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BRIMONIDINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Brimonidine is a relatively selective alpha-2-adrenergic agonist.

Specific Substances

    1) Brimonidine
    2) UK-14,304-18
    3) AGN 190342-LF
    4) SK&F 190342-LF
    5) 5-Bromo-6-[2-imidazolin-2-ylamino]-quinoxaline
    6) L-tartrate
    7) Molecular Formula: C11-H10-Br-N5-C4-H6-O6
    8) CAS 59803-98-4 (brimonidine)
    9) CAS 79570-19-7 (brimonidine tartrate)
    10) UK-14304-18

Available Forms Sources

    A) FORMS
    1) Brimonidine ophthalmic solution is available as a 0.1% and 0.15% solution containing 1 or 1.5 mg/mL brimonidine tartrate, respectively (Prod Info ALPHAGAN(R) P ophthalmic solution, 2010).
    2) Brimonidine topical gel is available in a 0.33% concentration, with each gram of gel containing 5 mg of brimonidine tartrate (equivalent to 3.3 mg of brimonidine as the base) (Prod Info MIRVASO(R) topical gel, 2013).
    B) USES
    1) Brimonidine ophthalmic solution is used for lowering intraocular pressure in patients with open angle glaucoma or ocular hypertension (Prod Info ALPHAGAN(R) P ophthalmic solution, 2010).
    2) Brimonidine topical gel is used to treat persistent facial erythema of rosacea in adults (Prod Info MIRVASO(R) topical gel, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Brimonidine ophthalmic solution is used for lowering intraocular pressure in patients with open angle glaucoma or ocular hypertension, and the topical gel is used to treat persistent facial erythema of rosacea in adults.
    B) PHARMACOLOGY: A relatively selective alpha-adrenergic receptor agonist. With ophthalmic administration, brimonidine lowers intraocular pressure in open-angle glaucoma or ocular hypertension by reducing aqueous humor production and increasing uveoscleral outflow. When applied as a topical gel to the facial area, brimonidine may decrease erythema via direct vasoconstriction.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Fatigue, drowsiness, headache, and ocular symptoms (ie, ocular hyperemia, burning, stinging, pruritus, blurring, conjunctival follicles, and foreign body sensation) are the most commonly reported adverse effects, occurring in 10% to 30% of patients following therapeutic administration.
    2) Other effects that may occur less frequently include: mild hypotension, miosis, allergic reactions, upper respiratory symptoms (3% to 9%), and dizziness (3% to 9%), and erythema and flushing following topical gel therapy.
    E) WITH POISONING/EXPOSURE
    1) Drowsiness, lethargy, hypotension, bradycardia, hypotonia, respiratory depression, and hypothermia have been reported after intraocular use in infants and ingestion in toddlers.
    2) Since ocular dosing is not weight-adjusted, children may experience systemic toxic effects more frequently.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Hypothermia has been reported with brimonidine therapy.
    B) WITH POISONING/EXPOSURE
    1) Hypothermia has occurred in children following brimonidine overdose.
    0.2.20) REPRODUCTIVE
    A) The manufacturer has classified brimonidine as FDA pregnancy category B. The manufacturer has classified the combinations brimonidine/brinzolamide and brimonidine/timolol as FDA pregnancy category C. No impairment of fertility has been observed in mice and rats.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    C) Monitor pulse oximetry in patients with decreased respirations.
    D) Plasma brimonidine concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Bradycardia is typically mild and usually doesn't require any treatment.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Severe bradycardia associated with hypotension should be treated with atropine.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS or respiratory depression.
    E) ANTIDOTE
    1) There is no antidote for brimonidine. Brimonidine-induced respiratory depression, hypotension, and coma may respond to naloxone, although naloxone administration was reportedly ineffective in several case reports of children with brimonidine-induced CNS and respiratory depression. Some patients with clonidine intoxication (another alpha-2 agonist) have responded to naloxone (reversal of altered mental status, respiratory depression or apnea, and miosis) with inconsistent success.
    F) ENHANCED ELIMINATION PROCEDURE
    1) It is unknown if hemodialysis would be useful following an oral exposure.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients who are asymptomatic after an inadvertent exposure may be managed at home. All children with brimonidine ingestions should be evaluated at a healthcare facility.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, or who are symptomatic, should be sent to a health care facility for observation until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with worsening symptoms or severe systemic symptoms should be admitted to the hospital for further evaluation. Patients with mental status changes or severe respiratory distress require ICU admission. Patients should remain admitted until they are clearly improving and clinically stable.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected brimonidine overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Brimonidine is extensively metabolized, primarily in the liver. Urinary excretion is the major route of elimination of brimonidine and its metabolites; approximately 87% of an orally administered radioactive dose was eliminated within 120 hours, with 74% found in the urine. The systemic half-life of brimonidine is approximately 3 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hypotension, bradycardia, altered mental status, respiratory depression (eg, calcium channel antagonists, beta-blockers, centrally-acting alpha-2 adrenergic agonists (clonidine, tizanidine), opioids).

Range Of Toxicity

    A) TOXICITY: Minimum toxic dose has not been established. OPHTHALMIC ADMINISTRATION: Infants have developed hypotension, bradycardia, lethargy, hypothermia, and respiratory depression after receiving adult therapeutic doses of ophthalmic products ranging in concentration from 0.15% to 0.2% brimonidine. INGESTION: A 2-week-old infant developed cardiorespiratory depression, somnolence, and hyperglycemia after ingesting 1 drop of 0.2% brimonidine. A 2-year-old boy developed somnolence and bradycardia after ingesting 2 mL (220 mcg/kg body weight) 0.2% brimonidine eye drops.
    B) THERAPEUTIC DOSE: ADULTS AND CHILDREN 2 YEARS AND OLDER: Instill 1 drop in the affected eye every 8 hours.

