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GUANFACINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Guanfacine, a selective alpha-2-adrenergic receptor agonist, is used in the management of hypertension and the extended-release formulation is used for the treatment of ADHD.

Specific Substances

    1) Guanfacine hydrochloride
    2) BS-100-141
    3) LON-798
    4) CAS 29110-47-2
    1.2.1) MOLECULAR FORMULA
    1) C9H9Cl2 N3O.HCl (Prod Info INTUNIV(TM) extended-release oral tablets, 2009)

Available Forms Sources

    A) FORMS
    1) GUANFACINE HYDROCHLORIDE: TABLETS: Available as 1 and 2 mg strength tablets (Prod Info guanfacine HCl oral tablets, 2015).
    2) GUANFACINE: EXTENDED-RELEASE: Available as 1 mg, 2 mg , 3 mg, and 4 mg strength extended-release tablets (Prod Info INTUNIV(R) oral extended-release tablets, 2015).
    B) USES
    1) Guanfacine (immediate-release) is used in the management of hypertension either as a monotherapy or in combination with other antihypertensives, especially thiazide-type diuretics (Prod Info guanfacine HCl oral tablets, 2015). The extended-release formulation is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children as a monotherapy and as adjunctive therapy to stimulant medications (Prod Info INTUNIV(R) oral extended-release tablets, 2015).

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: Guanfacine (immediate-release) is used in the management of hypertension either as a monotherapy or in combination with other antihypertensives, especially thiazide-type diuretics. The extended-release formulation is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as a monotherapy and as adjunctive therapy to stimulant medications in children and adolescents.
    B) PHARMACOLOGY: Guanfacine is a selective alpha 2 adrenoceptor agonist. By stimulating alpha 2A-adrendergic receptors, it can reduce sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. Guanfacine is structurally related to clonidine.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Orthostatic hypotension, bradycardia, and somnolence are the primary adverse effects reported with therapeutic use. Constipation, indigestion, nausea, dizziness, headache, and fatigue have also been commonly reported. Dose related events reported commonly in children include somnolence, abdominal pain, hypotension, dry mouth and constipation.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Drowsiness, lethargy, bradycardia, QTc prolongation, hypotension and transient hypertension have been reported with overdose of guanfacine.
    2) SEVERE TOXICITY: CNS depression and cardiac events should be anticipated. Hypotension may be delayed and prolonged.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) A decrease in heart rate and blood pressure may be noted.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Delayed and prolonged hypotension may occur. Bradycardia and paradoxical hypertension has also occurred.
    0.2.6) RESPIRATORY
    A) ANIMAL STUDIES: Dyspnea preceded death in animal studies.
    0.2.7) NEUROLOGIC
    A) Drowsiness and lethargy have been reported in children following guanfacine exposure.
    0.2.20) REPRODUCTIVE
    A) Guanfacine is classified as FDA pregnancy category B. In animal studies, maternal death, reduced weight gain, abortion, and postimplantation loss were observed at higher dosages.

