Page 3
`NDA 20-490/S-007
`NDA 20-613/S-018
`NDA 21-262/S-006
`
`ALPHAGAN
`(brimonidine tartrate ophthalmic solution) 0.5%
`
`
`Sterile
`
`
`DESCRIPTION
`
`ALPHAGAN (brimonidine tartrate ophthalmic solution) 0.5% 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 has a molecular weight of 442.24 as the tartrate
`salt and is water soluble (34 mg/mL) pH 6.5. The structural formula is:
`
`
`COOH
`OH
`H
`OOH
`
`C C C
`
`H
`HO
`
`NN
`
`HN
`
`NH
`
`Br
`
`N
`
`
`
`Formula: C11H10BrN5⋅C4H6O6
`
`CAS Number: 59803-98-4
`
`In solution, ALPHAGAN® (brimonidine tartrate ophthalmic solution) 0.5% has a clear, greenish-
`yellow color. It has a pH of 5.6 - 6.6.
`
`Each mL of ALPHAGAN contains:
`Active ingredient: brimonidine tartrate 0.5% (5 mg/mL).
`Preservative: benzalkonium chloride (0.05 mg).
`Inactives: citric acid; polyvinyl alcohol; sodium chloride; sodium citrate; and purified water.
`Hydrochloric acid and/or sodium hydroxide may be added to adjust pH.
`
`CLINICAL PHARMACOLOGY
`Mechanism of action:
`
`ALPHAGAN 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.
`
`
`

`

`Page 4
`NDA 20-490/S-007
`NDA 20-613/S-018
`NDA 21-262/S-006
`
`Pharmacokinetics:
`After ocular administration of a 0.5% solution, plasma concentrations peaked within 1 to 4 hours and
`declined with a systemic half-life of approximately 3 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.
`
`Clinical Studies
`Acute elevations in intraocular pressure (IOP) are a potentially serious complication of argon laser
`trabeculoplasty (ALT). The etiology of the IOP rise is not well understood. Acute elevations in IOP in
`susceptible patients can result in further optic nerve damage and visual field loss.
`
`
`In two controlled, multi-center studies, ALPHAGAN 0.5% ophthalmic solution was significantly
`more effective in decreasing the incidence of post-operative IOP elevations (increases of ≥10 mm Hg
`or more) than was the vehicle at one, two and three hours post-argon laser trabeculoplasty. An overall
`incidence of 1% of eyes treated with ALPHAGAN ophthalmic solution had IOP elevations compared
`with an incidence of 23% of vehicle-treated eyes. An IOP increase of 5 mm Hg or greater post-ALT
`was reported in 6% of the ALPHAGAN ophthalmic solution eyes compared with 40% of vehicle-
`treated eyes.
`
`Incidence (%) of IOP Elevation ≥10 mmHg following Argon Laser Trabeculoplasty (360º of angle
`treated) when ALPHAGAN ophthalmic solution 0.5% was used before and after ALT.
`
`Brimonidine
`
`Study 1 1/62 (2%)
`Study 2 1/60 (0%)
`
`INDICATIONS AND USAGE
`ALPHAGAN 0.5% is indicated for the prevention of post-operative IOP elevations in patients
`undergoing argon laser trabeculoplasty (ALT).
`
`CONTRAINDICATIONS
`ALPHAGAN 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 ALPHAGAN had minimal effect on blood pressure of patients in clinical studies, caution
`should be exercised in treating patients with severe cardiovascular disease.
`
`ALPHAGAN has not been studied in patients with hepatic or renal impairment; caution should be
`used in treating such patients.
`
`
`Placebo
`14/60 (23%)
`13/56 (23%)
`
`P-Value
`>0.05
`<0.05
`
`

