A Patient’s Guide to ALPHAGAN® P 0.1%

Not an actual patient.

INDICATIONS AND USAGE ALPHAGAN® P (brimonidine tartrate ophthalmic solution) 0.1% or 0.15% is an alpha-adrenergic receptor agonist indicated for the reduction of elevated (IOP) in patients with open-angle or ocular hypertension. Important Safety Information CONTRAINDICATIONS Neonates and Infants (under the age of 2 years): ALPHAGAN® P is contraindicated in neonates and infants (under the age of 2 years). Hypersensitivity Reactions: ALPHAGAN® P is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this medication in the past. Please see additional Important Safety Information inside. All about high eye pressure and ALPHAGAN® P 0.1% This brochure will help you learn more about how Not actual patients. ALPHAGAN® P 0.1% may help to reduce high eye pressure, known as intraocular pressure (IOP), What is open-angle glaucoma and for people who have open-angle glaucoma or ocular hypertension? ocular hypertension. Open-angle glaucoma is a disease of the eye marked We hope that you will find this information useful. by increased pressure within the eyeball. This can If you have any questions, please discuss them result in damage to the and gradual with your physicians. loss of vision.1 Ocular hypertension is elevated pressure in the eye without the presence of optic nerve or vision damage.2 Remember that open-angle glaucoma is a lifelong disease—there is no cure—so treatment will be lifelong too.

Important Safety Information (continued) Important Safety Information (continued) WARNINGS AND PRECAUTIONS WARNINGS AND PRECAUTIONS (continued) Potentiation of Vascular Insufficiency: ALPHAGAN® P may Contamination of Topical Ophthalmic Products After Use: potentiate syndromes associated with vascular insufficiency. There have been reports of bacterial associated with the ALPHAGAN® P should be used with caution in patients with use of multiple-dose containers of topical ophthalmic products. depression, cerebral or coronary insufficiency, Raynaud’s These containers had been inadvertently contaminated by phenomenon, orthostatic hypotension, or thromboangiitis obliterans. patients who, in most cases, had a concurrent corneal Severe Cardiovascular Disease: Although brimonidine tartrate disease or a disruption of the ocular epithelial surface. ophthalmic solution had minimal effect on the blood pressure Please see additional of patients in clinical studies, caution should be exercised in Important Safety Information treating patients with severe cardiovascular disease. on following pages. 2 3 Why is eye pressure important? An eye without high pressure4 A number of factors may contribute to open-angle glaucoma, but high pressure inside the eye (IOP) plays a very important role. • Your eyes contain fluid that keeps them nourished and healthy • Normally, this fluid flows within the eye and drains freely • In people who have open-angle glaucoma, the Optic fluid does not drain properly nerve • The buildup of fluid causes pressure inside the eye to rise • If the pressure remains high for a long time, it can slowly cause damage to the optic nerve, which could lead to glaucoma-related vision loss An eye with high eye pressure4 • The higher the eye pressure becomes, the greater the risk for optic nerve damage and vision loss3

IMPORTANT SAFETY INFORMATION (continued) Pressure inside eye DRUG INTERACTIONS Antihypertensives/Cardiac Glycosides: Because ALPHAGAN® P (brimonidine tartrate ophthalmic solution) Optic 0.1% or 0.15% may reduce blood pressure, caution in using nerve drugs such as antihypertensives and/or cardiac glycosides with ALPHAGAN® P is advised. Please see additional Important Safety Information on following pages. 4 5 Medication like ALPHAGAN® P 0.1% can lower high eye pressure What is ALPHAGAN® P 0.1%? ALPHAGAN® P 0.1% is approved for the lowering of elevated IOP in patients with open-angle glaucoma or ocular hypertension.3 Why has my physician prescribed Not an actual patient. ALPHAGAN® P 0.1%? Approximately 2.7 million people (aged 40 and older) in the United States have open-angle glaucoma.5 Important Safety Information (continued) ALPHAGAN® P 0.1% ophthalmic solution is approved DRUG INTERACTIONS (continued) to lower high IOP in patients with open-angle CNS Depressants: Although specific drug interaction studies have not been conducted with ALPHAGAN® P glaucoma or ocular hypertension. (brimonidine tartrate ophthalmic solution) 0.1% or 0.15%, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered. Tricyclic Antidepressants: Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with ALPHAGAN® P in humans can lead to resulting interference with the IOP-lowering effect. Caution is advised in patients taking tricyclic antidepressants, which can affect the metabolism and uptake of circulating amines. Please see additional Important Safety Information on following pages. 6 7 How does ALPHAGAN® P 0.1% work? ALPHAGAN® P 0.1% is believed to work in 2 different ways3,*: 1. It decreases the amount of fluid produced in the eye. 2. It increases fluid that flows out of the eye (different from tears). Not actual patients.

