s syndrome. Advise patients to seek immediate medical care if signs and symptoms of potentiation of vascular insufficiency develop. 5.4 Risk of Angle Closure Glaucoma UPNEEQ may increase the risk of angle closure glaucoma in patients with untreated narrow-angle glaucoma. Advise patients to seek immediate medical care if signs and symptoms of acute angle closure glaucoma develop. 5.5 Risk of Contamination Patients should not touch the tip of the single patient-use container to their eye or to any surface, in order to avoid eye injury or contamination of the solution. 5.2 Potential Impacts on Cardiovascular Disease Alpha-adrenergic agonists may impact blood pressure. UPNEEQ should be used with caution in patients with severe or unstable cardiovascular disease, orthostatic hypotension, and uncontrolled hypertension or hypotension. Advise patients with cardiovascular disease, orthostatic hypotension, and/or uncontrolled hypertension/hypotension to seek immediate medical care if their condition worsens. 5.3 Potentiation of Vascular Insufficiency UPNEEQ should be used with caution in patients with cerebral or coronary insufficiency, or Sjögren’s syndrome. Advise patients to seek immediate medical care if signs and symptoms of potentiation of vascular insufficiency develop. 5.4 Risk of Angle Closure Glaucoma UPNEEQ may increase the risk of angle closure glaucoma in patients with untreated narrow-angle glaucoma. Advise patients to seek immediate medical care if signs and symptoms of acute angle closure glaucoma develop. 5.5 Risk of Contamination Patients should not touch the tip of the single patient-use container to their eye or to any surface, in order to avoid eye injury or contamination of the solution.

7 DRUG INTERACTIONS 7.1 Anti-hypertensives/Cardiac Glycosides Alpha-adrenergic agonists, as a class, may impact blood pressure. Caution in using drugs such as beta-blockers, anti-hypertensives, and/or cardiac glycosides is advised. Caution should also be exercised in patients receiving alpha adrenergic receptor antagonists such as in the treatment of cardiovascular disease, or benign prostatic hypertrophy. 7.2 Monoamine Oxidase Inhibitors Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines. 7.1 Anti-hypertensives/Cardiac Glycosides Alpha-adrenergic agonists, as a class, may impact blood pressure. Caution in using drugs such as beta-blockers, anti-hypertensives, and/or cardiac glycosides is advised. Caution should also be exercised in patients receiving alpha adrenergic receptor antagonists such as in the treatment of cardiovascular disease, or benign prostatic hypertrophy. 7.2 Monoamine Oxidase Inhibitors Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

6 ADVERSE REACTIONS Most common adverse reactions (incidence 1-5%) are: punctate keratitis, conjunctival hyperemia, dry eye, vision blurred, instillation site pain, eye irritation and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact RVL Pharmaceuticals, Inc. at 1-877-482-3788 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. A total of 360 subjects with acquired blepharoptosis were treated with UPNEEQ once daily in each eye for at least 6 weeks in three controlled Phase 3 clinical trials, including 203 subjects treated with UPNEEQ for 6 weeks and 157 subjects treated with UPNEEQ for 12 weeks. Adverse reactions that occurred in 1-5% of subjects treated with UPNEEQ were punctate keratitis, conjunctival hyperemia, dry eye, blurred vision, instillation site pain, eye irritation and headache. 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. A total of 360 subjects with acquired blepharoptosis were treated with UPNEEQ once daily in each eye for at least 6 weeks in three controlled Phase 3 clinical trials, including 203 subjects treated with UPNEEQ for 6 weeks and 157 subjects treated with UPNEEQ for 12 weeks. Adverse reactions that occurred in 1-5% of subjects treated with UPNEEQ were punctate keratitis, conjunctival hyperemia, dry eye, blurred vision, instillation site pain, eye irritation and headache.

8.1 Pregnancy Risk Summary There are no available data on UPNEEQ use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, there were no adverse developmental effects observed after oral administration of oxymetazoline hydrochloride in pregnant rats and rabbits at systemic exposures up to 7 and 278 times the maximum recommended human ophthalmic dose (MRHOD), respectively, based on dose comparison. [see Data] . The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Animal Data Effects on embryo-fetal development were evaluated in rats and rabbits following oral administration of oxymetazoline hydrochloride during the period of organogenesis. Oxymetazoline hydrochloride did not cause adverse effects to the fetus at oral doses up to 0.2 mg/kg/day in pregnant rats during the period of organogenesis (28 times the MRHOD, on a dose comparison basis). Oxymetazoline hydrochloride did not cause adverse effects to the fetus at oral doses up to 1 mg/kg/day in pregnant rabbits during the period of organogenesis (278 times the MRHOD, on a dose comparison basis). Maternal toxicity, including decreased maternal body weight, was produced at the high dose of 1 mg/kg/day in pregnant rabbits and was associated with findings of delayed skeletal ossification. In a rat prenatal and postnatal development study, oxymetazoline hydrochloride was orally administered to pregnant rats once daily from gestation day 6 through lactation day 20. Maternal toxicity was produced at the high dose of 0.2 mg/kg/day (28 times the MRHOD, on a dose comparison basis) in pregnant rats and was associated with an increase in pup mortality and reduced pup body weights. Delayed sexual maturation was noted at 0.1 mg/kg/day (14 times the MRHOD, on a dose comparison basis). Oxymetazoline hydrochloride did not have any adverse effects on fetal development at a dose of 0.05 mg/kg/day (7 times the MRHOD, on a dose comparison basis).