`

`Page 5
`NDA 20-490/S-007
`NDA 20-613/S-018
`NDA 21-262/S-006
`
`ALPHAGAN should be used with caution in patients with depression, cerebral or coronary
`insufficiency, Raynaud’s phenomenon, orthostatic hypotension or thromboangiitis obliterans.
`
`Information for Patients:
`The preservative in ALPHAGAN, benzalkonium chloride, may be absorbed by soft contact lenses.
`Patients wearing soft contact lenses should be instructed to wait at least 15 minutes after instilling
`ALPHAGAN to insert soft contact lenses.
`
`As with other drugs of this class, ALPHAGAN may cause fatigue and/or drowsiness in some
`patients. On the day of surgery, patients should be cautioned of the potential for a decrease in mental
`alertness.
`
`Do not touch the tip of the unit-dose container to the eye or any other surface.
`
` Drug Interactions:
`Although specific drug interaction studies have not been conducted with ALPHAGAN, 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 beta blockers (ophthalmic and systemic),
`antihypertensives 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 in humans can lead to
`resulting interference with the IOP lowering effect. No data on the level of circulating catecholamines
`after ALPHAGAN instillation are available. Caution, however, is advised in patients taking tricyclic
`antidepressants which can affect the metabolism and uptake of circulating amines.
`
`Carcinogenesis, mutagenesis, impairment of fertility:
`No compound-related carcinogenic effects were observed in either mice or rats following a 21month
`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 ~77 and 118 times, respectively,
`the plasma drug concentration estimated in humans treated with one drop ALPHAGAN® 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 aberation assay in Chinese Hamster Ovary (CHO) cells, a host-mediated
`assay and cytogenic studies in mice, and dominant lethal assay.
`
`Reproductive studies performed in rats with oral doses of 0.66 mg base/kg revealed no evidence of
`impaired fertility due to ALPHAGAN.
`
`
`

`

`Page 6
`NDA 20-490/S-007
`NDA 20-613/S-018
`NDA 21-262/S-006
`
`Pregnancy: Teratogenic Effects: Pregnancy Category B
`Reproductive studies performed in rats with oral doses of 0.66 mg base/kg revealed no evidence of
`harm to the fetus due to ALPHAGAN. Dosing at this level produced 100 times the plasma drug
`concentration level seen in humans following multiple ophthalmic doses. 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 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; 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 daily 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 ALPHAGAN® have not been studied in pediatric patients below the
`age of 2 years. ALPHAGAN® is not recommended for use in pediatric patients under the age of 2
`years.
`
`Geriatric Use:
`No overall differences in safety or effectiveness have been observed between elderly and other adult
`patients.
`
`ADVERSE REACTIONS
`The most common adverse events reported in association with the use of ALPHAGAN 0.5% in
`conjunction with ALT was transient conjunctival blanching in 50% of patients and upper lid retraction
`in 30% of patients.
`
`The following adverse reactions were reported in 1% to 4% of the patients: corneal edema, dizziness,
`drowsiness/tiredness, and ocular irritation (encompassing discomfort, foreign body sensation, and
`ocular pain.
`
`The following were reported in 1% or less of patients: browache, dry mouth, nausea.
`
`
`