Important Safety Information (continued) Iris DRUG INTERACTIONS (continued) Monoamine Oxidase Inhibitors: Monoamine oxidase Cornea (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine and potentially result in an Fluid drains increased systemic side effect such as hypotension. Caution here is advised in patients taking MAO inhibitors, which can affect the metabolism and uptake of circulating amines. ADVERSE REACTIONS Adverse reactions occurring in approximately 10% to 20% Fluid of the subjects receiving brimonidine ophthalmic solution exits here (0.1% to 0.2%) included: allergic , conjunctival Lens hyperemia, and eye pruritus. Adverse reactions occurring in approximately 5% to 9% included: burning sensation, conjunctival folliculosis, hypertension, ocular allergic reaction, oral dryness, and visual disturbance. Fluid forms here Please see accompanying full Prescribing Information *The exact way ALPHAGAN® P 0.1% may work is unknown. inside pocket at the back of this brochure. 8 9 Why is it important to get the Green Bottle? Your doctor specifically prescribed ALPHAGAN® P 0.1% for you. Ensure You Get • In clinical trials, ALPHAGAN® P 0.1% had fewer THE patients discontinue treatment (8.8%) (n = 19/215) than ALPHAGAN® 0.2% (15.1%) (n = 33/218) due to side effects6 • If you experience a hypersensitivity to brimonidine, GREEN BOTTLE you can no longer use any medication that contains brimonidine—even if the concentration of ® ALPHAGAN P 0.1% is precisely brimonidine is lower 3,7,8 formulated to contain the lowest • ALPHAGAN® P 0.1% is contraindicated in patients concentration of brimonidine who have exhibited a hypersensitivity reaction to (active drug) offered by Allergan any component of this medication in the past with the same IOP-lowering effects as original ALPHAGAN® 0.2%.

IMPORTANT SAFETY INFORMATION CONTrAINDICATIONS INDICATIONS AND USAGE Neonates and Infants (under the age of 2 years): ALPHAGAN® P is contraindicated in neonates and infants ALPHAGAN® P (brimonidine tartrate ophthalmic solution) 0.1% or 0.15% is an alpha-adrenergic receptor agonist (under the age of 2 years). indicated for the reduction of elevated intraocular Please see additional pressure (IOP) in patients with open-angle glaucoma Important Safety Information or ocular hypertension. on following pages. 10 11 How can I make sure I get the Green Bottle? • Be sure you receive the correct medication— ALPHAGAN® P 0.1% in the Green Bottle— by checking your prescription at the pharmacy Not an actual patient.

Is there a generic version of ALPHAGAN® P 0.1%? There is no FDA-approved generic formulation for ALPHAGAN® P 0.1%.9

Important Safety Information (continued) CONTRAINDICATIONS (continued) Hypersensitivity Reactions: ALPHAGAN® P is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this medication in the past. Please see additional Important Safety Information on following pages. Not an actual patient. 12 13 Visit www.AlphaganP.com How much will ALPHAGAN® P 0.1% cost? for a cost-saving rebate The cost of ALPHAGAN® P 0.1% will be determined by your health plan. ALPHAGAN® P 0.1% is covered for most patients with Commercial or Medicare Part D Be sure to ask your physician about any other offers or coupons that may be available at the office. health plans.10 Individual plans and out-of-pocket costs will vary. If you need financial assistance with your prescriptions, visit www.RxHope.com/Allergan for more information on the Allergan PATIENT ASSISTANCE PROGRAM™. It offers free or low-cost prescriptions for those who qualify financially.