Laboratory Monitoring

    A) Monitor vital signs frequently. Evaluate for CNS or respiratory depression. Institute continuous cardiac monitoring and obtain an ECG.
    B) Routine laboratory studies are not needed unless otherwise indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive; bradycardia and hypotension can develop. Monitor vital signs and neurologic function frequently (ie somnolence, lethargy are common (especially in children)). Atropine is first-line therapy for symptomatic bradycardia. Patients may initially present with transient hypertension which generally does not require treatment. For hypotension, administer IV fluids, dopamine, norepinephrine as needed. NALOXONE: May be useful in treating hypotension, CNS depression, and apnea. DOSE: Adult or Pediatric: Initial: 0.4 to 2 mg IV; repeat as needed. SEVERE TOXICITY: CNS depression and cardiac events should be anticipated. Hypotension may be delayed and prolonged. Frequently monitor vital signs and cardiac monitoring. Assess airway and respiratory function; airway support may be necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) CNS depression and cardiac events should be anticipated. Hypotension may be delayed and prolonged. Frequently monitor vital signs and cardiac monitoring. Assess airway and respiratory function; airway support may be necessary.
    C) AIRWAY MANAGEMENT
    1) Airway management may be necessary following exposure. Assess airway and respiratory function. Administer oxygen. Endotracheal intubation and mechanical ventilation may be necessary due to significant CNS depression or cardiac toxicity.
    D) ANTIDOTE
    1) None.
    E) DECONTAMINATION
    1) PREHOSPITAL: GI decontamination is generally not warranted because of the risk of CNS depression.
    2) HOSPITAL: Administer activated charcoal after a potentially, recent toxic ingestion if the patient is alert and able to maintain airway or if airway is protected.
    F) HYPOTENSION
    1) IV 0.9% NaCl at 10 mL to 20 mL/kg, dopamine, norepinephrine. Isoproterenol has been used with guanfacine overdose.
    G) BRADYCARDIA
    1) ATROPINE: ADULT: BOLUS: 0.5 mg IV may repeat every 3 to 5 min. Maximum: 3 mg. PEDIATRIC: 0.02 mg/kg IV/IO (0.04 to 0.06 mg/kg ET). Repeat once, if needed. Minimum dose: 0.1 mg. Maximum single dose: Child: 0.5 mg; Adolescent: 1 mg. Maximum total dose: Child: 1 mg; Adolescent: 2 mg.
    H) HYPERTENSION
    1) Paradoxical hypertension is likely to be transient and generally should not be treated. Nitroprusside is rapidly reversible and maybe used to treat LIFE-THREATENING hypertension. Administer 0.5 to 10 mcg/kg/min IV; adjust rate based upon patient response.
    I) ENHANCED ELIMINATION
    1) Guanfacine is not dialyzable. It has a plasma protein binding of 70% (immediate or extended release) and a high volume of distribution (mean 6.3 L/kg).
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: Home management in a young child is not indicated, since respiratory and CNS depression can occur following a single 1 mg dose. All children with a history of ingestion should be evaluated in a medical facility.
    2) OBSERVATION CRITERIA: All pediatric ingestions, adolescents/adults who are symptomatic after inadvertent ingestions, and patients with a deliberate self-harm ingestion should be sent to a healthcare facility for evaluation and treatment. If patients develop lethargy, they should be observed for the development of more serious events (ie, coma, bradycardia and hypotension) for up to 24 hours due to a potential delayed onset of hypotension.
    a) IMMEDIATE RELEASE: Monitor for at least 6 hours (time to peak plasma concentration is 1 to 4 hours; average 2.6 hours after a single oral dose).
    b) EXTENDED RELEASE: Monitor for at least 8 to 14 hours (time to peak plasma concentration is 6 hours (range: 4 to 8 hours) and admit if signs or symptoms of toxicity develop. Patients may be discharged to home once all symptoms have resolved and laboratory studies are within normal limits.
    3) ADMISSION CRITERIA: All patients with lethargy, altered mental status, bradycardia, hypo- or hypertension require observation (frequent monitoring of vital signs and ECG) for a minimum of 24 hours due to the long half-life of guanfacine (either formulation).
    4) CONSULT CRITERIA: Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    K) PHARMACOKINETICS
    1) SUMMARY: Guanfacine is rapidly and almost completely absorbed from the gastrointestinal tract. 70% bound to plasma proteins; degree of protein binding is independent of the drug concentration. IMMEDIATE RELEASE: Peak plasma concentration occur from 1 to 4 hours after a single oral dose; average time 2.6 hours. Volume of distribution is high (mean, 6.3 L/kg). Elimination half-life is approximately 17 hours; range 10 to 30 hours. EXTENDED RELEASE: Time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD and 6 hours for adults (range 4 to 8 hours). Elimination half-life is 18 hours (+/- 4 hours) for a 1 mg once daily dose. IMMEDIATE RELEASE vs. EXTENDED RELEASE: The 2 formulations of guanfacine have different pharmacokinetics; therefore a dose substitution on a mg for mg basis is not the same and will result in differences in exposure.
    L) DIFFERENTIAL DIAGNOSIS
    1) Other drugs that have alpha2-adrenoreceptor agonist properties.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. An adult ingested 60 mg of guanfacine and developed severe drowsiness and bradycardia (45 bpm). A teenager ingested 25 mg and initially developed hypertension, followed by orthostatic hypotension that developed about 30 hours after exposure. She recovered with supportive care. A toddler developed lethargy, bradycardia and hypotension after ingesting 4 mg (0.33 mg/kg).
    B) THERAPEUTIC DOSE: ANTIHYPERTENSIVE: IMMEDIATE RELEASE: ADULT: Initial dose: 1 mg recommended at bedtime; range: 1 to 3 mg daily. PEDIATRIC: ATTENTION DEFICIT HYPERACTIVITY DISORDER: EXTENDED RELEASE: Children 6 years of age and older: Initial dose: 1 mg once daily; maintenance: 1 to 4 mg once daily as a monotherapy or as an adjunctive therapy in combination with a psychostimulant.

