ALPHAGAN P (brimonidine tartrate ophthalmic solution) is a relatively selective alpha-2 adrenergic agonist for ophthalmic use. The chemical name of brimonidine tartrate is 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate. It is an off-white to pale yellow powder. It has a molecular weight of 442.24 as the tartrate salt, and is both soluble in water (0.6 mg/mL) and in the product vehicle (1.4 mg/mL) at pH 7.7. The structural formula is:

Formula: C₁₁H₁₀BrN₅•C₄H₆O₆

CAS Number: 70359-46-5

In solution, ALPHAGAN® P (brimonidine tartrate ophthalmic solution) has a clear, greenish-yellow color. It has an osmolality of 250-350 mOsmol/kg and a pH of 7.4-8.0 (0.1%) or 6.6-7.4 (0.15%).

Each mL of ALPHAGAN®P contains:

Active ingredient: brimonidine tartrate 0.1% (1.0 mg/mL) or 0.15% (1.5 mg/mL)

Inactives: sodium carboxymethylcellulose; sodium borate; boric acid; sodium chloride; potassium chloride; calcium chloride; magnesium chloride; Purite® 0.005% (0.05mg/mL) as a preservative; purified water; with hydrochloric acid and/or sodium hydroxide to adjust pH.

ALPHAGAN^Ò P is indicated for the lowering of intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

The recommended dose is one drop of ALPHAGAN^Ò P in the affected eye(s) three times daily, approximately 8 hours apart.

ALPHAGAN^Ò P may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic product is being used, the products should be administered at least 5 minutes apart.

ALPHAGAN^Ò P is supplied sterile in opaque teal LDPE plastic bottles and droppers with purple high impact polystyrene (HIPS) caps as follows:

NOTE: Store at 15°-25°C (59-77°F).

Adverse events occurring in approximately 10-20% of the subjects receiving brimonidine ophthalmic solution (0.1- 0.2%) included: allergic conjunctivitis, conjunctival hyperemia, and eye pruritis. Adverse events occurring in approximately 5-9% included: burning sensation, conjunctival foliculosis, hypertension, ocular allergic reaction, oral dryness, and visual disturbance.

Adverse events occurring in approximately 1-4% of subjects receiving brimonidine ophthalmic solution (0.1-0.2%) included: allergic reaction, asthenia, blepharitis, blepharoconjunctivitis, blurred vision, bronchitis, cataract, conjunctival edema, conjunctival hemorrhage, conjunctivitis, cough, dizziness, dyspepsia, dyspnea, epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema, fatigue, flu syndrome, follicular conjunctivitis, foreign body sensation, gastrointestinal disorder, headache, hypercholesterolemia, hypotension, infection (primarily colds and respiratory infections), insomnia, keratitis, lid disorder, pharyngitis, photophobia, rash, rhinitis, sinus infection, sinusitis, somnolence, stinging, superficial punctate keratopathy, tearing, visual field defect, vitreous detachment, vitreous disorder, vitreous floaters, and worsened visual acuity.

The following events were reported in less than 1% of subjects: corneal erosion, hordeolum, nasal dryness, and taste perversion.

The following events have been identified during post-marketing use of brimonidine tartrate ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or a combination of these factors, include: bradycardia; depression; iritis; keratoconjunctivitis sicca; miosis; nausea; skin reactions (including erythema, eyelid pruritis, rash, and vasodilation); and tachycardia. Apnea; bradycardia; hypotension; hypothermia; hypotonia; and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions.

Although specific drug interaction studies have not been conducted with ALPHAGAN^Ò P , the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered. Alpha-agonists, as a class, may reduce pulse and blood pressure. Caution in using concomitant drugs such as anti-hypertensives and/or cardiac glycosides is advised.

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^Ò P in humans can lead to resulting interference with the IOP lowering effect. No data on the level of circulating catecholamines after ALPHAGAN^Ò P administration are available. Caution, however, is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

No information provided.

General:

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.

ALPHAGAN^Ò P has not been studied in patients with hepatic or renal impairment; caution should be used in treating such patients.