Important Safety Information (continued) WARNINGS AND PRECAUTIONS Potentiation of Vascular Insufficiency: ALPHAGAN® P may potentiate syndromes associated with vascular insufficiency. ALPHAGAN® P should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans. Severe Cardiovascular Disease: Although brimonidine tartrate ophthalmic solution had minimal effect on the blood pressure of patients in clinical studies, caution should be exercised in treating patients with severe cardiovascular disease. Please see additional Important Safety Information on following pages. Not an actual patient. 14 15 How many times a day do I need to take Handling your eyedrop bottles ALPHAGAN® P (brimonidine tartrate It is very important to handle your eyedrop bottles ophthalmic solution) 0.1%? carefully. Always wash your hands before putting The recommended dosing of ALPHAGAN® P 0.1% drops into your eyes. Don’t allow anything to touch is 3 times a day—approximately 8 hours apart. the tip—not even your eyes or the areas around Always follow your physician’s instructions for taking your eyes! Potentially harmful bacteria could enter ALPHAGAN® P 0.1%.3 the bottle and cause a serious eye infection. Always replace the cap after using. Contact your physician if If you take other eyedrops besides ALPHAGAN® P 0.1%, you think your bottle may have been contaminated. you should take them at least 5 minutes apart.3

Follow these 5 steps:

Wash your hands. Tilt your head Gently squeeze 1 drop into the pocket. back and look at the ceiling. Do not let the bottle tip touch your eye, 1 3 your fingers, or anything else.

Using your index finger, gently Gently close your eyes and pull down your lower to form lightly press on the inside 2 a pocket. 4 corners of your eyes.

Important Safety Information (continued) WARNINGS AND PRECAUTIONS (continued) Then carefully blot away any Contamination of Topical Ophthalmic Products excess liquid that may be on After Use: There have been reports of bacterial keratitis 5 your skin. associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the Please see additional Important Safety Information ocular epithelial surface. on following pages. 16 17 Why is it important to take my ALPHAGAN® P 0.1% drops? Even if you feel fine, it’s important to continue using ALPHAGAN® P 0.1% every day as your physician prescribed. Make it part of your daily routine. Do not skip or stop treatment before speaking with your physician. Follow some helpful tips to remember to take your eyedrops every day: Not an actual patient. • Associate using your eyedrops with other daily routines you’ve established for yourself, such as brushing your teeth Important Safety Information (continued) • Set a daily clock or watch alarm that can remind DRUG INTERACTIONS you to use your eyedrops Antihypertensives/Cardiac Glycosides: Because ALPHAGAN® P (brimonidine tartrate ophthalmic solution) • Ask a friend or family member to remind you 0.1% or 0.15% may reduce blood pressure, caution in when it’s time to use your eyedrops using drugs such as antihypertensives and/or cardiac glycosides with ALPHAGAN® P is advised. CNS Depressants: Although specific drug interaction studies have not been conducted with ALPHAGAN® P, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered. Please see additional Important Safety Information on following pages. 18 19 What should I expect with ALPHAGAN® P 0.1% therapy? Large clinical studies have shown that ALPHAGAN® P 0.1% is effective for reducing high eye pressure

in patients with open-angle glaucoma and ocular Not actual patients. hypertension. In 5% to 20% (n = 215) of patients, the following adverse events were reported3,6: • Eye allergies and inflammation • Redness of the eyes Important Safety Information (continued) • Itchiness or burning sensation in the eyes DRUG INTERACTIONS (continued) Tricyclic Antidepressants: Tricyclic antidepressants have • High blood pressure been reported to blunt the hypotensive effect of systemic • Dryness of the mouth clonidine. It is not known whether the concurrent use of these agents with ALPHAGAN® P in humans can lead to • Vision changes resulting interference with the IOP-lowering effect. Caution is advised in patients taking tricyclic antidepressants, which ALPHAGAN® P 0.1% ophthalmic solution may cause can affect the metabolism and uptake of circulating amines. fatigue and/or drowsiness. If you drive or perform Monoamine Oxidase Inhibitors: Monoamine oxidase hazardous work, such as operating machinery, make (MAO) inhibitors may theoretically interfere with the sure you feel appropriately alert.3 metabolism of brimonidine and potentially result in an increased systemic side effect such as hypotension. These are not the only risks associated with Caution is advised in patients taking MAO inhibitors, ALPHAGAN® P 0.1%. If you experience these or which can affect the metabolism and uptake other side effects, you should immediately contact of circulating amines. your physician. Please see additional Important Safety Information on following pages.