`

`Page 7
`NDA 20-490/S-007
`NDA 20-613/S-018
`NDA 21-262/S-006
`
`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
`Instill 1 drop of ALPHAGAN in the operative eye 30-45 minutes before ALT surgery and
`immediately following ALT surgery.
`
`HOW SUPPLIED
`ALPHAGAN (brimonidine tartrate ophthalmic solution) 0.5% is supplied sterile in unit dose vials of
`LDPE plastic containing 0.4 mL each and packaged in cartons containing 24 vials; NDC 0023-XXXX-
`XX
`
`NOTE: Store between 15°-25° C (59-77° F). Properly dispose of unit-dose vial after each single
`patient use.
`
`Rx only
`
` ©
`
` 2001 Allergan, Inc
`Irvine, CA 92612, U.S.A.
`® Marks owned by Allergan.
`US Patent 6,194,415
`Revised December 2001
`7831X
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`Page 8
`NDA 20-490/S-007
`NDA 20-613/S-018
`NDA 21-262/S-006
`
`ALPHAGAN
`(brimonidine tartrate ophthalmic solution) 0.2%
`
`
`Sterile
`
`
`DESCRIPTION
`ALPHAGAN (brimonidine tartrate ophthalmic solution) 0.5% 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 has a molecular weight of 442.24 as the tartrate
`salt and is water soluble (34 mg/mL) at pH 6.5. The structural formula is:
`
`
`
`
`COOH
`OH
`H
`OOH
`
`C C C
`
`H
`HO
`
`NN
`
`HN
`
`NH
`
`Br
`
`N
`
`
`
`Formula: C11H10BrN5⋅C4H6O6
`
`CAS Number 59803-98-4
`
`In solution, ALPHAGAN® (brimonidine tartrate ophthalmic solution) 0.2% has a clear, greenish-
`yellow color. It has an osmolality of 280 – 330 mOsml/kg and a pH of 5.6 - 6.6.
`
`Each mL of ALPHAGAN contains:
`Active ingredient: brimonidine tartrate: 0.2% (2 mg/mL).
`Preservative: benzalkonium chloride (0.05 mg).
`Inactives: citric acid; polyvinyl alcohol; sodium chloride; sodium citrate; and purified water.
`Hydrochloric acid and/or sodium hydroxide may be added to adjust pH.
`
`CLINICAL PHARMACOLOGY
`Mechanism of action:
`ALPHAGAN 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.
`
`
`

`

`Page 9
`NDA 20-490/S-007
`NDA 20-613/S-018
`NDA 21-262/S-006
`
`Pharmacokinetics:
`After ocular administration of a 0.2% solution, plasma concentrations peaked within 1 to 4 hours and
`declined with a systemic half-life of approximately 3 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.
`
`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.
`
`In comparative clinical studies with timolol 0.5%, lasting up to one year, the IOP lowering effect of
`ALPHAGAN was approximately 4-6 mm Hg compared with approximately 6 mm Hg for timolol. In
`these studies, both patient groups were dosed BID; however, due to the duration of action of
`ALPHAGAN, it is recommended that ALPHAGAN be dosed TID. Eight percent of subjects were
`discontinued from studies due to inadequately controlled intraocular pressure, which in 30% of these
`patients occurred during the first month of therapy. Approximately 20% were discontinued due to
`adverse experiences.
`
`INDICATIONS AND USAGE
`ALPHAGAN is indicated for lowering intraocular pressure in patients with open-angle glaucoma or
`ocular hypertension. The IOP lowering efficacy of ALPHAGAN Ophthalmic Solution diminishes
`over time in some patients. This loss of effect appears with a variable time of onset in each patient and
`should be closely monitored.
`
`CONTRAINDICATIONS
`ALPHAGAN 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 ALPHAGAN had minimal effect on blood pressure of patients in clinical studies, caution
`should be exercised in treating patients with severe cardiovascular disease.
`
`ALPHAGAN has not been studied in patients with hepatic or renal impairment; caution should be
`used in treating such patients.
`
`ALPHAGAN should be used with caution in patients with depression, cerebral or coronary
`insufficiency, Raynaud's phenomenon, orthostatic hypotension or thromboangiitis obliterans.
`
`
`

`

`Page 10
`NDA 20-490/S-007
`NDA 20-613/S-018
`NDA 21-262/S-006
`
`During the studies there was a loss of effect in some patients. The IOP-lowering efficacy observed
`with ALPHAGAN Ophthalmic Solution during the first month of therapy may not always reflect the
`long-term level of IOP reduction. Patients prescribed IOP-lowering medication should be routinely
`monitored for IOP.
`
`Information for Patients:
`The preservative in ALPHAGAN, benzalkonium chloride, may be absorbed by soft contact lenses.
`Patients wearing soft contact lenses should be instructed to wait at least 15 minutes after instilling
`ALPHAGAN to insert soft contact lenses.
`
`As with other drugs in this class, ALPHAGAN 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.
`
`Drug Interactions:
`Although specific drug interaction studies have not been conducted with ALPHAGAN, 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 beta-blockers (ophthalmic and systemic),
`antihypertensives 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 in humans can lead to
`resulting interference with the IOP lowering effect. No data on the level of circulating catecholamines
`after ALPHAGAN are available. Caution, however, is advised in patients taking tricyclic
`antidepressants which can affect the metabolism and uptake of circulating amines.
`
`Carcinogenesis, mutagenesis, 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 ~77 and 118 times, respectively,
`the plasma drug concentration estimated in humans treated with one drop ALPHAGAN® 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 aberation assay in Chinese Hamster Ovary (CHO) cells, a host-mediated
`assay and cytogenic studies in mice, and dominant lethal assay.
`
`Reproductive studies performed in rats with oral doses of 0.66 mg base/kg revealed no evidence of
`harm to the fetus due to ALPHAGAN®.
`
`
`