ALPHAGAN^Ò P should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension, or thromboangiitis obliterans. Patients prescribed IOP-lowering medication should be routinely monitored for IOP.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

No compound-related carcinogenic effects were observed in either mice or rats following a 21-month and 24-month study, respectively. In these studies, dietary administration of brimonidine tartrate at doses up to 2.5 mg/kg/day in mice and 1.0 mg/kg/day in rats achieved 150 and 120 times or 90 and 80 times, respectively, the plasma drug concentration estimated in humans treated with one drop of ALPHAGAN^Ò P 0.1% or 0.15% into both eyes 3 times per day.

Brimonidine tartrate was not mutagenic or cytogenic in a series of in vitro and in vivo studies including the Ames test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, a host-mediated assay and cytogenic studies in mice, and dominant lethal assay.

Pregnancy: Teratogenic effects: Pregnancy Category B

Reproductive studies performed in rats with oral doses of 0.66 mg base/kg revealed no evidence of impaired fertility or harm to the fetus due to ALPHAGAN^Ò P. Dosing at this level produced an exposure in rats and rabbits that is 190 and 100 times or 120 and 60 times higher, respectively, than the exposure seen in humans following multiple ophthalmic doses of ALPHAGAN^Ò P 0.1% or 0.15%.

There are no adequate and well-controlled studies in pregnant women. In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. ALPHAGAN^Ò P should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Nursing Mothers:

It is not known whether this drug is excreted in human milk; although in animal studies brimonidine tartrate was excreted in breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:

In a well-controlled clinical study conducted in pediatric glaucoma patients (ages 2 to 7 years) the most commonly observed adverse events with brimonidine tartrate ophthalmic solution 0.2% dosed three times a day were somnolence (50% - 83% in patients ages 2 to 6 years) and decreased alertness. In pediatric patients 7 years of age or older (>20kg), somnolence appears to occur less frequently (25%). Approximately 16% of patients on brimonidine tartrate ophthalmic solution discontinued from the study due to somnolence.

The safety and effectiveness of brimonidine tartrate ophthalmic solution have not been studied in pediatric patients below the age of 2 years. Brimonidine tartrate ophthalmic solution is not recommended for use in pediatric patients under the age of 2 years. (Also refer to Adverse Reactions section.)

Geriatric Use:

No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

No information is available on overdosage in humans. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.

ALPHAGAN^Ò P is contraindicated in patients with hypersensitivity to brimonidine tartrate or any component of this medication. It is also contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy.

ALPHAGAN^Ò P is an alpha adrenergic receptor agonist. It has a peak ocular hypotensive effect occurring at two hours post-dosing. Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action by reducing aqueous humor production and increasing uveoscleral outflow.

After ocular administration of either a 0.1% or 0.2% solution, plasma concentrations peaked within 0.5 to 2.5 hours and declined with a systemic half-life of approximately 2 hours. In humans, systemic metabolism of brimonidine is extensive. It is metabolized primarily by the liver. Urinary excretion is the major route of elimination of the drug and its metabolites. Approximately 87% of an orally-administered radioactive dose was eliminated within 120 hours, with 74% found in the urine.

Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. Brimonidine tartrate has the action of lowering intraocular pressure with minimal effect on cardiovascular and pulmonary parameters.

Clinical studies were conducted to evaluate the safety, efficacy, and acceptability of ALPHAGAN^Ò P (brimonidine tartrate ophthalmic solution) 0.15% compared with ALPHAGAN^Ò administered three-times-daily in patients with open-angle glaucoma or ocular hypertension. Those results indicated that ALPHAGAN^Ò P (brimonidine tartrate ophthalmic solution) 0.15% is comparable in IOP lowering effect to ALPHAGAN^Ò (brimonidine tartrate ophthalmic solution) 0.2%, and effectively lowers IOP in patients with open-angle glaucoma or ocular hypertension by approximately 2-6 mmHg.

A clinical study was conducted to evaluate the safety, efficacy, and acceptability of ALPHAGAN^Ò P (brimonidine tartrate ophthalmic solution) 0.1% compared with ALPHAGAN^Ò administered three-times-daily in patients with open-angle glaucoma or ocular hypertension. Those results indicated that ALPHAGAN^Ò P (brimonidine tartrate ophthalmic solution) 0.1% is equivalent in IOP lowering effect to ALPHAGAN^Ò (brimonidine tartrate ophthalmic solution) 0.2%, and effectively lowers IOP in patients with open-angle glaucoma or ocular hypertension by approximately 2-6 mmHg.