20 21 Who should NOT use ALPHAGAN® P (brimonidine tartrate ophthalmic solution) 0.1%? ALPHAGAN® P 0.1% should not be used in neonates and infants (children under the age of 2). You should also not use ALPHAGAN® P 0.1% if you have allergies to any of the ingredients in ALPHAGAN® P 0.1%.3 ALPHAGAN® P 0.1% eyedrops can be absorbed by your body, which may be of concern if you have other medical conditions or are taking other drugs. Tell your physician about your other medications, especially3: • Heart or blood pressure medicines, such as beta-blockers and calcium-channel blockers • Sedatives Not actual patients. • Certain types of antidepressants, including those known as “tricyclic antidepressants” and “MAO inhibitors” It is also very important to tell your physician if you have3: Important Safety Information (continued) • Depression ADVERSE REACTIONS • Heart problems Adverse reactions occurring in approximately 10% to 20% of the subjects receiving brimonidine ophthalmic solution • Upcoming surgery for your eyes (0.1% to 0.2%) included: , conjunctival • Eye injury or infection hyperemia, and eye pruritus. Adverse reactions occurring in approximately 5% to 9% included: burning sensation, These risks are not the only risks associated with conjunctival folliculosis, hypertension, ocular allergic ALPHAGAN® P 0.1%. If you experience these or reaction, oral dryness, and visual disturbance. other side effects, you should immediately contact Please see accompanying full Prescribing Information your physician. inside pocket at the back of this brochure. 22 23 Notes Notes

24 25 Notes Notes

Please see accompanying full Prescribing Information inside pocket. 26 27 Visit www.AlphaganP.com for more information about ALPHAGAN® P 0.1% and to download a cost-saving rebate.

1. MedTerms®. MedicineNet.com website. http://www.medterms.com/script /main/art.asp?articlekey=3596. Accessed June 10, 2013. 2. American Optometric Association. Ocular hypertension. American Optometric Association website. http://www.aoa.org/ocular-hypertension.xml. Accessed July 1,2013. 3. ALPHAGAN® P Prescribing Information. 4. PubMed Health. Glaucoma. US National Library of Medicine website. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002587/. Updated September 14, 2011. Accessed June 11, 2013. 5. BrightFocusTM Foundation. Glaucoma facts & statistics. BrightFocusTM Foundation website. http://www.brightfocus.org/glaucoma/about/ understanding/facts.html. Accessed July 10, 2013. 6. Data on file, Allergan, Inc., 2003; Study number: 190342-021. 7. Brimonidine tartrate ophthalmic solution 0.15% Prescribing Information. 8. Brimonidine tartrate ophthalmic solution 0.2% Prescribing Information. 9. US Food and Drug Administration. Drugs@FDA. US Food and Drug Administration website. http://www.accessdata.fda.gov/scripts/cder /drugsatfda/. Accessed April 11, 2013. 10. Managed Markets Insight & Technology, LLC, database as of April 2013.

©2013 Allergan, Inc., Irvine, CA 92612 ® and ™ marks owned by Allergan, Inc. BrightFocus is a trademark owned by the American Health Assistance Foundation. Managed Markets Insight & Technology is a portfolio company of Susquehanna Growth Equity. MedTerms is a registered service mark owned by WebMD, Inc. www.AlphaganP.com APC58UL13 131824 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ALPHAGAN® P safely ------ADVERSE REACTIONS------and effectively. See full prescribing information for ALPHAGAN® P. Most common adverse reactions occurring in approximately 5% to 20% of patients receiving