Clinical Effects

Summary Of Exposure

    A) USES: Guanfacine (immediate-release) is used in the management of hypertension either as a monotherapy or in combination with other antihypertensives, especially thiazide-type diuretics. The extended-release formulation is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as a monotherapy and as adjunctive therapy to stimulant medications in children and adolescents.
    B) PHARMACOLOGY: Guanfacine is a selective alpha 2 adrenoceptor agonist. By stimulating alpha 2A-adrendergic receptors, it can reduce sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. Guanfacine is structurally related to clonidine.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Orthostatic hypotension, bradycardia, and somnolence are the primary adverse effects reported with therapeutic use. Constipation, indigestion, nausea, dizziness, headache, and fatigue have also been commonly reported. Dose related events reported commonly in children include somnolence, abdominal pain, hypotension, dry mouth and constipation.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Drowsiness, lethargy, bradycardia, QTc prolongation, hypotension and transient hypertension have been reported with overdose of guanfacine.
    2) SEVERE TOXICITY: CNS depression and cardiac events should be anticipated. Hypotension may be delayed and prolonged.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) A decrease in heart rate and blood pressure may be noted.
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) A peak decrease in blood pressure is seen 4 to 8 hours post administration (Jerie, 1986).
    B) WITH POISONING/EXPOSURE
    1) Hypotension has been reported following overdose (Minns et al, 2010; Prod Info TENEX(R) oral tablets, 2006).
    a) CASE REPORT/PEDIATRIC: A 2-year-old boy (12 kg) became lethargic after ingesting 4 mg (0.33 mg/kg) of guanfacine. Gastric lavage and activated charcoal were administered within 2 hours of ingestion. Some tablet fragments were recovered. The boy was admitted to the ICU for 24 hours of observation. Sixteen hours postingestion, the boy became hypotensive with a systolic blood pressure of 58 mm Hg and a heart rate of 70. No intervention was required (Prod Info TENEX(R) oral tablets, 2006; VanDyke et al, 1990).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Decrease in heart rate is seen in most patients within 2 hours after administration (Prod Info TENEX(R) oral tablets, 2006).
    B) WITH POISONING/EXPOSURE
    1) Bradycardia has been reported with overdose (Prod Info INTUNIV(R) oral extended-release tablets, 2011; Prod Info TENEX(R) oral tablets, 2006).
    a) CASE REPORT: A 25-year-old woman presented with severe drowsiness and bradycardia (45 beats/minute) after ingesting 60 mg of guanfacine. She recovered with supportive care (Prod Info TENEX(R) oral tablets, 2006).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Delayed and prolonged hypotension may occur. Bradycardia and paradoxical hypertension has also occurred.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension occurs commonly with overdose and may be severe and prolonged; patients may initially develop hypertension followed by hypotension (Minns et al, 2010; Prod Info INTUNIV(R) oral extended-release tablets, 2011; Prod Info TENEX(R) oral tablets, 2006). The peak decrease occurs 4 to 8 hours after administration and can persist for 24 to 36 hours.
    b) CASE SERIES: In one study, guanfacine exposures (reported to the Toxic Exposure Surveillance System from 1993 to 1999) in children less than 19 years of age (n=478, less than 6 years old; n=304, 6 to 12 years old; n=88, 13 to 18 years old; 674 acute, 182 acute on chronic and 14 chronic cases) were evaluated. Overall, only 324 patients were symptomatic (doses were not reported; 195 minor effect, 232 moderate effects, 8 major effects). In these patients, the most common symptoms were drowsiness/lethargy (76.8%), hypotension (25.8%) and bradycardia (30%) (McGrath & Klein-Schwartz, 2001).
    c) CASE REPORT: An 18-year-old man, with history of acute lymphoblastic leukemia, hydromorphone dependency, intermittent cocaine abuse and depression, developed bradycardia and prolonged hypotension after taking 6 1 mg guanfacine tablets. Treatment with dopamine (5 mcg/kg/min titrated up to 20 mcg/kg/min) was required for 7 days before successful weaning. Guanfacine levels were 0.934 ng/mL, 0.142 ng/mL, and undetectable at 2, 5, and 8 days postingestion, respectively. The authors speculated that this patient had prolonged hypotension despite low guanfacine levels, possibly due to the synergy of guanfacine with prescribed medications (paroxetine, methadone, clonazepam, trimethoprim/sulfamethoxazole, fluconazole, and gabapentin; a course of cytarabine, etoposide, vincristine, and methotrexate one week prior to admission) (Muller et al, 2002).
    d) CASE REPORT/PEDIATRIC: A 2-year-old boy became lethargic after ingesting 4 mg (0.33 mg/kg) of guanfacine. Gastric lavage and activated charcoal were administered within 2 hours of ingestion. Some tablet fragments were recovered. The boy was admitted to the ICU for 24 hours of observation. Sixteen hours postingestion, the boy became hypotensive with a systolic blood pressure of 58 mm Hg and a heart rate of 70. No intervention was required (Prod Info TENEX(R) oral tablets, 2006; VanDyke et al, 1990).
    B) ORTHOSTATIC HYPOTENSION
    1) WITH THERAPEUTIC USE
    a) Syncope was reported in 1% of children and adolescents (age range, 6 to 17 years) administered guanfacine extended-release (ER) oral tablets during clinical trials for ADHD. The majority of cases occurred in open-label, long-term studies (n=446) with mean exposure of approximately 10 months (Prod Info INTUNIV(R) oral extended-release tablets, 2011a).