Clinical Effects

Summary Of Exposure

    A) USES: Brimonidine ophthalmic solution is used for lowering intraocular pressure in patients with open angle glaucoma or ocular hypertension, and the topical gel is used to treat persistent facial erythema of rosacea in adults.
    B) PHARMACOLOGY: A relatively selective alpha-adrenergic receptor agonist. With ophthalmic administration, brimonidine lowers intraocular pressure in open-angle glaucoma or ocular hypertension by reducing aqueous humor production and increasing uveoscleral outflow. When applied as a topical gel to the facial area, brimonidine may decrease erythema via direct vasoconstriction.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Fatigue, drowsiness, headache, and ocular symptoms (ie, ocular hyperemia, burning, stinging, pruritus, blurring, conjunctival follicles, and foreign body sensation) are the most commonly reported adverse effects, occurring in 10% to 30% of patients following therapeutic administration.
    2) Other effects that may occur less frequently include: mild hypotension, miosis, allergic reactions, upper respiratory symptoms (3% to 9%), and dizziness (3% to 9%), and erythema and flushing following topical gel therapy.
    E) WITH POISONING/EXPOSURE
    1) Drowsiness, lethargy, hypotension, bradycardia, hypotonia, respiratory depression, and hypothermia have been reported after intraocular use in infants and ingestion in toddlers.
    2) Since ocular dosing is not weight-adjusted, children may experience systemic toxic effects more frequently.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hypothermia has been reported with brimonidine therapy.
    B) WITH POISONING/EXPOSURE
    1) Hypothermia has occurred in children following brimonidine overdose.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) CASE REPORT: Bradycardia, hypotension, apnea, and hypothermia (36.3 degrees C) developed in a 3-week-old girl after topical treatment with 0.2% brimonidine and 0.25% timolol (Mungan et al, 2003).
    2) CASE REPORT: A 24-day-old boy experienced repeated episodes of lethargy, hypotonia, hypothermia, bradycardia, irregular breathing, oxygen desaturation, and intermittent apnea, all of which were temporally related to the twice daily instillation of brimonidine eye drops after surgical repair of bilateral congenital cataracts. The episodes all occurred suddenly and then resolved after 2 to 3 hours (Prok & Hall, 2003).
    B) WITH POISONING/EXPOSURE
    1) CASE REPORT: Hypothermia (rectal temperature 95.5 degrees F) was reported in a 27-day-old infant with congenital glaucoma receiving adult dosing of brimonidine (Berlin et al, 1997). Other systemic effects included hypotension, bradycardia, and hypotonia.
    2) CASE REPORT: Hypothermia (rectal temperature 35 degrees Celsius) was reported in a 4-week-old boy with Peters anomaly after receiving brimonidine. He was also lethargic, hypotonic, and unresponsive to stimulation (Berlin et al, 2001).
    3) CASE REPORT: A 50-day-old infant became hypotonic, hypothermic (35.5 degrees C), and comatose after an inadvertent accidental oral administration of 4 drops of 0.2% brimonidine tartrate ophthalmic solution. Irregular breathing pattern with hypoventilation was also noted. Two doses of naloxone failed to reverse the toxic effects of brimonidine. Following symptomatic treatment, she was discharged 20 hours after admission without any sequelae (Sztajnbok, 2002).
    4) CASE REPORT: Hypoventilation (respiratory rate of 12), bradycardia (60 bpm), hypoxemia (arterial oxygen saturation of 85%), and hypothermia (36.3 degrees C) developed in an 8-week-old girl after topical treatment with 0.2% brimonidine, 0.5% betaxolol, and 2% dorzolamide. Although the baby did not respond to the administration of naloxone, she recovered completely after topical dipivefrin 0.1% was substituted for brimonidine and betaxolol (Mungan et al, 2003).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) MIOSIS: Ocular administration of brimonidine results in miosis and reduction of intraocular pressure in healthy young men (Nordlund et al, 1995) and in patients undergoing Argon Laser Trabeculoplasty (David et al, 1993).
    2) The manufacturer reports the following ocular symptoms in 10% to 30% of patients: ocular hyperemia, burning, stinging, pruritus, blurring, foreign body sensation, conjunctival follicles (Prod Info brimonidine tartrate 0.2% ophthalmic solution, 2014).
    3) The manufacturer reports the following ocular effects in 3% to 9% of patients: corneal staining/erosion, photophobia, eyelid erythema, ocular pain, dryness, tearing, eyelid edema, conjunctival edema, blepharitis, abnormal vision (Prod Info brimonidine tartrate 0.2% ophthalmic solution, 2014).
    4) ANTERIOR UVEITIS: Late occurring acute anterior uveitis has been reported in four elderly patients with topical use of 0.2% brimonidine tartrate for chronic glaucoma (Byles et al, 2000).
    5) PARADOXICAL EFFECTS: A paradoxical effect of brimonidine, increased intraocular pressure, was reported both after use and rechallenge with 0.2% brimonidine eye drops in a 70-year-old woman with bilateral normal tension glaucoma (Mushtaq et al, 2003).
    6) ANIMAL EFFECTS: Miosis and reduction of intraocular pressure by brimonidine are also reported for rabbits and monkeys (Burke et al, 1995).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Mild hypotension has been reported with therapeutic ocular doses (Nordlund et al, 1995).
    2) WITH POISONING/EXPOSURE
    a) According to a retrospective review of brimonidine poisonings in children (0 to 5 years of age) reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System database and to the FDA Medwatch Adverse Events Reporting System from 1997 to 2005, hypotension was reported in 4% of patients (n=170) (Becker et al, 2009).