® brimonidine ophthalmic solution (0.1%-0.2%) included allergic conjunctivitis, burning sensation, ALPHAGAN P (brimonidine tartrate ophthalmic solution) 0.1% and 0.15% conjunctival folliculosis, conjunctival hyperemia, eye pruritus, hypertension, ocular allergic Initial U.S. Approval: 1996 reaction, oral dryness, and visual disturbance. (6.1) ------INDICATIONS AND USAGE------To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-433-8871 or the ALPHAGAN® P is an alpha adrenergic receptor agonist indicated for the reduction of elevated FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. (1) ------DRUG INTERACTIONS------DOSAGE AND ADMINISTRATION------• Antihypertensives/cardiac glycosides may lower blood pressure. (7.1) • One drop in the affected eye(s), three times daily, approximately 8 hours apart. (2) • Use with CNS depressants may result in an additive or potentiating effect. (7.2) ------DOSAGE FORMS AND STRENGTHS------• Tricyclic antidepressants may potentially blunt the hypotensive effect of systemic clonidine. (7.3) • Solution containing 1 or 1.5 mg/mL brimonidine tartrate. (3) • Monoamine oxidase inhibitors may result in increased hypotension. (7.4) ------CONTRAINDICATIONS------USE IN SPECIFIC POPULATIONS------• Neonates and infants (under the age of 2 years). (4.1) • Use with caution in children ≥ 2 years of age. (8.4) ------WARNINGS AND PRECAUTIONS------See 17 for PATIENT COUNSELING INFORMATION. Potentiation of vascular insufficiency. (5.1) Revised: 09/2013 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 8 USE IN SPECIFIC POPULATIONS 2 DOSAGE AND ADMINISTRATION 8.1 Pregnancy 3 DOSAGE FORMS AND STRENGTHS 8.3 Nursing Mothers 4 CONTRAINDICATIONS 8.4 Pediatric Use 4.1 Neonates and Infants (under the age of 2 years) 8.5 Geriatric Use 4.2 Hypersensitivity Reactions 8.6 Special Populations 5 WARNINGS AND PRECAUTIONS 10 OVERDOSAGE 5.1 Potentiation of Vascular Insufficiency 11 DESCRIPTION 5.2 Severe Cardiovascular Disease 12 CLINICAL PHARMACOLOGY 5.3 Contamination of Topical Ophthalmic Products After Use 12.1 Mechanism of Action 6 ADVERSE REACTIONS 12.3 Pharmacokinetics 6.1 Clinical Studies Experience 13 NONCLINICAL TOXICOLOGY 6.2 Postmarketing Experience 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 7 DRUG INTERACTIONS 14 CLINICAL STUDIES 7.1 Antihypertensives/Cardiac Glycosides 16 HOW SUPPLIED/STORAGE AND HANDLING 7.2 CNS Depressants 17 PATIENT COUNSELING INFORMATION 7.3 Tricyclic Antidepressants 7.4 Monoamine Oxidase Inhibitors *Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION 6 ADVERSE REACTIONS 1 INDICATIONS AND USAGE 6.1 Clinical Studies Experience ALPHAGAN® P (brimonidine tartrate ophthalmic solution) 0.1% or 0.15% is an alpha adrenergic Because clinical studies are conducted under widely varying conditions, adverse reaction rates receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies open-angle glaucoma or ocular hypertension. of another drug and may not reflect the rates observed in practice. 2 DOSAGE AND ADMINISTRATION Adverse reactions occurring in approximately 10-20% of the subjects receiving brimonidine ophthalmic solution (0.1-0.2%) included: allergic conjunctivitis, conjunctival hyperemia, and The recommended dose is one drop of ALPHAGAN® P in the affected eye(s) three times daily, ® eye pruritus. Adverse reactions occurring in approximately 5-9% included: burning sensation, approximately 8 hours apart. ALPHAGAN P ophthalmic solution may be used concomitantly conjunctival folliculosis, hypertension, ocular allergic reaction, oral dryness, and visual disturbance. with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart. Adverse reactions occurring in approximately 1-4% of the subjects receiving brimonidine ophthalmic solution (0.1-0.2%) included: abnormal taste, allergic reaction, asthenia, , 3 DOSAGE FORMS AND STRENGTHS blepharoconjunctivitis, blurred vision, bronchitis, , conjunctival edema, conjunctival Solution containing 1 mg/mL or 1.5 mg/mL brimonidine tartrate. hemorrhage, conjunctivitis, cough, dizziness, dyspepsia, dyspnea, , eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema, fatigue, flu syndrome, follicular 4 CONTRAINDICATIONS conjunctivitis, foreign body sensation, gastrointestinal