NDA 21-262/S-018
`Page 3
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`ALPHAGAN® P
`(brimonidine tartrate ophthalmic solution) 0.1% and 0.15%
`
`Sterile
`
`
`
`DESCRIPTION
`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:
`
`
`
`
`COOH
`OH
`H
`OOH
`
`C C C
`
`H
`HO
`
`NN
`
`HN
`
`NH
`
`Br
`
`N
`
`
`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.
`CLINICAL PHARMACOLOGY
`
`Mechanism of action:
`ALPHAGAN® 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.
`
`
`Pharmacokinetics:
`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.
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`NDA 21-262/S-018
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`Clinical Evaluations:
`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® P
`(brimonidine tartrate ophthalmic solution) 0.15% compared with ALPHAGAN® administered three-
`times-daily in patients with open-angle glaucoma or ocular hypertension. Those results indicated that
`ALPHAGAN® P (brimonidine tartrate ophthalmic solution) 0.15% is comparable in IOP lowering
`effect to ALPHAGAN® (brimonidine tartrate ophthalmic solution) 0.2%, and effectively lowers IOP
`in patients with open-angle glaucoma or ocular hypertension by approximately 2-6 mmHg.
` clinical study was conducted to evaluate the safety, efficacy, and acceptability of ALPHAGAN® P
`(brimonidine tartrate ophthalmic solution) 0.1% compared with ALPHAGAN® administered three-
`times-daily in patients with open-angle glaucoma or ocular hypertension. Those results indicated 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 in
`patients with open-angle glaucoma or ocular hypertension by approximately 2-6 mmHg.
`
`
` A
`
`INDICATIONS AND USAGE
`ALPHAGAN® P is indicated for the lowering of intraocular pressure in patients with open-angle
`glaucoma or ocular hypertension.
`
`CONTRAINDICATIONS
`ALPHAGAN® 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.
`
`PRECAUTIONS
`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® P has not been studied in patients with hepatic or renal impairment; caution should be
`used in treating such patients.
`
`ALPHAGAN® 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.
`
`Information for Patients:
`As with other drugs in this class, ALPHAGAN® 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.
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`NDA 21-262/S-018
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`Drug Interactions:
`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. 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® P in humans can lead to
`resulting interference with the IOP lowering effect. No data on the level of circulating catecholamines
`after ALPHAGAN® P administration are available. Caution, however, is advised in patients taking
`tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.
`
`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® 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® 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® 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® 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.
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`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.
`
`
`ADVERSE REACTIONS
`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.
`
`OVERDOSAGE
`No information is available on overdosage in humans. Treatment of an oral overdose includes
`supportive and symptomatic therapy; a patent airway should be maintained.
`
`DOSAGE AND ADMINISTRATION
`The recommended dose is one drop of ALPHAGAN® P in the affected eye(s) three times daily,
`approximately 8 hours apart.
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`NDA 21-262/S-018
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`ALPHAGAN® 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.
`
`HOW SUPPLIED:
`ALPHAGAN® P is supplied sterile in opaque teal LDPE plastic bottles and droppers with purple high
`impact polystyrene (HIPS) caps as follows:
`
`0.1%
`
`
`5 mL in 10 mL bottle
`10 mL in 10 mL bottle
`15 mL in 15 mL bottle
`
`
`
`0.15%
`5 mL in 10 mL bottle
`
`10 mL in 10 mL bottle
`15 mL in 15 mL bottle
`
`
`
`NOTE: Store at 15°-25o C (59-77oF).
`
`Rx Only
`
`
`® ALLERGAN
`
`NDC 0023-9321-05
`NDC 0023-9321-10
`NDC 0023-9321-15
`
`NDC 0023-9177-05
`NDC 0023-9177-10
`NDC 0023-9177-15
`
`
`©2005 Allergan, Inc
`
`
`
`
`Irvine, CA 92612, U.S.A.
`® Marks owned by Allergan
`US Patent 5,424,078; 5,736,165; 6,194,415; 6,248,741
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`0.1%-9541X
`0.15%-9174X
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