    b) CASE REPORT: Hypotension, bradycardia, hypotonia, and hypothermia developed in a 27-day-old infant with congenital glaucoma given brimonidine (1 drop twice daily) (Berlin et al, 1997).
    c) CASE REPORT: Several episodes of lethargy, hypotension, hypotonia, hypothermia, and bradycardia (lasting 3 to 9 hours) developed in a 4-week-old infant with Peters anomaly following the use of brimonidine ophthalmic drops. After each episode, the administration of naloxone transiently reversed the toxic effects. His signs and symptoms resolved upon discontinuation of brimonidine therapy (Berlin et al, 2001).
    d) CASE REPORT: Bradycardia, hypotension (74/31 mmHg), apnea, and hypothermia developed in a 3-week-old girl after topical treatment with 0.2% brimonidine and 0.25% timolol (Mungan et al, 2003).
    e) CASE REPORT: A 6-week-old boy with congenital glaucoma developed hypotension (62/25 mmHg), somnolence, and respiratory depression after receiving his third dose of 1 drop of 0.15% brimonidine every 8 hours (Daubert, 2006).
    B) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) According to a retrospective review of brimonidine poisonings in children (0 to 5 years of age) reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System database and to the FDA Medwatch Adverse Events Reporting System from 1997 to 2005, bradycardia was reported in 4% of patients (n=170) (Becker et al, 2009).
    b) CASE REPORT: A 27-day-old infant developed bradycardia after receiving brimonidine (adult dosing) for congenital glaucoma (Berlin et al, 1997). Other effects included hypotension, hypotonia, and hypothermia.
    c) CASE REPORT: A 4-week-old boy with Peters anomaly developed bradycardia following the use of brimonidine ophthalmic drops. His symptoms resolved upon discontinuation of brimonidine therapy (Berlin et al, 2001).
    d) CASE REPORT: Bradycardia (60 bpm), hypotension, apnea, and hypothermia developed in a 3-week-old girl after topical treatment with 0.2% brimonidine and 0.25% timolol (Mungan et al, 2003).
    e) CASE REPORT: Hypoventilation (respiratory rate of 12), bradycardia (60 bpm), hypoxemia (arterial oxygen saturation of 85%), and hypothermia (36.3 degrees C) developed in an 8-week-old girl after topical treatment with 0.2% brimonidine, 0.5% betaxolol, and 2% dorzolamide. Although the baby did not respond to the administration of naloxone, she recovered completely after topical dipivefrin 0.1% was substituted for brimonidine and betaxolol (Mungan et al, 2003).
    f) CASE REPORT: A 24-day-old boy experienced repeated episodes of lethargy, hypotonia, hypothermia, bradycardia, irregular breathing, oxygen desaturation, and intermittent apnea, all of which were temporally related to the twice daily instillation of brimonidine eye drops after surgical repair of bilateral congenital cataracts. The episodes all occurred suddenly and then resolved after 2 to 3 hours (Prok & Hall, 2003).
    g) CASE REPORT: A two-week-old infant developed bradycardia, apnea, somnolence and hyperglycemia after inadvertent ingestion of 1 drop of 0.2% brimonidine instead of the prescribed 1 drop/2 days of 1-alphaLeo(R) (alfacalcidol). With supportive care, the patient recovered within 36 hours (Vanhaesebrouck et al, 2009).
    h) CASE REPORTS: Two young children of a parent participating in a clinical trial, inadvertently ingested an unknown amount of brimonidine topical gel and developed sinus bradycardia, lethargy, respiratory distress with episodes of apnea, necessitating intubation, confusion, psychomotor hyperactivity, and diaphoresis. Following overnight hospital observation, both patients recovered and were discharged the following day (Prod Info MIRVASO(R) topical gel, 2013).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOTENSION
    a) Monkeys developed hypotension (34% decrease in blood pressure) and bradycardia (42% decrease in pulse rate) after ocular instillation of 50 microliters of 3% brimonidine (Burke et al, 1995).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPOVENTILATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 50-day-old infant became hypotonic, hypothermic (35.5 degrees C), and comatose after an inadvertent accidental oral administration of 4 drops of 0.2% brimonidine tartrate ophthalmic solution. Irregular breathing pattern with hypoventilation was also noted. Two doses of naloxone failed to reverse the toxic effects of brimonidine. Following symptomatic treatment, she was discharged 20 hours after admission without any sequelae (Sztajnbok, 2002).
    b) CASE REPORT: A 6-week-old boy with congenital glaucoma developed hypotension (62/25 mmHg, oxygen saturation 87-88% on room air) after receiving his third dose of 1 drop of 0.15% brimonidine every 8 hours (Daubert, 2006).
    c) CASE REPORT: Hypoventilation (respiratory rate of 12), bradycardia (60 bpm), hypoxemia (arterial oxygen saturation of 85%), and hypothermia (36.3 degrees C) developed in an 8-week-old girl after topical treatment with 0.2% brimonidine, 0.5% betaxolol, and 2% dorzolamide. Although the baby did not respond to the administration of naloxone, she recovered completely after topical dipivefrin 0.1% was substituted for brimonidine and betaxolol (Mungan et al, 2003).
    d) CASE REPORT: A 24-day-old boy experienced repeated episodes of lethargy, hypotonia, hypothermia, bradycardia, irregular breathing, oxygen desaturation, and intermittent apnea, all of which were temporally related to the twice daily instillation of brimonidine eye drops after surgical repair of bilateral congenital cataracts. The episodes all occurred suddenly and then resolved after 2 to 3 hours (Prok & Hall, 2003).