`

`Page 11
`NDA 20-490/S-007
`NDA 20-613/S-018
`NDA 21-262/S-006
`
`Pregnancy: Teratogenic Effects: Pregnancy Category B
`Reproductive studies performed in rats with oral doses of 0.66 mg base/kg revealed no evidence of
`harm to the fetus due to ALPHAGAN. Dosing at this level produced 100 times the plasma drug
`concentration level seen in humans following multiple ophthalmic doses.
`
`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 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; 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 daily 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%).
`The most commonly observed adverse event was somnolence. Approximately 16% of patients on
`brimonidine tartrate ophthalmic solution discontinued from the study due to somnolence.
`
`The safety and effectiveness of ALPHAGAN® have not been studied in pediatric patients below the
`age of 2 years. ALPHAGAN® 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 10-30% of the subjects, in descending order of incidence,
`included oral dryness, ocular hyperemia, burning and stinging, headache, blurring, foreign body
`sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus.
`
`Events occurring in approximately 3-9% of the subjects, in descending order included corneal
`staining/erosion, photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper
`respiratory symptoms, eyelid edema, conjunctival edema, dizziness, blepharitis, ocular irritation,
`gastrointestinal symptoms, asthenia, conjunctival blanching, abnormal vision and muscular pain.
`
`
`

`

`Page 12
`NDA 20-490/S-007
`NDA 20-613/S-018
`NDA 21-262/S-006
`
`The following adverse reactions were reported in less than 3% of the patients: lid crusting, conjunctival
`hemorrhage, abnormal taste, insomnia, conjunctival discharge, depression, hypertension, anxiety,
`palpitations/arrhythmias, nasal dryness and syncope.
`
`The following events have been identified during post-marketing use of ALPHAGAN® 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 ALPHAGAN®, or a combination of
`these factors, include: bradycardia; hypotension; iritis; miosis; skin reactions (including erythema,
`eyelid pruritis, rash, and vasodilation); and tachycardia. Apnea, bradycardia, hypotension,
`hypothermia, hypotonia, and somnolence have been reported in infants receiving ALPHAGAN®.
`
`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 in the affected eye(s) three times daily,
`approximately 8 hours apart.
`
`ALPHAGAN® 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(brimonidine tartrate ophthalmic solution) 0.2% is supplied sterile in white opaque
`LPDE plastic bottles with tips with purple high impact polystyrene (HIPS) caps as follows:
`
` 5 mL in 10 mL bottle
`10 mL in 10 mL bottle
`15 mL in 15 mL bottle
`
`
`NOTE: Store between 15°-25° C (59-77° F).
`
`Rx only
`
`
`NDC 0023-8665-05
`NDC 0023-8665-10
`NDC 0023-8665-15
`
` ALLERGAN
` 2001 Allergan, Inc
`Irvine, CA 92612
`
` ®
`
` Marks owned by Allergan
`US Patent 6,194,415
`Revised December 2001
`7831X
`
`
`