    b) A syncopal episode occurred in 4 children who were treated with guanfacine for Tourette's syndrome and attention-deficit hyperactivity disorder. The children, aged 9 to 14 years, had been titrated up to a single bedtime dose of guanfacine 1.5 to 2 milligrams. Two of the children were receiving guanfacine alone, while one child was also receiving risperidone and the other child was also taking paroxetine. Each child experienced only 1 syncopal episode and an ECG, obtained within 48 hours after the episode, was normal in each case. No other cause of syncope were identified. Subsequently, guanfacine was tapered off and discontinued and there was no recurrence of syncope (King et al, 2006).
    c) Orthostatic hypotension, reported during treatment with guanfacine for hypertension, occurred in 15% of patients after one year of therapy. A peak decrease in blood pressure is seen 4 to 8 hours after administration (Jerie, 1986a; Jerie & Lasance, 1984; Jerie, 1980a).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 16-year-old girl with a history of Tourette's syndrome intentionally ingested 25 mg of guanfacine immediate-release to help control her tics. Eight hours after exposure she informed her family and was taken to the hospital with an elevated blood pressure (BP 123-144/81-110 mmHg) and was observed for several hours. She was given a dose of activated charcoal and remained normotensive and was discharged 2 hours later. Approximately 30 hours after exposure she developed near syncopal episodes and became hypotensive (BP 97/57 mmHg at home) and was readmitted with orthostatic hypotension (lying BP 104 /50 mmHg; standing BP 67/30 mmHg). She remained alert and oriented. An ECG showed normal sinus rhythm with a QTc interval of 593 ms. A toxicology screen was negative. She was treated with intravenous saline only. Approximately 60 hours after exposure her vital signs were normal and the ECG showed a QTc interval of 511 ms. She was discharged to home with no further symptoms (Minns et al, 2010).
    C) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Bradycardia occurs commonly with overdosage (Prod Info INTUNIV(R) oral extended-release tablets, 2011; Prod Info TENEX(R) oral tablets, 2006).
    b) In one study, guanfacine exposures (reported to the Toxic Exposure Surveillance System from 1993 to 1999) in children less than 19 years of age (n=478, <6 years old; n=304, 6 to 12 years old; n=88, 13 to 18 years old; 674 acute, 182 acute on chronic and 14 chronic cases) were evaluated. Overall, only 324 patients were symptomatic (doses were not reported; 195 minor effect, 232 moderate effects, 8 major effects). In these patients, the most common symptoms were drowsiness/lethargy (76.8%), hypotension (25.8%) and bradycardia (30%) (McGrath & Klein-Schwartz, 2001).
    c) CASE REPORT: An 18-year-old man, with history of acute lymphoblastic leukemia, hydromorphone dependency, intermittent cocaine abuse and depression, developed bradycardia (HR 63) and prolonged hypotension after taking 6 1 mg guanfacine tablets. Treatment with dopamine (5 mcg/kg/min titrated up to 20 mcg/kg/min) was required for 7 days before successful weaning. Guanfacine levels were 0.934 ng/mL, 0.142 ng/mL, and undetectable at 2, 5, and 8 days postingestion, respectively. The authors speculated that this patient had prolonged hypotension despite low guanfacine levels, possibly due to the synergy of guanfacine with prescribed medications (paroxetine, methadone, clonazepam, trimethoprim/sulfamethoxazole, fluconazole, and gabapentin; a course of cytarabine, etoposide, vincristine, and methotrexate one week prior to admission) (Muller et al, 2002).
    D) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) PARADOXICAL hypertension may also occur due to direct stimulation of peripheral alpha-adrenoceptors; this is usually followed by hypotension (Prod Info INTUNIV(R) oral extended-release tablets, 2011).
    b) CASE REPORT: A 16-year-old girl with a history of Tourette's syndrome intentionally ingested 25 mg of guanfacine immediate-release to help control her tics and initially developed an elevated blood pressure (BP 123-144/81-110 mmHg) that was followed about 30 hours later by orthostatic hypotension. She was treated with intravenous saline only and decontaminated with activated charcoal. A toxicology screen was negative. Approximately 60 hours after exposure her vital signs were normal and she was discharged to home with no further symptoms (Minns et al, 2010).
    E) PROLONGED QT INTERVAL
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 16-year-old girl with a history of Tourette's syndrome intentionally ingested 25 mg of guanfacine immediate-release to help control her tics. Eight hours after exposure she informed her family and was taken to the hospital with an elevated blood pressure (BP 123-144/81-110 mmHg) and was observed for several hours. She was given a dose of activated charcoal and remained normotensive and was discharged 2 hours later. Approximately 30 hours after exposure she developed near syncopal episodes and became hypotensive (BP 97/57 mmHg at home) and was readmitted with orthostatic hypotension (lying BP 104 /50 mmHg; standing BP 67/30 mmHg). She remained alert and oriented. An ECG showed normal sinus rhythm with a QTc interval of 593 ms. A toxicology screen was negative. She was treated with intravenous saline only. Approximately 60 hours after exposure her vital signs were normal and the ECG showed a QTc interval of 511 ms. She was discharged to home with no further symptoms (Minns et al, 2010).