    B) APNEA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 10-week-old infant became pale and lethargic with episodes of intermittent apnea (respiratory rate of 8/minute) approximately 20 minutes after receiving 1 drop of 0.2% brimonidine ophthalmic drops instilled into each eye. With periodic tactile stimulation, his mental status and respiratory status improved and he was discharged without sequelae 24 hours later (Rangan et al, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 6-month-old infant developed apnea after intraocular administration of adult strength ophthalmic solutions of brimonidine 0.2% and Cosopt(R) (dorzolamide hydrochloride/timolol maleate/20 mg/5 mg/mL). She was discharged several hours after admission without any sequelae (Chu et al, 2001).
    b) CASE REPORT: Bradycardia, hypotension, apnea, and hypothermia developed in a 3-week-old girl after topical treatment with 0.2% brimonidine and 0.25% timolol (Mungan et al, 2003).
    c) CASE REPORT: A two-week-old infant developed bradycardia, apnea, somnolence and hyperglycemia after inadvertent ingestion of 1 drop of 0.2% brimonidine instead of the prescribed 1 drop/2 days of 1-alphaLeo(R) (alfacalcidol). With supportive care, the patient recovered within 36 hours (Vanhaesebrouck et al, 2009).
    d) CASE REPORTS: Two young children of a parent participating in a clinical trial, inadvertently ingested an unknown amount of brimonidine topical gel and developed sinus bradycardia, lethargy, respiratory distress with episodes of apnea, necessitating intubation, confusion, psychomotor hyperactivity, and diaphoresis. Following overnight hospital observation, both patients recovered and were discharged the following day (Prod Info MIRVASO(R) topical gel, 2013).
    C) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 28-month-old boy developed respiratory and CNS depression, necessitating intubation after an unintentional ingestion of brimonidine tartrate 0.2% ophthalmic drops (2 mL; 0.26 mg/kg). Naloxone failed to reverse the toxic effects of brimonidine. Following symptomatic treatment, he was discharged 36 hours after admission without any sequelae (Ali et al, 2001).
    D) DISORDER OF RESPIRATORY SYSTEM
    1) WITH THERAPEUTIC USE
    a) Upper respiratory symptoms have been reported in approximately 3% to 9% of patients in clinical trials (Prod Info brimonidine tartrate 0.2% ophthalmic solution, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Fatigue, drowsiness and headache have been reported in 10% to 30% of patients following ocular use. Dizziness has been reported in 3% to 9% of patients in clinical trials (Prod Info brimonidine tartrate 0.2% ophthalmic solution, 2014).
    b) Somnolence was reported in four children receiving therapeutic doses of brimonidine (0.2%) eye drops (Levy & Zadok, 2004).
    c) CASE REPORT: A 10-week-old infant became pale and lethargic with episodes of intermittent apnea approximately 20 minutes after receiving 1 drop of 0.2% brimonidine ophthalmic drops instilled into each eye. With periodic tactile stimulation, his mental status and respiratory status improved and he was discharged without sequelae 24 hours later (Rangan et al, 2008).
    2) WITH POISONING/EXPOSURE
    a) According to a retrospective review of brimonidine poisonings in children (0 to 5 years of age) reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System database and to the FDA Medwatch Adverse Events Reporting System from 1997 to 2005, drowsiness appeared to be the most common toxic effect reported, occurring in 40.9% of patients (n=170) (Becker et al, 2009).
    b) CASE REPORT: A 28-month-old boy developed respiratory and CNS depression, necessitating intubation after an unintentional ingestion of brimonidine tartrate 0.2% ophthalmic drops (2 mL; 0.26 mg/kg). Naloxone failed to reverse the toxic effects of brimonidine. Following symptomatic treatment, he was discharged 36 hours after admission without any sequelae (Ali et al, 2001).
    c) CASE REPORT: A 2-year-old previously healthy boy developed lethargy and pallor within 20 minutes of ingesting 2 mL brimonidine eye drops (220 mcg/kg body weight). Other findings included bradypnea, bradydysrhythmia, and decreased muscle tone. The patient regained alertness within 5 hours and returned to baseline vital signs by 10 hours postingestion, with only close monitoring and no need for therapeutic interventions. Maximal plasma brimonidine concentrations were 40 ng/mL 5 hours after ingestion. Plasma brimonidine levels declined with an elimination half-life of 2.7 hours; urinary levels revealed most of the drug was excreted within 24 hours (Hoffmann et al, 2004).
    d) CASE REPORT: A 6-week-old boy with congenital glaucoma developed hypotension (62/25 mmHg), somnolence, and respiratory depression after receiving his third dose of 1 drop of 0.15% brimonidine every 8 hours (Daubert, 2006).
    e) CASE REPORT: A two-week-old infant developed bradycardia, apnea, somnolence and hyperglycemia after inadvertent ingestion of 1 drop of 0.2% brimonidine instead of the prescribed 1 drop/2 days of 1-alphaLeo(R) (alfacalcidol). With supportive care, the patient recovered within 36 hours (Vanhaesebrouck et al, 2009).
    f) CASE REPORTS: Two young children of a parent participating in a clinical trial, inadvertently ingested an unknown amount of brimonidine topical gel and developed sinus bradycardia, lethargy, respiratory distress with episodes of apnea, necessitating intubation, confusion, psychomotor hyperactivity, and diaphoresis. Following overnight hospital observation, both patients recovered and were discharged the following day (Prod Info MIRVASO(R) topical gel, 2013).
    B) DECREASED MUSCLE TONE
    1) WITH POISONING/EXPOSURE
    a) Hypotonia was reported in a 27-day-old infant with congenital glaucoma after receiving adult dosing of brimonidine (Berlin et al, 1997).