`

`Page 13
`NDA 20-490/S-007
`NDA 20-613/S-018
`NDA 21-262/S-006
`
`ALPHAGAN P
`(brimonidine tartrate ophthalmic solution) 0.15%
`
`
`
`Sterile
`
`
`
`
`
`
`DESCRIPTION
`ALPHAGAN P (brimonidine tartrate ophthalmic solution) 0.15% 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 (1.5 mg/mL) and in the
`product vehicle (3.0 mg/mL) at pH 7.2. The structural formula is:
`
`
`
`
`COOH
`OH
`H
`OOH
`
`C C C
`
`H
`HO
`
`NN
`
`HN
`
`NH
`
`Br
`
`N
`
`
`Formula: C11H10BrN5⋅C4H6O6
`
`CAS Number: 59803-98-4
`
`In solution, ALPHAGAN P (brimonidine tartrate ophthalmic solution) 0.15% has a clear, greenish-
`yellow color. It has an osmolality of 250-350 mOsmol/kg and a pH of 6.6-7.4.
`
`Each mL of ALPHAGAN P contains:
`Active ingredient: brimonidine tartrate 0.15% (1.5 mg/mL)
`Preservative: Purite 0.005% (0.05mg/mL)
`Inactives: boric acid; calcium chloride; magnesium chloride; potassium chloride; purified water;
`sodium borate; sodium carboxymethylcellulose; sodium chloride; 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.
`
`
`
`

`

`Page 14
`NDA 20-490/S-007
`NDA 20-613/S-018
`NDA 21-262/S-006
`
`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.
`
`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.
`
`Two 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
`2-5 mmHg.
`
`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 ALPHAGAN P 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 thromboangitis 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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`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 beta-blockers (ophthalmic and systemic), 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 86 and 55 times, respectively,
`the plasma drug concentration estimated in humans treated with one drop of ALPHAGAN P 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.
`
`Reproductive studies performed in rats with oral doses of 0.66 mg base/kg revealed no evidence of
`impaired fertility due to ALPHAGAN® P.
`
`Pregnancy: Teratogenic effects: Pregnancy Category B
`Reproductive studies performed in rats with oral doses of 0.66 mg base/kg revealed no evidence of
`harm to the fetus due to ALPHAGAN P. Dosing at this level produced an exposure that is 189 times
`higher than the exposure seen in humans following multiple ophthalmic doses.
`
`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; 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.
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`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.
`
`ADVERSE REACTIONS
`Adverse events occurring in approximately 10-20% of the subjects included: allergic conjunctivitis,
`conjunctival hyperemia, and eye pruritis.
`
`Adverse events occurring in approximately 5-9% of the subjects included: burning sensation,
`conjunctival foliculosis, hypertension, oral dryness, and visual disturbance.
`
`Events occurring in approximately 1-4% of subjects included: allergic reaction, asthenia, blepharitis,
`bronchitis, conjunctival edema, conjunctival hemorrhage, conjunctivitis, cough, dizziness, dyspepsia,
`dyspnea, epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema,
`flu syndrome, follicular conjunctivitis, foreign body sensation, headache, pharyngitis, photophobia,
`rash, rhinitis, sinus infection, sinusitis, stinging, superficial punctate keratopathy, visual field defect,
`vitreous floaters, and worsened visual acuity.
`
`The following events were reported in less than 1% of subjects: corneal erosion, insomnia, nasal
`dryness, somnolence, and taste perversion.
`
`The following events have been identified during post-marketing use of ALPHAGAN® 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 ALPHAGAN®, or a combination of
`these factors, include: bradycardia; hypotension; iritis; miosis; skin reactions (including erythema,
`eyelid pruritis, rash, and vasodilation); and tachycardia. Apnea, bradycardia, hypotension,
`hypothermia, hypotonia, and somnolence have been reported in infants receiving ALPHAGAN®.
`
`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.
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`DOSAGE AND ADMINISTRATION
`The recommended dose is one drop of ALPHAGAN P in the affected eye(s) three times daily,
`approximately 8 hours apart.
`
`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 (brimonidine tartrate ophthalmic solution) 0.15% is supplied sterile in opaque teal
`LDPE plastic bottles and tips with purple high impact polystyrene (HIPS) caps as follows:
`
` 5 mL in 10 mL bottle
`10 mL in 10 mL bottle
`15 mL in 15 mL bottle
`
`NOT