Alphagan/Alphagan P 0.1%

Alphagan: Each mL contains brimonidine tartrate 2 mg (equivalent to 1.32 mg as brimonidine free base).
Alphagan P 0.1%: In solution, ALPHAGAN P (brimonidine tartrate ophthalmic solution) 0.1% has a clear, greenish-yellow color.
Each mL of ALPHAGAN P 0.1% contains brimonidine tartrate 0.1% (1.0 mg/mL).
ALPHAGAN P (brimonidine tartrate ophthalmic solution) 0.1% is a relatively selective alpha-2 adrenergic agonist for ophthalmic use. The chemical name of brimonidine tartrate is 5-Bromo-N-(imidazolidin-2-ylidene) quinoxalin-6-amine (2R,3R)-2,3 dihydroxybutanedioate.
Formula: C₁₁H₁₀BrN₅·C₄H₆O₆.
CAS Number: 70359-46-5.
Excipients/Inactive Ingredients: Alphagan: Polyvinyl alcohol 14 mg, sodium chloride, sodium citrate, citric acid and purified water.
Preservative: Benzalkonium chloride 0.05 mg.
Alphagan P 0.1%: Sodium carboxymethylcellulose, sodium borate, boric acid, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, purified water; with hydrochloric acid and/or sodium hydroxide to adjust pH.
Preservative: PURITE 0.005% (0.05 mg/mL).

Pharmacology: Pharmacodynamics: Mechanism of Action: ALPHAGAN/ALPHAGAN P 0.1% is a relatively selective alpha-2 adrenergic 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: 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.
Alphagan: 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.
Alphagan P 0.1%: 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.
Clinical studies/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.
Alphagan: In comparative clinical studies with timolol 0.5%, lasting up to one year, the IOP lowering effect of ALPHAGAN was approximately 4-6 mmHg compared with approximately 6 mmHg for timolol. 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.
Alphagan P 0.1%: A 3-month (with a double-masked extension to 1 year) clinical study (N=433) was conducted to evaluate the safety, efficacy, and acceptability of ALPHAGAN P 0.1% compared with ALPHAGAN 0.2% administered 3 times daily in patients with glaucoma or ocular hypertension.
A 3-month analysis of the pivotal study indicated that ALPHAGAN P 0.1% is equivalent in IOP-lowering effect to ALPHAGAN 0.2% and effectively lowers IOP in patients with glaucoma or ocular hypertension (mean change from baseline IOP -3.3 to -5.4 mmHg).
Additionally, 12-month analysis of the pivotal study indicated ALPHAGAN P 0.1% continued to be equivalent to ALPHAGAN 0.2% and effectively lowered IOP in patients with glaucoma or ocular hypertension (mean change from baseline IOP at hours 0, 2, and 8 ranged from -2.7 to -5.4 mmHg). ALPHAGAN P 0.1% is well-tolerated and provides a superior safety profile when compared with ALPHAGAN 0.2%. ALPHAGAN P 0.1% is the lowest effective dose of brimonidine tartrate that combines the IOP lowering efficacy with the most favorable safety and tolerability profile.

ALPHAGAN/ALPHAGAN P 0.1% is indicated for lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
Alphagan: 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.

Recommended Dose: Alphagan: The recommended dose is one drop of ALPHAGAN in the affected eye(s) two times daily.
For those patients whose IOP peaks in the afternoon or need additional IOP control, an additional drop of brimonidine in the afternoon can be added.
Alphagan P 0.1%: The recommended dose is one drop of ALPHAGAN P (brimonidine tartrate ophthalmic solution) 0.1% in the affected eye(s) three times daily, approximately 8 hours apart.
Mode of Administration: ALPHAGAN/ALPHAGAN P 0.1% is administered topically to the eye.
If more than one topical ophthalmic drug is to be used, the different drugs should be instilled at least 5 minutes apart.

Ophthalmic overdose: In those cases received, the events reported have generally been those already listed as adverse reactions.
Systemic overdose resulting from accidental ingestion: There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.
Symptoms of brimonidine overdose such as apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in neonates, infants, and children receiving ALPHAGAN/ALPHAGAN P 0.1% as part of medical treatment of congenital glaucoma or by accidental oral ingestion.

ALPHAGAN/ALPHAGAN P 0.1% is contraindicated in the following patients: Patients with hypersensitivity to brimonidine tartrate or any component of this medication; patients receiving monoamine oxidase (MAO) inhibitor therapy; neonates and infants (children under the age of 2 years). Refer to Use in Children under Precautions.