    b) CASE REPORT: A 2-year-old previously healthy boy developed lethargy and pallor within 20 minutes of ingesting 2 mL brimonidine eye drops (220 mcg/kg body weight). Other findings included bradypnea, bradydysrhythmia, and decreased muscle tone. The patient regained alertness within 5 hours and returned to baseline vital signs by 10 hours postingestion, with only close monitoring and no need for therapeutic interventions. Maximal plasma brimonidine concentrations were 40 ng/mL 5 hours after ingestion. Plasma brimonidine levels declined with an elimination half-life of 2.7 hours; urinary levels revealed most of the drug was excreted within 24 hours (Hoffmann et al, 2004).
    c) CASE REPORT: A 24-day-old boy experienced repeated episodes of lethargy, hypotonia, hypothermia, bradycardia, irregular breathing, oxygen desaturation, and intermittent apnea, all of which were temporally related to the twice daily instillation of brimonidine eye drops after surgical repair of bilateral congenital cataracts. The episodes all occurred suddenly and then resolved after 2 to 3 hours (Prok & Hall, 2003).
    C) COMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 4-week-old boy with Peters anomaly had several episodes (lasting 3 to 9 hours) of lethargy, hypotension, hypotonia, hypothermia, bradycardia and unresponsiveness following the use of brimonidine ophthalmic drops. After each episode, the administration of naloxone transiently reversed the toxic effects. His signs and symptoms resolved upon discontinuation of brimonidine therapy. Brimonidine concentrations were 1459 pg/mL and 700 pg/mL in plasma samples obtained at 0 to 3 hours and 6 hours, respectively (Berlin et al, 2001).
    b) Since ocular dosing is not weight-adjusted, children may experience systemic toxic effects more frequently. Excessive systemic absorption, the inability to efficiently metabolize the drug, and/or immature blood-brain barrier may cause systemic toxic effects in children (Levy & Zadok, 2004; Prok & Hall, 2003; Berlin et al, 2001).
    c) CASE REPORT: A 50-day-old infant became hypotonic, hypothermic (35.5 degrees C), and comatose after an inadvertent accidental oral administration of 4 drops of 0.2% brimonidine tartrate ophthalmic solution. Irregular breathing pattern with hypoventilation was also noted. Two doses of naloxone failed to reverse the toxic effects of brimonidine. Following symptomatic treatment, she was discharged 20 hours after admission without any sequelae (Sztajnbok, 2002).
    d) According to a retrospective review of brimonidine poisonings in children (0 to 5 years of age) reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System database and to the FDA Medwatch Adverse Events Reporting System from 1997 to 2005, coma was only reported in 2 of 170 cases (Becker et al, 2009).
    D) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) According to a retrospective review of brimonidine poisonings in children (0 to 5 years of age) reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System database and to the FDA Medwatch Adverse Events Reporting System from 1997 to 2005, ataxia was reported in 4.5% of patients (n=170) (Becker et al, 2009).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERYTHEMA
    1) WITH THERAPEUTIC USE
    a) Erythema occasionally worsened with brimonidine topical gel therapy when compared to baseline. In 29-day clinical trials of patients with persistent erythema associated with rosacea, erythema occurred in 4% of patients (n=330) with once-daily brimonidine topical therapy compared with 1% of patients treated once daily with vehicle gel (n=331). Erythema led to treatment discontinuation in some subjects, which appeared to resolve with treatment withdrawal. In similar open-label trials of up to one year, erythema occurred in 8% of subjects with once-daily brimonidine topical therapy (n=276). Erythema may diminish within hours of application and appeared to resolve following discontinuation of brimonidine treatment (Prod Info MIRVASO(R) topical gel, 2013).
    B) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Intermittent flushing developed in some subjects with brimonidine topical gel therapy. In 29-day clinical trials of patients with persistent erythema associated with rosacea, flushing occurred in 3% of patients receiving once-daily brimonidine topical therapy (n=330) compared with 0% of patients treated once daily with vehicle gel (n=331). Flushing onset ranged from about 30 minutes to several hours after brimonidine application. Flushing led to treatment discontinuation in some subjects, which appeared to resolve with treatment withdrawal. In similar open-label trials of up to 1 year, flushing occurred in 10% of subjects with once-daily brimonidine topical therapy (n=276) (Prod Info MIRVASO(R) topical gel, 2013).
    C) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Two young children of a parent participating in a clinical trial, inadvertently ingested an unknown amount of brimonidine topical gel and developed sinus bradycardia, lethargy, respiratory distress with episodes of apnea, necessitating intubation, confusion, psychomotor hyperactivity, and diaphoresis. Following overnight hospital observation, both patients recovered and were discharged the following day (Prod Info MIRVASO(R) topical gel, 2013).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A two-week-old infant developed bradycardia, apnea, somnolence and hyperglycemia (243 mg/dL) after inadvertent ingestion of 1 drop of 0.2% brimonidine instead of the prescribed 1 drop/2 days of 1-alphaLeo(R) (alfacalcidol). With supportive care, the patient recovered within 36 hours (Vanhaesebrouck et al, 2009).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Allergic reactions have been reported following therapeutic use of brimonidine eye drops (Prod Info brimonidine tartrate 0.2% ophthalmic solution, 2014).