disorder, headache, hypercholesterolemia, 4.1 Neonates and Infants (under the age of 2 years) hypotension, infection (primarily colds and respiratory infections), insomnia, keratitis, lid disorder, ALPHAGAN® P is contraindicated in neonates and infants (under the age of 2 years). pharyngitis, , rash, rhinitis, sinus infection, sinusitis, somnolence, stinging, superficial punctate keratopathy, tearing, visual field defect, vitreous detachment, vitreous disorder, vitreous 4.2 Hypersensitivity Reactions , and worsened visual acuity. ALPHAGAN® P is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this medication in the past. The following reactions were reported in less than 1% of subjects: corneal erosion, hordeolum, nasal dryness, and taste perversion. 5 WARNINGS AND PRECAUTIONS 6.2 Postmarketing Experience 5.1 Potentiation of Vascular Insufficiency The following reactions have been identified during postmarketing use of brimonidine tartrate ALPHAGAN® P may potentiate syndromes associated with vascular insufficiency. ALPHAGAN® P ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population should be used with caution in patients with depression, cerebral or coronary insufficiency, of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans. for inclusion due to either their seriousness, frequency of reporting, possible causal connection to 5.2 Severe Cardiovascular Disease brimonidine tartrate ophthalmic solutions, or a combination of these factors, include: bradycardia, Although brimonidine tartrate ophthalmic solution had minimal effect on the blood pressure of patients depression, hypersensitivity, iritis, sicca, , nausea, skin reactions (including in clinical studies, caution should be exercised in treating patients with severe cardiovascular disease. erythema, eyelid pruritus, rash, and vasodilation), syncope, and tachycardia. Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence 5.3 Contamination of Topical Ophthalmic Products After Use have been reported in infants receiving brimonidine tartrate ophthalmic solutions. There have been reports of bacterial keratitis associated with the use of multiple-dose containers of 7 DRUG INTERACTIONS topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface (see 7.1 Antihypertensives/Cardiac Glycosides PATIENT COUNSELING INFORMATION, 17). Because ALPHAGAN® P may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with ALPHAGAN® P is advised. 7.2 CNS Depressants Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual Although specific drug interaction studies have not been conducted with ALPHAGAN® P, the mechanism of action by reducing aqueous humor production and increasing uveoscleral outflow. possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, 12.3 Pharmacokinetics sedatives, or anesthetics) should be considered. Absorption 7.3 Tricyclic Antidepressants After ocular administration of either a 0.1% or 0.2% solution, plasma concentrations peaked within Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. 0.5 to 2.5 hours and declined with a systemic half-life of approximately 2 hours. It is not known whether the concurrent use of these agents with ALPHAGAN® P in humans can lead to resulting interference with the IOP lowering effect. Caution is advised in patients taking Distribution tricyclic antidepressants which can affect the metabolism and uptake of circulating amines. The protein binding of brimonidine has not been studied. 7.4 Monoamine Oxidase Inhibitors Metabolism Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine In humans, brimonidine is extensively metabolized by the liver. and potentially result in an increased systemic side-effect such as hypotension. Caution is advised Excretion in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines. Urinary excretion is the major route of elimination of brimonidine and its metabolites. Approximately 87% of an orally-administered radioactive dose of brimonidine was eliminated within 120 hours, 8 USE IN SPECIFIC POPULATIONS with 74% found in the urine. 8.1 Pregnancy 13 NONCLINICAL TOXICOLOGY Pregnancy Category B: Teratogenicity studies have been performed in animals. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Brimonidine tartrate was not teratogenic when given orally during gestation days 6 through 15 in No compound-related carcinogenic effects were observed in either mice or rats following a rats and days 6 through 18 in rabbits. The highest doses of brimonidine tartrate in rats 21-month and 24-month study, respectively. In these studies, dietary administration of brimonidine (2.5 mg/kg/day) and rabbits (5.0 mg/kg/day) achieved AUC exposure values 360- and 20-fold tartrate at doses up to 2.5 mg/kg/day in mice and 1 mg/kg/day in rats achieved 150 and 120 higher, or 260- and 15-fold higher, respectively, than similar values estimated in humans treated ® times or 90 and 80 times, respectively, the plasma Cmax drug concentration in humans treated with with ALPHAGAN P 0.1% or 0.15%, 1 drop in both eyes three times daily. one drop of ALPHAGAN® P 0.1% or 0.15% into both eyes 3 times per day, the recommended There are no adequate and well-controlled studies in pregnant women; however, in animal studies, daily human dose. brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. Because ® Brimonidine tartrate was not mutagenic or clastogenic in a series of in vitro and in vivo studies animal reproduction studies are not always predictive of human response, ALPHAGAN P should including the Ames bacterial reversion test, chromosomal aberration assay in Chinese Hamster be used during pregnancy only if the potential benefit to the mother justifies the potential risk to Ovary (CHO) cells, and three in vivo studies in CD-1 mice: a host-mediated assay, cytogenetic the fetus. study, and dominant lethal assay. 8.3 Nursing Mothers Reproduction and fertility studies in rats with brimonidine tartrate demonstrated no adverse It is not known whether brimonidine tartrate is excreted in human milk, although in animal studies, effect on male or female fertility at doses which achieve up to approximately 125 and 90 brimonidine tartrate has been shown to be excreted in breast milk. Because of the potential for times the systemic exposure following the maximum recommended human ophthalmic dose of serious adverse reactions from ALPHAGAN® P in nursing infants, a decision should be made ALPHAGAN® P 0.1% or 0.15%, respectively. whether to discontinue nursing or to discontinue the drug, taking into account the importance of 14 CLINICAL STUDIES the drug to the mother. Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of 8.4 Pediatric Use IOP, the greater the likelihood of optic nerve damage and visual field loss. Brimonidine tartrate ALPHAGAN® P is contraindicated in children under the age of 2 years (see CONTRAINDICATIONS, has the action of lowering intraocular pressure with minimal effect on cardiovascular and 4.1). During postmarketing surveillance, apnea, bradycardia, coma, hypotension, hypothermia, pulmonary parameters. hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants Clinical studies were conducted to evaluate the safety, efficacy, and acceptability of ALPHAGAN® P receiving brimonidine. The safety and effectiveness of brimonidine tartrate have not been studied (brimonidine tartrate ophthalmic solution) 0.15% compared with ALPHAGAN® administered three- in children below the age of 2 years. times-daily in patients with open-angle glaucoma or ocular hypertension. Those results indicated In a well-controlled clinical study conducted in pediatric glaucoma patients (ages 2 to 7 years) that ALPHAGAN® P (brimonidine tartrate ophthalmic solution) 0.15% is comparable in IOP lowering the most commonly observed adverse reactions with brimonidine tartrate ophthalmic solution effect to ALPHAGAN® (brimonidine tartrate ophthalmic solution) 0.2%, and effectively lowers IOP 0.2% dosed three times daily were somnolence (50-83% in patients ages 2 to 6 years) and in patients with open-angle glaucoma or ocular hypertension by approximately 2-6 mmHg. decreased alertness. In pediatric patients 7 years of age (>20 kg), somnolence appears to occur A clinical study was conducted to evaluate the safety, efficacy, and acceptability of ALPHAGAN® P less frequently (25%). Approximately 16% of patients on brimonidine tartrate ophthalmic solution (brimonidine tartrate ophthalmic solution) 0.1% compared with ALPHAGAN® administered three- discontinued from the study due to somnolence. times-daily in patients with open-angle glaucoma or ocular hypertension. Those results indicated ® 8.5 Geriatric Use that ALPHAGAN P (brimonidine tartrate ophthalmic solution) 0.1% is equivalent in IOP lowering effect to ALPHAGAN® (brimonidine tartrate ophthalmic solution) 0.2%, and effectively lowers IOP No overall differences in safety or effectiveness have been observed between elderly and other in patients with open-angle glaucoma or ocular hypertension by approximately 2-6 mmHg. adult patients. 