As with other drugs in this class, ALPHAGAN^Ò P may cause fatigue and /or drowsiness in some patients. Patients who engage in hazardous activities should be cautioned of the potential for a decrease in mental alertness.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

BRIMONIDINE SOLUTION - OPHTHALMIC

(bry-MOW-nih-deen)

COMMON BRAND NAME(S): Alphagan P

USES: This medication is used to treat open-angle glaucoma or high fluid pressure in the eye. Lowering high fluid pressure in the eye reduces the risk of vision loss, nerve damage, or blindness. This medication lowers pressure by allowing better fluid drainage from within the eye and also by reducing the amount of fluid formed in the eye. It is known as an alpha agonist.

This drug is not recommended for use in children less than 2 years of age due to an increased risk of serious side effects such as very slowed breathing. Ask the doctor or pharmacist for details.

HOW TO USE: To apply eye drops, wash your hands first. To avoid contamination, do not touch the dropper tip or let it touch your eye or any other surface.

If you are wearing contact lenses, remove them before using this medication. After applying this medication, wait at least 15 minutes before putting in your contact lens.

Tilt your head back, look upward and pull down the lower eyelid to make a pouch. Hold the dropper directly over your eye and insert one drop, usually three times daily, or as directed by your doctor. Look downward and gently close your eyes for 1 to 2 minutes. Place one finger at the corner of your eye (near the nose) and apply gentle pressure. Try not to blink and do not rub your eye. This will prevent the medication from draining out. Repeat these steps for your other eye if so directed by your doctor.

Do not rinse the dropper. Replace the dropper cap after each use.

If you are using another kind of eye medication (e.g., drops or ointments), wait at least 5 minutes before applying the other medications. Use eye drops before eye ointments to allow the eye drops to enter the eye.

It is important to continue this medication even if you do not have any symptoms. Use this medication regularly in order to get the most benefit from it. Remember to use it at the same times each day. Do not stop using this medication without consulting your doctor.

Inform your doctor if your condition worsens.

SIDE EFFECTS: Eye discomfort/itching/redness, blurred vision, dizziness, dry mouth, drowsiness, or tiredness may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: fast/pounding heartbeats, persistent headache, eye pain/burning/swelling, extreme sensitivity to light, vision changes.

Tell your doctor immediately if any of these rare but very serious side effects occur: fainting, slow/irregular heartbeats.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using this medication, tell your doctor or pharmacist if you are allergic to it; or to apraclonidine; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood vessel diseases (thromboangiitis obliterans), blood circulation disorders (cerebral or coronary insufficiency), depression, severe heart disease, kidney disease, liver disease, Raynaud's disease, low blood pressure upon standing (orthostatic hypotension).

This drug may make you dizzy, drowsy, or cause blurred vision; use caution engaging in activities requiring alertness or clear vision such as driving or using machinery. Limit alcoholic beverages.

Caution is advised when using this medication in children because they may be more sensitive to its side effects, especially drowsiness. See also Uses section.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. However, this medication may have undesirable effects on a nursing infant. Breast-feeding is not recommended while using this medication. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: monoamine oxidase inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, selegiline, tranylcypromine).

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting this medication.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: beta-blockers (e.g., atenolol, metoprolol, timolol eye drops), digoxin, high blood pressure medications (e.g., clonidine, terazosin), tricyclic antidepressants (e.g., amitriptyline).

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: antihistamines that cause drowsiness (e.g., diphenhydramine), anti-anxiety drugs (e.g., diazepam), anti-seizure drugs (e.g., carbamazepine), barbiturates (e.g., phenobarbital), medicine for sleep (e.g., zolpidem), muscle relaxants (e.g., cyclobenzaprine), narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., phenothiazines such as chlorpromazine), tranquilizers.

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain drowsiness-causing ingredients. Ask your pharmacist about the safe use of those products.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. This medication may be harmful if swallowed.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., measuring intraocular pressure) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59 and 77 degrees F (15-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.