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  • CLASSES

    Ocular Decongestants, Sympathomimetics
    Other Miotics-Antiglaucoma Agents
    Topical Rosacea Agents

    DEA CLASS

    Rx, OTC

    DESCRIPTION

    Selective alpha-2 adrenergic agonist
    Used ophthalmically to reduce intraocular pressure in open-angle glaucoma and ocular hypertension and to relieve ocular redness due to irritation and topically to reduce persistent facial erythema of rosacea
    Minimal cardiopulmonary effects

    COMMON BRAND NAMES

    Alphagan, Alphagan P, LUMIFY, Mirvaso

    HOW SUPPLIED

    Alphagan/Alphagan P/Brimonidine/Brimonidine Tartrate Ophthalmic Sol: 0.025%, 0.1%, 0.15%, 0.2%
    Alphagan/Brimonidine/Brimonidine Tartrate Ophthalmic Drops: 0.2%
    Mirvaso Topical Gel: 0.33%

    DOSAGE & INDICATIONS

    For the treatment of increased intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
    Ophthalmic dosage (0.1%, 0.15%, 0.2% ophthalmic solution)
    Adults, Adolescents, and Children 2 years and older

    Instill 1 drop in the affected eye(s) 3-times daily, approximately 8 hours apart.

    For the treatment of persistent (nontransient) facial erythema of acne rosacea.
    Topical dosage
    Adults

    Apply a pea-size amount once daily to each of the 5 areas of the face: central forehead, chin, nose, each cheek.

    For the treatment of eye redness due to minor ocular pain or irritation.
    Ophthalmic dosage (0.025% ophthalmic solution)
    Adults, Adolescents, and Children 5 years and older

    Instill 1 drop into the affected eye(s) every 6 to 8 hours as needed. Do not use more than 4-times daily.

    MAXIMUM DOSAGE

    Adults

    3 drops/day/affected eye 0.1%, 0.15%, or 0.2% ophthalmic solution; 4 drops/day/affected eye 0.025% ophthalmic solution; 1 application/day topically brimonidine gel.

    Geriatric

    3 drops/day/affected 0.1%, 0.15%, or 0.2% ophthalmic solution; 4 drops/day/affected eye 0.025% ophthalmic solution; 1 application/day topically brimonidine gel.

    Adolescents

    3 drops/day/affected eye 0.1%, 0.15%, or 0.2% ophthalmic solution; 4 drops/day/affected eye 0.025% ophthalmic solution; safety and efficacy of brimonidine topical gel have not been established.

    Children

    5 years and older: 3 drops/day/affected eye 0.1%, 0.15%, or 0.2% ophthalmic solution; 4 drops/day/affected eye 0.025% ophthalmic solution; safety and efficacy of brimonidine topical gel have not been established.
    2 to 4 years: 3 drops/day/affected eye 0.1%, 0.15%, or 0.2% ophthalmic solution; safety and efficacy of brimonidine topical gel or 0.025% ophthalmic solution have not been established.
    less than 2 years: Use of ophthalmic solution not recommended; safety and efficacy of brimonidine topical gel have not been established.

    Infants

    Use of brimonidine ophthalmic solution not recommended; safety and efficacy of brimonidine topical gel have not been established.

    Neonates

    Use of brimonidine ophthalmic solution not recommended; safety and efficacy of brimonidine topical gel have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Brimonidine has not been studied in patients with hepatic impairment; use caution in treating these patients.

    Renal Impairment

    Brimonidine has not been studied in patients with renal impairment; use caution in treating these patients.

    ADMINISTRATION

    Topical Administration

    Apply smoothly and evenly as a thin layer across the face avoiding the eyes and lips.
    Wash hands after application.
    Not for oral, ophthalmic, or intravaginal use.