16 HOW SUPPLIED/STORAGE AND HANDLING 8.6 Special Populations ® ® ALPHAGAN P is supplied sterile, in teal opaque plastic LDPE bottles and tips, with purple high ALPHAGAN P has not been studied in patients with hepatic impairment. impact polystyrene (HIPS) caps as follows: ALPHAGAN® P has not been studied in patients with renal impairment. The effect of dialysis on brimonidine pharmacokinetics in patients with renal failure is not known. 0.1% 10 OVERDOSAGE 5 mL in 10 mL bottle NDC 0023-9321-05 10 mL in 10 mL bottle NDC 0023-9321-10 Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse 15 mL in 15 mL bottle NDC 0023-9321-15 reaction reported to date has been hypotension. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving ALPHAGAN® P as part of medical treatment 0.15% of congenital glaucoma or by accidental oral ingestion (see USE IN SPECIFIC POPULATIONS, 5 mL in 10 mL bottle NDC 0023-9177-05 8.4). Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway 10 mL in 10 mL bottle NDC 0023-9177-10 should be maintained. 15 mL in 15 mL bottle NDC 0023-9177-15 11 DESCRIPTION Storage: Store at 15°-25°C (59°-77°F). ALPHAGAN® P (brimonidine tartrate ophthalmic solution) 0.1% or 0.15%, sterile, is a relatively selective alpha-2 adrenergic receptor agonist (topical intraocular pressure lowering agent). 17 PATIENT COUNSELING INFORMATION The structural formula of brimonidine Patients should be instructed that ocular solutions, if handled improperly or if the tip of the tartrate is: dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and 5-Bromo-6-(2-imidazolidinylideneamino) subsequent loss of vision may result from using contaminated solutions (see WARNINGS AND quinoxaline L-tartrate; MW= 442.24 PRECAUTIONS, 5.3). Always replace the cap after using. If solution changes color or becomes In solution, ALPHAGAN® P (brimonidine cloudy, do not use. Do not use the product after the expiration date marked on the bottle. tartrate ophthalmic solution) has a clear, Patients also should be advised that if they have ocular surgery or develop an intercurrent ocular greenish-yellow color. It has an osmolality condition (e.g., trauma or infection), they should immediately seek their physician’s advice of 250-350 mOsmol/kg and a pH of concerning the continued use of the present multidose container. 7.4-8.0 (0.1%) or 6.9-7.4 (0.15%). If more than one topical ophthalmic drug is being used, the drugs should be administered at least Brimonidine tartrate appears as an off-white to pale-yellow powder and is soluble in both water five minutes apart. (0.6 mg/mL) and in the product vehicle (1.4 mg/mL) at pH 7.7. ® ® As with other similar medications, ALPHAGAN P may cause fatigue and/or drowsiness in some Each mL of ALPHAGAN P contains the active ingredient brimonidine tartrate 0.1% (1 mg/mL) or patients. Patients who engage in hazardous activities should be cautioned of the potential for a 0.15% (1.5 mg/mL) with the inactive ingredients sodium carboxymethylcellulose; sodium borate; decrease in mental alertness. boric acid; sodium chloride; potassium chloride; calcium chloride; magnesium chloride; PURITE® 0.005% (0.05 mg/mL) as a preservative; purified water; and hydrochloric acid and/or sodium ©2014 Allergan, Inc. hydroxide to adjust pH. Irvine, CA 92612, U.S.A. ® marks owned by Allergan, Inc. 12 CLINICAL PHARMACOLOGY Patented. See: www.allergan.com/products/patent_notices 12.1 Mechanism of Action Made in the U.S.A. ALPHAGAN® P is a relatively selective alpha-2 adrenergic receptor agonist with a peak ocular Based on 71816US16 hypotensive effect occurring at two hours post-dosing. APC63OI14