Respiratory

    3.6.1) SUMMARY
    A) ANIMAL STUDIES: Dyspnea preceded death in animal studies.
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DYSPNEA
    a) In toxic doses, dyspnea preceded death in studies in mice, rats, and rabbits.

Neurologic

    3.7.1) SUMMARY
    A) Drowsiness and lethargy have been reported in children following guanfacine exposure.
    3.7.2) CLINICAL EFFECTS
    A) LETHARGY
    1) WITH THERAPEUTIC USE
    a) Somnolence, including sedation and hypersomnia has been reported in 38% of children and adolescents (age range, 6 to 17 years) receiving guanfacine extended release (ER) tablets as monotherapy for ADHD (n=513) compared with 12% of those receiving placebo (n=149) in two, short-term, randomized, double-blind, parallel-group studies. Somnolence was one of the most commonly reported adverse events in clinical studies, leading to study discontinuation in 6% of patients. Approximately 6% of patients discontinued study treatment due to somnolence and/or sedation (Prod Info INTUNIV(R) oral extended-release tablets, 2011a).
    b) Guanfacine causes dose-related sedation or drowsiness, especially when initiating therapy, or when used concomitantly with centrally active depressants (eg, phenothiazines, barbiturates, or benzodiazepines) (Prod Info guanfacine hcl oral tablets, 2007).
    c) CASE REPORT: A 4-year-old boy with ADHD and taking the standard formulation of guanfacine for 7 months was started on 2 mg extended release (ER) guanfacine and developed increased sleepiness. The medication was held for 1 day and restarted at 1 mg, and after 3 days he was noted to again be sleepy while taking the ER formulation. Thirty-eight hours after the last dose, the patient was admitted to the ED with somnolence and a Glasgow Coma Scale (GCS) 12 to 14. Bradycardia and hypotension were also noted. A toxicology screen was negative, and a head CT was normal. Naloxone (0.1 mg/kg) was given and the GCS improved to 15; however, repeated doses were needed to maintain alertness and a normal GCS. A continuous infusion of naloxone was administered for 6 hours and gradually weaned over 15 hours. The child was discharged to home the following day with no sequelae (Tsze & Dayan, 2012).
    2) WITH POISONING/EXPOSURE
    a) SUMMARY
    1) Lethargy and drowsiness have been reported after overdosage (Fontane & Shiber, 2013; Prod Info INTUNIV(R) oral extended-release tablets, 2011; Prod Info TENEX(R) oral tablets, 2006).
    b) CASE REPORTS
    1) ADULT
    a) CASE REPORT: A 25-year-old woman presented with severe drowsiness and bradycardia after ingesting 60 mg of guanfacine. She recovered with supportive care (Prod Info TENEX(R) oral tablets, 2006).
    b) CASE REPORT: Lethargy was reported in a 28-year-old woman who ingested 30 to 40 mg of guanfacine. She received activated charcoal and was discharged after a 24 hour observation period (Prod Info TENEX(R) oral tablets, 2006).
    2) PEDIATRIC