Reproductive

    3.20.1) SUMMARY
    A) The manufacturer has classified brimonidine as FDA pregnancy category B. The manufacturer has classified the combinations brimonidine/brinzolamide and brimonidine/timolol as FDA pregnancy category C. No impairment of fertility has been observed in mice and rats.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) Developmental toxicity studies of rats administered oral brimonidine 0.66 mg/kg showed no evidence of fetal harm. At this dose, plasma drug concentrations were approximately 100 times higher in rats than levels seen in humans at the recommended dose level (Prod Info brimonidine tartrate 0.2% ophthalmic solution, 2014; Prod Info SIMBRINZA(TM) ophthalmic suspension, 2013).
    b) In animal studies, there was no evidence of teratogenicity with oral administration of brimonidine tartrate up to 2.5 mg/kg/day to rats during gestation days 6 through 15 and up to 5 mg/kg/day to rabbits during gestation days 6 through 18. (Prod Info MIRVASO(R) topical gel, 2013)In rats, brimonidine tartrate 2.5 mg/kg/day produced AUC exposure values 580-fold higher than similar values estimated in humans treated with 1 drop of brimonidine 0.1% or 0.15% in both eyes 2 times daily. In rabbits, brimonidine tartrate 5 mg/kg/day produced AUC exposure values 37-fold higher than similar values estimated in humans treated with 1 drop of brimonidine 0.1% or 0.15% in both eyes 2 times daily (Prod Info Combigan(R) ophthalmic solution, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) BRIMONIDINE
    a) The manufacturer has classified brimonidine as FDA pregnancy category B (Prod Info brimonidine tartrate 0.2% ophthalmic solution, 2014; Prod Info MIRVASO(R) topical gel, 2013).
    2) BRIMONIDINE AND BRINZOLAMIDE COMBINATION
    a) The manufacturer has classified brimonidine and brinzolamide combination as FDA pregnancy category C (Prod Info SIMBRINZA(TM) ophthalmic suspension, 2013).
    3) BRIMONIDINE AND TIMOLOL COMBINATION
    a) The manufacturer has classified brimonidine and timolol combination as FDA pregnancy category C (Prod Info Combigan(R) ophthalmic solution, 2013).
    B) ANIMAL STUDIES
    1) Brimonidine crossed the placenta and entered into fetal circulation (Prod Info SIMBRINZA(TM) ophthalmic suspension, 2013; Prod Info MIRVASO(R) topical gel, 2013; Prod Info brimonidine tartrate 0.2% ophthalmic solution, 2014; Prod Info Combigan(R) ophthalmic solution, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether brimonidine is excreted in human milk; however, excretion into breast milk has been demonstrated in animals. Because the potential for serious adverse reactions in nursing infants exists, it is recommended to either discontinue nursing or brimonidine, considering the importance of the drug to the mother (Prod Info brimonidine tartrate 0.2% ophthalmic solution, 2014; Prod Info Combigan(R) ophthalmic solution, 2013; Prod Info SIMBRINZA(TM) ophthalmic suspension, 2013; Prod Info MIRVASO(R) topical gel, 2013).
    B) ANIMAL STUDIES
    1) Excretion into breast milk has been demonstrated in animals (Prod Info MIRVASO(R) topical gel, 2013; Prod Info brimonidine tartrate 0.2% ophthalmic solution, 2014; Prod Info Combigan(R) ophthalmic solution, 2013; Prod Info SIMBRINZA(TM) ophthalmic suspension, 2013).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) No impairment of fertility was observed in rats given brimonidine at oral doses up to 1 mg/kg/day (Prod Info MIRVASO(R) topical gel, 2013; Prod Info brimonidine tartrate 0.2% ophthalmic solution, 2014) or at does up to approximately 100 times the systemic exposure following the maximum recommended human ophthalmic dose (Prod Info Combigan(R) ophthalmic solution, 2013).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) No carcinogenic effects were observed in a 21-month study in mice and a 24-month study in rats given oral doses of 2.5 mg/kg/day (Prod Info MIRVASO(R) topical gel, 2013) (approximately 150- and 120-fold the plasma Cmax from the recommended human doses of ophthalmic drops 0.1% and 0.15%, respectively, 3 times/day) and 1 mg/kg/day, respectively (approximately 90- and 80-fold the plasma Cmax from the recommended human doses of ophthalmic drops 0.1% and 0.15%, respectively, 3 times/day) (Prod Info ALPHAGAN(R) P ophthalmic solution, 2010a).
    2) No drug-related neoplasms were noted in a 24-month dermal carcinogenicity study in rats administered brimonidine tartrate topical gel at doses of 0.9 mg/kg/day (0.03% gel), 1.8 mg/kg/day (0.06% gel), and 5.4 mg/kg/day (0.18% gel) in males and 5.4 mg/kg/day, 30 mg/kg/day (1% gel) during Days 1 to 343 and 10.8 mg/kg/day (0.36% gel) thereafter, and 60 mg/kg/day (2% gel) during Days 1 to 343 with 21.6 mg/kg/day (0.72% gel) thereafter in females. Treatment with brimonidine tartrate is not expected to enhance photo-carcinogenesis, as no drug-related adverse effects were observed in a 12-month dermal photo-carcinogenicity study in hairless albino mice administered topical doses of 0% (gel vehicle), 0.18%, 1%, and 2% brimonidine tartrate gel once daily for 5 days/week with concurrent exposure to simulated sunlight (Prod Info MIRVASO(R) topical gel, 2013).