    Ophthalmic Administration

    Brimonidine is applied topically to the eye.
    Wash hands before and after use. Tilt the head back slightly and pull the lower eyelid down with the index finger to form a pouch. Squeeze one drop into the pouch and gently close eyes for 1 to 2 minutes. Do not blink.
    Care should be taken to avoid contamination. Do not touch the tip of the dropper to the eye, fingertips, or other surface. To avoid the risk of infection, use one open bottle per individual patient.
    Brimonidine may be used concomitantly with other topical ophthalmic agents used to lower IOP. Administer each agent at least 5 minutes apart.[29281] [64299] [64300]
    Contact lenses should be removed prior to instilling brimonidine; they can be reinserted 15 minutes after the dose is instilled.[64304]

    STORAGE

    Alphagan:
    - Store between 59 to 77 degrees F
    Alphagan P:
    - Store between 59 to 77 degrees F
    LUMIFY:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Store between 59 to 77 degrees F
    Mirvaso:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Cardiac disease, cerebrovascular disease, coronary artery disease

    Although brimonidine has minimal effects on blood pressure and other cardiopulmonary hemodynamics, it should be used with caution in patients with severe, unstable, or uncontrolled cardiac disease, cerebrovascular disease or coronary artery disease.

    Contact lenses

    Some brimonidine ophthalmic solutions contain benzalkonium chloride, a preservative that may be absorbed by soft contact lenses. Patients should remove contact lenses prior to instilling brimonidine ophthalmic solutions containing benzalkonium chloride and wait 15 minutes before replacing them.

    Depression, orthostatic hypotension, Raynaud's phenomenon, scleroderma, Sjogren's syndrome, thromboangiitis obliterans (Buerger's disease)

    Brimonidine should be used with caution in patients with Raynaud's phenomenon, thromboangiitis obliterans (Buerger's disease), depression, scleroderma, Sjogren's syndrome, and orthostatic hypotension.

    Hepatic disease, renal impairment

    Brimonidine has not been studied in patients with renal impairment or hepatic disease. It should be used carefully in these patient populations.

    Children, infants, neonates

    Brimonidine 0.1%, 0.15%, and 0.2% ophthalmic solutions are contraindicated for use in neonates, infants, and children younger than 2 years. During postmarketing use of these ophthalmic solutions in infants, the following adverse events were noted: apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence. Brimonidine 0.025% ophthalmic solution is not indicated for use in patients younger than 5 years of age, and the topical gel is only approved for use in adults 18 years or older.[29281] [64299] [55747] [64300] [52720]

    Pregnancy

    Brimonidine is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies in pregnant women. According to the manufacturer, brimonidine should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

    Breast-feeding

    According to the manufacturer, a decision should be made whether to discontinue nursing or to discontinue brimonidine, taking into account the importance of the drug to the mother. It is not known whether brimonidine is excreted in breast milk. However, limited data in nursing mothers using brimonidine ophthalmic products have not demonstrated adverse reactions in nursing infants. To minimize the amount of drug that reaches the systemic circulation and breast milk, apply pressure over the tear duct by the corner of the eye for 1 minute after ophthalmic administration. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 3.0-9.0
    keratitis / Delayed / 1.0-4.0
    ocular hypertension / Delayed / 4.0-4.0
    ocular hemorrhage / Delayed / 0-4.0
    bradycardia / Rapid / 0-1.0
    keratoconjunctivitis / Early / 0-1.0
    coma / Early / 0-1.0
    apnea / Delayed / 0-1.0
    angioedema / Rapid / Incidence not known

    Moderate

    blurred vision / Early / 1.0-30.0
    conjunctival hyperemia / Early / 10.0-30.0
    conjunctivitis / Delayed / 1.0-20.0
    respiratory depression / Rapid / 1.0-10.0
    hypertension / Early / 0-9.0
    blepharitis / Early / 1.0-9.0
    photophobia / Early / 1.0-9.0
    erythema / Early / 4.0-8.0
    hypotension / Rapid / 1.0-4.0
    keratopathy / Delayed / 1.0-4.0
    cataracts / Delayed / 1.0-4.0
    epiphora / Early / 1.0-4.0
    dyspnea / Early / 1.0-4.0
    hypercholesterolemia / Delayed / 1.0-4.0
    palpitations / Early / 0-3.0
    depression / Delayed / 0-3.0
    sinus tachycardia / Rapid / 0-1.0
    iritis / Delayed / 0-1.0
    hypotonia / Delayed / 0-1.0
    contact dermatitis / Delayed / 1.0-1.0
    orthostatic hypotension / Delayed / Incidence not known