ALPHAGAN/ALPHAGAN P 0.1% 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.
Effects on Ability to Drive and Use Machines: As with other similar medications, ALPHAGAN/ALPHAGAN P 0.1% may cause fatigue and/or drowsiness in some patients. Patients who engage in activities such as driving and operating machinery should be cautioned of the potential for a decrease in mental alertness. ALPHAGAN/ALPHAGAN P 0.1% may also cause blurred vision or visual disturbance in some patients. The patient should wait until these symptoms have cleared before driving or using machinery.
ALPHAGAN/ALPHAGAN P 0.1% has not been studied in patients with hepatic or renal impairment; caution should be used in treating such patients.
Alphagan: Although ALPHAGAN 0.2% had minimal effect on the blood pressure and heart rate of patients in clinical studies, caution should be exercised in treating patients receiving ALPHAGAN with severe cardiovascular disease.
Delayed ocular hypersensitivity reactions have been reported with ALPHAGAN 0.2%, with some reported to be associated with an increase in IOP.
During the studies there was a loss of effect in some patients. The IOP-lowering efficacy observed with ALPHAGAN 0.2% ophthalmic solution during the first month of therapy may not always reflect the long-term level of IOP reduction. For those patients whose IOP is not adequately controlled with twice-daily dosing, an additional drop of brimonidine in the afternoon can be added. Patients prescribed IOP-lowering medication should be routinely monitored for IOP.
The preservative in ALPHAGAN 0.2%, benzalkonium chloride, may be absorbed by soft contact lenses. Patients wearing soft (hydrophilic) contact lenses should be instructed to wait at least 15 minutes after instilling ALPHAGAN to insert soft contact lenses.
Use in Children: Children 2 years of age and above, especially those weighing ≤20 kg, should be treated with caution and closely monitored due to the high incidence and severity of somnolence. Refer to information as follows.
In a 3-month, Phase 3 study in children aged 2-7 years with glaucoma inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with ALPHAGAN/ALPHAGAN P 0.1% as adjunctive treatment. This was severe in 8% of the children and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, the least being in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in children weighing ≤20 kg (63%) compared to those weighing >20 kg (25%).
Safety and effectiveness of ALPHAGAN/ALPHAGAN P 0.1% in children under the age of 2 years have not been established. During post-marketing surveillance, apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in neonates, infants and children receiving brimonidine either for congenital glaucoma or by accidental ingestion.
Use in the Elderly: No overall differences in safety or effectiveness have been observed between elderly and other adult patients. The C_max and apparent half-life of brimonidine were similar in elderly subjects (65 years or older) and younger adults, indicating that its systemic absorption and elimination were not significantly affected by age.

Pregnancy: Teratogenic effects: Pregnancy Category B.
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response. ALPHAGAN/ALPHAGAN P 0.1% should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Lactation: Studies in rats have indicated brimonidine is excreted in the milk of the lactating rat. Since it is not known whether this drug is excreted in human 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.

Alphagan: 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.
The following adverse reactions were reported in less than 3% of the patients: lid crusting, conjunctival hemorrhage, abnormal taste, insomnia, conjunctival discharge, conjunctival papillae, depression, hypertension, anxiety, palpitations, nasal dryness and syncope.
Postmarketing Experience: Brimonidine Ophthalmic Solution 0.2%: The following adverse reactions have been identified during postmarketing use of ALPHAGAN 0.2% in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.
Eye disorders: Iritis, iridocyclitis (anterior uveitis), miosis, conjunctivitis, eyelids pruritus.
Immune system disorders: Hypersensitivity, skin reaction (including erythema, face edema, pruritus, rash, and vasodilatation).
Cardiac disorders: Palpitations/arrhythmias (including bradycardia or tachycardia).
Vascular disorders: Hypotension, syncope.
Carcinogenesis, mutagenesis, impairment of fertility: No compound-related carcinogenic effects were observed in 21 month and 2 year studies in mice and rats given oral doses of 2.5 mg/kg/day (as the free base) and 1.0 mg/kg/day, respectively (~77 and 118 times, respectively, the human plasma drug concentration following the recommended ophthalmic dose).
ALPHAGAN was not mutagenic or cytogenic in a series of in vitro and in vivo stdies including the Ames test, host-mediated assay, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, cytogenic studies in mice and dominant lethal assay.
Alphagan P 0.1%: Adverse events occurring in approximately 10-20% of the subjects included: allergic conjunctivitis and conjunctival hyperemia.
Adverse events occurring in approximately 5-9% of the subjects included: conjunctival folliculosis.
Events occurring in approximately 1-4% of subjects included: somnolence, oral dryness, asthenia, burning sensation in the eye, foreign body sensation, ocular pruritus/eye pruritus, erythema eyelid, eye pain (ocular ache/pain), ocular dryness/eye dryness, follicular conjunctivitis, superficial punctate keratitis and conjunctivitis.
Postmarketing Experience: Brimonidine Ophthalmic Solution 0.1%: The following adverse reactions have been identified during postmarketing use of ALPHAGAN P 0.1% in clinical practice.
Eye disorders: Lacrimation increased, blurred vision.
Nervous system disorders: Dizziness, headache.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenesis and Mutagenesis Studies: No compound-related carcinogenic effects were observed in either mice or rats following a 21-month and 24-month study, respectively. 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 118 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 clastogenic 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 assay, and dominant lethal assay.
Fertility Studies: No impairment of fertility and reproduction occurred in male rats when treated for 70 days prior to mating and female rats when treated for 14 days prior to mating and continuing through gestation and lactation with oral doses of brimonidine tartrate. The highest dose (0.66 mg base/kg/day) produced 244 times the plasma drug concentration seen in humans treated multiple times with 1 drop of brimonidine tartrate ophthalmic solution 0.2% into each eye twice a day. Although no blood drug levels were determined in this study, it is estimated that the highest dose of brimonidine tartrate (0.66 mg base/kg/day), achieved AUC values 60 times those seen in humans treated with 1 drop of brimonidine tartrate ophthalmic solution 0.15% in both eyes 3 times per day. These reproduction and fertility studies in rats with brimonidine tartrate demonstrated no adverse effect on male or female fertility at doses which achieve up to approximately 477 and 302 times the systemic exposure following the maximum recommended human ophthalmic dose of ALPHAGAN P 0.1% or 0.15%, respectively.

Although specific drug interaction studies have not been conducted with ALPHAGAN/ALPHAGAN P 0.1%, 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 (including ALPHAGAN 0.2%), 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/ALPHAGAN P 0.1% in humans can lead to resulting interference with the IOP lowering effect. In experiments on rabbits, however, MAO inhibitors and tricyclic antidepressants did not alter the IOP response to brimonidine.
No data on the level of circulating catecholamines after ALPHAGAN/ALPHAGAN P 0.1% administration are available. Caution, however, is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

Store below 30°C.

Antiglaucoma Preparations

S01EA05 - brimonidine ; Belongs to the class of sympathomimetics used in the treatment of glaucoma.

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