Genotoxicity

    A) There were no evidence of mutagenicity or clastogenicity from the following tests with brimonidine tartrate: the Ames bacterial reversion test, a chromosomal aberration assay in Chinese hamster ovary cells, and 3 in vivo studies in CD1 mice (a host-mediated assay, a cytogenetic study, and a dominant lethal assay) (Prod Info MIRVASO(R) topical gel, 2013; Prod Info ALPHAGAN(R) P ophthalmic solution, 2010a)

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    C) Monitor pulse oximetry in patients with decreased respirations.
    D) Plasma brimonidine concentrations are not readily available or clinically useful in the management of overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with worsening symptoms or severe systemic symptoms should be admitted to the hospital for further evaluation. Patients with mental status changes or severe respiratory distress require ICU admission. Patients should remain admitted until they are clearly improving and clinically stable.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients who are asymptomatic after an inadvertent exposure may be managed at home.
    B) Since young children have reportedly developed severe systemic symptoms (hypotension, bradycardia, CNS and/or respiratory depression) following brimonidine ingestions (Vanhaesebrouck et al, 2009; Ali et al, 2001), all children ingesting brimonidine should be evaluated in a medical facility.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, or who are symptomatic, should be sent to a healthcare facility for observation until they are clearly improving and clinically stable.

Monitoring

    A) Monitor vital signs and mental status.
    B) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    C) Monitor pulse oximetry in patients with decreased respirations.
    D) Plasma brimonidine concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Bradycardia is typically mild and usually doesn't require any treatment.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Severe bradycardia associated with hypotension should be treated with atropine.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    3) Monitor pulse oximetry in patients with decreased respirations.
    4) Plasma brimonidine concentrations are not readily available or clinically useful in the management of overdose.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) BRADYCARDIA
    1) Bradycardia following brimonidine overdose may not be symptomatic and may not require treatment. Treat bradycardia associated with symptoms or hypotension with atropine.
    2) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    E) NALOXONE
    1) Anecdotal reports suggest that naloxone may reverse bradycardia and CNS depression in clonidine (another alpha-2-adrenergic agonist) overdose (Cook, 1987). Brimonidine induced respiratory depression, hypotension, and coma may respond to naloxone. However, in several case reports of children, naloxone failed to reverse brimonidine-induced respiratory and CNS depression, and coma (Mungan et al, 2003; Sztajnbok, 2002; Ali et al, 2001).
    2) DOSING: 0.4 to 2 mg intravenous bolus in both children and adults. This dose can also be given intralingually (via injection to mid-ventral surface of the tongue) in the absence of intravenous access (Maio et al, 1987) or intratracheally.
    3) CASE REPORT/INFANT: A 27-day-old infant was given adult dosing of brimonidine drops for congenital glaucoma. The patient developed alpha-2-adrenergic agonist effects (hypotension, bradycardia, hypotonia, and hypothermia). Naloxone 0.5 mg was given intravenously, with immediate but transient reversal of effects. No further episodes were reported following drug cessation (Berlin et al, 1997).

Enhanced Elimination

    A) EXTRACORPOREAL ELIMINATION
    1) It is unknown if hemodialysis would be useful following an oral exposure.

Range Of Toxicity

Summary

    A) TOXICITY: Minimum toxic dose has not been established. OPHTHALMIC ADMINISTRATION: Infants have developed hypotension, bradycardia, lethargy, hypothermia, and respiratory depression after receiving adult therapeutic doses of ophthalmic products ranging in concentration from 0.15% to 0.2% brimonidine. INGESTION: A 2-week-old infant developed cardiorespiratory depression, somnolence, and hyperglycemia after ingesting 1 drop of 0.2% brimonidine. A 2-year-old boy developed somnolence and bradycardia after ingesting 2 mL (220 mcg/kg body weight) 0.2% brimonidine eye drops.
    B) THERAPEUTIC DOSE: ADULTS AND CHILDREN 2 YEARS AND OLDER: Instill 1 drop in the affected eye every 8 hours.

Therapeutic Dose

    7.2.1) ADULT
    A) BRIMONIDINE
    1) OPHTHALMIC SOLUTION: The recommended therapeutic dose is one drop of a 0.1% or 0.15% solution in each eye 3 times daily, approximately 8 hours apart (Prod Info ALPHAGAN(R) P ophthalmic solution, 2010a).
    2) TOPICAL GEL: The recommended dose is 1 pea-sized amount applied to each of the 5 areas of the face (central forehead, chin, nose, and each cheek) once daily; smooth evenly over entire face avoiding lips and eyes (Prod Info MIRVASO(R) topical gel, 2013).
    B) BRIMONIDINE/BRINZOLAMIDE
    1) The recommended dose is one drop 3 times daily in the affected eye(s) (Prod Info SIMBRINZA(TM) ophthalmic suspension, 2013).
    7.2.2) PEDIATRIC
    A) BRIMONIDINE
    1) LESS THAN 2 YEARS OF AGE: Use of ophthalmic solution is contraindicated (Prod Info ALPHAGAN(R) P ophthalmic solution, 2010a).
    2) The safety and effectiveness of brimonidine tartrate topical gel in children has not been established (Prod Info MIRVASO(R) topical gel, 2013).
    B) BRIMONIDINE/BRINZOLAMIDE
    1) LESS THAN 2 YEARS OF AGE: Use is contraindicated (Prod Info SIMBRINZA(TM) ophthalmic suspension, 2013).