    Mild

    foreign body sensation / Rapid / 1.0-30.0
    ocular pruritus / Rapid / 10.0-30.0
    fatigue / Early / 1.0-30.0
    drowsiness / Early / 1.0-30.0
    headache / Early / 1.0-30.0
    xerostomia / Early / 5.0-30.0
    flushing / Rapid / 3.0-10.0
    xerophthalmia / Early / 1.0-9.0
    ocular pain / Early / 1.0-9.0
    ocular irritation / Rapid / 3.0-9.0
    dizziness / Early / 1.0-9.0
    asthenia / Delayed / 1.0-9.0
    musculoskeletal pain / Early / 3.0-9.0
    pharyngitis / Delayed / 1.0-5.0
    ocular discharge / Delayed / 0-4.0
    insomnia / Early / 0-4.0
    rhinitis / Early / 1.0-4.0
    cough / Delayed / 1.0-4.0
    sinusitis / Delayed / 1.0-4.0
    dysgeusia / Early / 0-4.0
    dyspepsia / Early / 1.0-4.0
    rash / Early / 1.0-4.0
    influenza / Delayed / 1.0-4.0
    infection / Delayed / 1.0-4.0
    syncope / Early / 0-3.0
    anxiety / Delayed / 0-3.0
    nasal dryness / Early / 0-3.0
    miosis / Early / 0-1.0
    hypothermia / Delayed / 0-1.0
    paresthesias / Delayed / 1.0-1.0
    lethargy / Early / 0-1.0
    nasal congestion / Early / 1.0-1.0
    nausea / Early / 0-1.0
    acne vulgaris / Delayed / 1.0-1.0
    urticaria / Rapid / Incidence not known
    pallor / Early / Incidence not known

    DRUG INTERACTIONS

    Alprazolam: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Amitriptyline; Chlordiazepoxide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Anxiolytics; Sedatives; and Hypnotics: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of anxiolytics, sedatives, and hypnotics.
    Barbiturates: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including barbiturates.
    Benzodiazepines: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Cardiac glycosides: (Minor) Alpha-agonists as a class, may reduce heart rate and blood pressure. Although ophthalmic brimonidine administration generally does not have clinically significant effects on pulse and blood pressure, it should be used with caution with cardiac glycosides.
    Chlordiazepoxide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Chlordiazepoxide; Clidinium: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Clonazepam: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Clorazepate: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Diazepam: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Estazolam: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Ethanol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of alcohol.
    Flurazepam: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Linezolid: (Moderate) Use brimonidine with caution with MAOIs because they can affect the metabolism and uptake of circulating amines. Linezolid is an antibiotic that is also a reversible, non-selective inhibitor of MAO. MAOIs may theoretically interfere with the metabolism of brimonidine resulting in increased systemic side effects like hypotension.
    Lorazepam: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Mepenzolate: (Moderate) Anticholinergics, such as mepenzolate, antagonize the effects of antiglaucoma agents. Mepenzolate is contraindicated in patients with glaucoma and therefore should not be coadministered with medications being prescribed for the treatment of glaucoma. In addition, anticholinergic drugs taken concurrently with corticosteroids in the presence of increased intraocular pressure may be hazardous.
    Midazolam: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Monoamine oxidase inhibitors: (Moderate) Use caution during concurrent administration of brimonidine and monoamine oxidase inhibitors (MAOIs). MAOIs can affect the metabolism and uptake of circulating amines. MAOIs may theoretically interfere with the metabolism of brimonidine resulting in increased systemic side effects like hypotension.
    Opiate Agonists: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Oxazepam: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Quazepam: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Rasagiline: (Moderate) Use caution during concurrent administration of brimonidine and monoamine oxidase inhibitors (MAOIs). MAOIs can affect the metabolism and uptake of circulating amines. MAOIs may theoretically interfere with the metabolism of brimonidine resulting in increased systemic side effects like hypotension.
    Remimazolam: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Selegiline: (Moderate) Use caution during concurrent administration of brimonidine and monoamine oxidase inhibitors (MAOIs). MAOIs can affect the metabolism and uptake of circulating amines. MAOIs may theoretically interfere with the metabolism of brimonidine resulting in increased systemic side effects like hypotension.
    Temazepam: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Triazolam: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Tricyclic antidepressants: (Moderate) Tricyclic antidepressants have been reported to decrease the antihypertensive effects of systemic clonidine. It is not known whether tricyclic antidepressants will affect the IOP-lowering efficacy of brimonidine eye solution. There are no data concerning the levels of systemic catecholamines after ophthalmic administration of brimonidine; however, monitor patients carefully who are taking brimonidine and tricyclic antidepressants.

