ALPHAGAN® P is a relatively selective alpha-2 adrenergic receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with open angle glaucoma or ocular hypertension.

The recommended dose is one drop of ALPHAGAN® P in the affected eye(s) three times daily, approximately 8 hours apart. ALPHAGAN® P ophthalmic solution may be used concomitantly 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.

Additional information on special populations:

Renal/hepatic impairment:
ALPHAGAN® P has not been studied in patients with hepatic impairment.
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.

Pediatric population:
ALPHAGAN® P is contraindicated in children under the age of 2 years (see 4.3 CONTRAINDICATIONS).
During postmarketing surveillance, apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine. The safety and effectiveness of brimonidine tartrate have not been studied in children below the age of 2 years.
In a well-controlled clinical study conducted in pediatric glaucoma patients (ages 2 to 7 years) the most commonly observed adverse reactions 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 (>20 kg), somnolence appears to occur less frequently (25%). Approximately 16% of patients on brimonidine tartrate ophthalmic solution discontinued from the study due to somnolence.

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

4.4.1 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.

4.4.2 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.

4.4.3 Contamination of Topical Ophthalmic Products After Use
There have been reports of bacterial keratitis 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 ocular epithelial surface.
Patients should be instructed that ocular solutions, if handled improperly or if the tip of the 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 subsequent
loss of vision may result from using contaminated solutions. Always replace the cap after using. If solution changes color or becomes cloudy, do not use. Do not use the product after the expiration date marked on the bottle.
Patients also should be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician’s advice concerning the continued use of the present multidose container.
If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.

4.5.1 Antihypertensives/Cardiac Glycosides
Because ALPHAGAN® P may reduce pulse and blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with ALPHAGAN® P is advised.

4.5.2 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.

4.5.3 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 tricyclicantidepressants which can affect the metabolism and uptake of circulating amines.

4.5.4 Monoamine Oxidase Inhibitors
Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine and potentially result in an increased systemic side-effect such as hypotension. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

Pregnancy Category B: Teratogenicity studies have been performed in animals.
Brimonidine tartrate was not teratogenic when given orally during gestation days 6 through 15 in rats and days 6 through 18 in rabbits. The highest doses of brimonidine tartrate in rats (2.5 mg/kg/day) and rabbits (5.0 mg/kg/day) achieved AUC exposure values 360- and 20-fold higher, or 260- and 15-fold higher, respectively, than similar values estimated in humans treated with ALPHAGAN® P 0.15%,1 drop in both eyes three times daily.
There are no adequate and well-controlled studies in pregnant women; however, in animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. Because animal reproduction studies are not always predictive of human response, 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 brimonidine tartrate is excreted in human milk, although in animal studies, brimonidine tartrate has been shown to be excreted in breast milk. Because of the potential for serious adverse reactions from ALPHAGAN® P in nursing infants, 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.

As with other similar medications, 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. Alphagan P 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.

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), unknown (cannot be estimated from available data).
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

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

Common adverse reactions occurring in approximately 1-4% of the subjects receiving brimonidine ophthalmic solution (0.1-0.2%) included: abnormal taste, 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.

Uncommon adverse reactions were reported in less than 1% of subjects: corneal erosion, hordeolum, nasal dryness, and taste perversion.

The following reactions 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 reactions, 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, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), syncope, andtachycardia. Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions.

To reports any side effect(s):
• Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse 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 of congenital glaucoma or by accidental oral ingestion. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.

Description:
Pharmacotherapeutic group: Sympathomimetics used in ophthalmic – glaucoma treatment
ATC Code is S01EA05
Mechanism of Action: ALPHAGAN® P (brimonidine tartrate ophthalmic solution) 0.15%, sterile, is a relatively selective alpha-2 adrenergic receptor agonist (topical intraocular pressure lowering agent) with 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.

CLINICAL STUDIES:
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.

Absorption: 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.

Distribution: The protein binding of brimonidine has not been studied.

Metabolism: In humans, brimonidine is extensively metabolized by the liver.

Excretion: 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, with 74% found in the urine.

Carcinogenesis, Mutagenesis, Impairment of Fertility (Nonclinical Toxicology)
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 mg/kg/day in rats achieved 150 and 120 times or 90 and 80 times, respectively, the plasma Cmax drug concentration in humans treated with one drop of ALPHAGAN® P 0.1% or 0.15% into both eyes 3 times per day, the recommended daily human dose.
Brimonidine tartrate was not mutagenic or clastogenic in a series of in vitro and in vivo studies including the Ames bacterial reversion test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, and three in vivo studies in CD-1 mice: a host-mediated assay, cytogenetic study, and dominant lethal assay.
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 125 and 90 times the systemic exposure following the maximum recommended human ophthalmic dose of ALPHAGAN® P 0.1% or 0.15%, respectively.

Sodium carboxymethylcellulose; sodium borate; 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 hydroxide to adjust pH.

Not reported.

Store ALPHAGAN® P at or below 25°C.

ALPHAGAN® P is supplied sterile, in teal opaque plastic LDPE 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 all pack sizes may be marketed.

No special requirements