Maximum Tolerated Exposure

    A) CHILDREN
    1) INGESTION
    a) CASE REPORT: A 50-day-old infant became hypotonic, hypothermic (35.5 degrees C), and comatose after an inadvertent accidental oral administration of 4 drops of 0.2% brimonidine tartrate ophthalmic solution. Irregular breathing pattern with hypoventilation was also noted. Two doses of naloxone failed to reverse the toxic effects of brimonidine. Following symptomatic treatment, she was discharged 20 hours after admission without any sequelae (Sztajnbok, 2002).
    b) CASE REPORT: A 28-month-old boy developed respiratory and CNS depression, necessitating intubation after an unintentional ingestion of brimonidine tartrate 0.2% ophthalmic drops (2 mL; 0.26 mg/kg). Naloxone failed to reverse the toxic effects of brimonidine. Following symptomatic treatment, he was discharged 36 hours after admission without any sequelae (Ali et al, 2001).
    c) CASE REPORT: A 2-year-old previously healthy boy developed lethargy and pallor within 20 minutes of ingesting 2 mL brimonidine eye drops (220 mcg/kg body weight). Other findings included bradypnea, bradydysrhythmia, and decreased muscle tone. The patient regained alertness within 5 hours and returned to baseline vital signs by 10 hours postingestion, with only close monitoring and no need for therapeutic interventions. Maximal plasma brimonidine concentrations were 40 ng/mL 5 hours after ingestion (Hoffmann et al, 2004).
    d) CASE REPORT: A two-week-old infant developed bradycardia, apnea, somnolence and hyperglycemia after inadvertent ingestion of 1 drop of 0.2% brimonidine instead of the prescribed 1 drop/2 days of 1-alphaLeo(R) (alfacalcidol). With supportive care, the patient recovered within 36 hours (Vanhaesebrouck et al, 2009).
    2) OPHTHALMIC ADMINISTRATION
    a) CASE REPORT: A 24-day-old boy experienced repeated episodes of lethargy, hypotonia, hypothermia, bradycardia, irregular breathing, oxygen desaturation, and intermittent apnea, all of which were temporally related to the twice daily instillation of brimonidine eye drops after surgical repair of bilateral congenital cataracts. The episodes all occurred suddenly and then resolved after 2 to 3 hours (Prok & Hall, 2003).
    b) CASE REPORT: A 6-week-old boy with congenital glaucoma developed hypotension, respiratory depression, and somnolence after receiving the third dose of brimonidine 0.15% one drop every 8 hours (Daubert, 2006).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) GENERAL
    a) In adult studies, plasma brimonidine concentrations revealed a maximum concentration of 60 pg/mL (Berlin et al, 2001).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CHILDREN
    a) CASE REPORT - A 27-day-old infant with congenital glaucoma was receiving adult dosing (1 drop twice daily) of brimonidine and developed hypotension, hypotonia, bradycardia, and hypothermia. Plasma concentration was measured by gas chromatography/mass spectrometry and was 12 and 24 times higher than the maximum concentrations found in adults (Berlin et al, 1997).
    b) CASE REPORT - A 4-week-old boy with Peters anomaly had several episodes (lasting 3 to 9 hours) of lethargy, hypotension, hypotonia, hypothermia, bradycardia and unresponsiveness following the use of brimonidine ophthalmic drops. After each episode, the administration of naloxone transiently reversed the toxic effects. His signs and symptoms resolved upon discontinuation of brimonidine therapy. Plasma brimonidine concentrations were 1459 pg/mL and 700 pg/mL, obtained at 0 to 3 hours and 6 hours, respectively (Berlin et al, 2001).
    c) CASE REPORT - A 2-year-old previously healthy boy developed lethargy and pallor within 20 minutes of ingesting 2 mL brimonidine eye drops (220 mcg/kg body weight). Other findings included bradypnea, bradydysrhythmia, and decreased muscle tone. The patient regained alertness within 5 hours and returned to baseline vital signs by 10 hours postingestion, with only close monitoring and no need for therapeutic interventions. Maximal plasma brimonidine concentrations were 40 ng/mL 5 hours after ingestion. Plasma brimonidine levels declined with an elimination half-life of 2.7 hours; urinary levels revealed most of the drug was excreted within 24 hours (Hoffmann et al, 2004).

References

General Bibliography

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    30) Product Information: ALPHAGAN(R) P ophthalmic solution, brimonidine tartrate 0.1%, 0.15% ophthalmic solution. Allergan, Inc., Irvine, CA, 2010.
    31) Product Information: Alphagan(R), brimonidine tartrate, ophthalmic solution. Allergan, Inc, Irvine, CA, 2000.
    32) Product Information: Combigan(R) ophthalmic solution, brimonidine tartrate 0.2% timolol maleate 0.5% ophthalmic solution. Allergan, Inc. (per DailyMed), Irvine, CA, 2013.
    33) Product Information: MIRVASO(R) topical gel, brimonidine topical gel. GALDERMA LABORATORIES, L.P. (per FDA), Ft Worth, TX, 2013.
    34) Product Information: SIMBRINZA(TM) ophthalmic suspension, brinzolamide 1% brimonidine tartrate 0.2% ophthalmic suspension. Alcon Laboratories, Inc. (per FDA), Fort Worth, TX, 2013.
    35) Product Information: brimonidine tartrate 0.2% ophthalmic solution, brimonidine tartrate 0.2% ophthalmic solution. Osmotica Pharmaceutical Corp. (per DailyMed), Wilmington, NC, 2014.
    36) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    37) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
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