    PREGNANCY AND LACTATION

    Pregnancy

    Brimonidine is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies in pregnant women. According to the manufacturer, brimonidine should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

    According to the manufacturer, a decision should be made whether to discontinue nursing or to discontinue brimonidine, taking into account the importance of the drug to the mother. It is not known whether brimonidine is excreted in breast milk. However, limited data in nursing mothers using brimonidine ophthalmic products have not demonstrated adverse reactions in nursing infants. To minimize the amount of drug that reaches the systemic circulation and breast milk, apply pressure over the tear duct by the corner of the eye for 1 minute after ophthalmic administration. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Brimonidine is a potent alpha-2 adrenergic receptor agonist that shows up to 1,700-fold selectivity for alpha-2 receptors over alpha-1 receptors. When administered via the ophthalmic route, brimonidine decreases intraocular pressure by 2 mechanisms: reducing aqueous humor production (primary short-term mechanism) and stimulating aqueous humor outflow through the uveoscleral pathway (primary long-term mechanism). In addition to lowering intraocular pressure, data from animal studies suggest brimonidine may provide a neuroprotective effect against the progressive neuropathy that is associated with glaucoma.[64303] [64304] When administered topically, brimonidine binds to alpha-adrenergic receptors on smooth muscles surrounding the vessels of the superficial and deep dermal plexuses. By binding to these receptors, brimonidine causes vasoconstriction, thereby diverting blood flow away from the central face and reducing facial erythema associated with rosacea.[64302]

    PHARMACOKINETICS

    Brimonidine is administered as an ophthalmic solution to the eye or topically to the skin. Once in systemic circulation, brimonidine has a plasma elimination half-life of approximately 2 to 5 hours. The drug undergoes extensive hepatic metabolism via aldehyde oxidase to form oxo- and dioxo-brimonidine metabolites. Elimination of brimonidine and its metabolites occurs primarily via the kidneys (60% to 75%), with approximately 87% of an orally administered dose being excreted within 120 hours, of which, 74% is found in urine.[29281] [64299] [55747] [64304]
     
    Affected cytochrome P450 isoenzymes: None

    Topical Route

    Following topical administration of 1 gram of brimonidine 0.33% gel to the face once daily for 29 days, the mean Cmax and AUC were highest on day 15 with values of 46 +/- 62 pg/mL and 417 +/- 264 pg x hour/mL, respectively. On day 29, the systemic drug exposure was slightly lower indicating no further drug accumulation.

    Other Route(s)

    Ophthalmic Route
    Following ophthalmic administration of brimonidine, the Tmax occurred in 0.5 to 4 hours with a systemic half-life of approximately 2 to 3 hours. The time to peak hypotensive effect on IOP is about 2 hours.