    a) CASE REPORT: A previously, healthy 2-year-old boy was brought to the ED by his mother reporting that he "keeps falling asleep" and that he might have ingested his brother's ADHD (long-acting guanfacine is approved for ADHD treatment) medication. During the previous evening, the child was watched by his older siblings for a few hours. The next morning, the child was difficult to arouse, and the family became aware that the guanfacine bottle was empty; however, the exact amount ingested remained unknown. One sibling noted that the toddler was spitting out "pink" material the evening before, but did not report it to her mother. During initial examination, the toddler was very drowsy and only opened his eyes to a sternal rub and withdrew to noxious stimuli. His pulse rate was 70 bpm, blood pressure 128/79 mm Hg (slightly elevated) with a normal pulse oximetry (99%) on room air. An ECG showed sinus bradycardia. Initial treatment included a 300 mL bolus of normal saline and 2 mg of IV naloxone with little neurologic change; a total of 10 mg naloxone was given. Gastric decontamination was not considered based on the length of time since exposure. He remained somnolent during a 3-hour stay in the ED and was admitted to the pediatric ICU for ongoing observation and monitoring. By the following day, he was awake and alert with normal vital signs (Fontane & Shiber, 2013).
    b) CASE REPORT: A 2-year-old boy (12 kg) became lethargic after ingesting 4 mg (0.33 mg/kg) of guanfacine. Gastric lavage and activated charcoal were administered within 2 hours of ingestion. Some tablet fragments were recovered. The boy was observed for 24 hours and did not require any further interventions before discharge (Prod Info TENEX(R) oral tablets, 2006; VanDyke et al, 1990).
    c) CASE SERIES: In one study, guanfacine exposures (reported to the Toxic Exposure Surveillance System from 1993 to 1999) in children less than 19 years of age (n=478, less than 6 years old; n=304, 6 to 12 years old; n=88, 13 to 18 years old; 674 acute, 182 acute on chronic and 14 chronic cases) were evaluated. Overall, only 324 patients were symptomatic (doses were not reported; 195 minor effect, 232 moderate effects, 8 major effects). In these patients, the most common symptoms were drowsiness/lethargy (76.8%), hypotension (25.8%) and bradycardia (30%) (McGrath & Klein-Schwartz, 2001).
    B) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue was reported in 14% of children and adolescents (age range, 6 to 17 years) receiving guanfacine extended release (ER) tablets as monotherapy for ADHD (n=513) compared with 3% of those receiving placebo (n=149) in two, short-term, randomized, double-blind, parallel-group studies (Prod Info INTUNIV(R) oral extended-release tablets, 2011a).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was reported in 24% of children and adolescents (age range, 6 to 17 years) receiving guanfacine extended release (ER) tablets monotherapy for ADHD (n=513) compared with 19% of those receiving placebo (n=149) in two, short-term, randomized, double-blind, placebo-controlled, parallel-group studies. Approximately 1% of patients discontinued study treatment due to headache (Prod Info INTUNIV(R) oral extended-release tablets, 2011a).
    b) Headache occurred in 13%, 7%, 5%, and 3% of patients receiving immediate-release guanfacine at daily doses of 0.5 mg (n=60), 1 mg (n=61), 2 mg (n=60), and 3 mg (n=59), respectively, compared with placebo at 8% (n=59) in a dose-response monotherapy study (Prod Info guanfacine hcl oral tablets, 2007).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness was reported in 6% of children and adolescents (age range, 6 to 17 years) receiving monotherapy with guanfacine extended release tablets (fixed dose 1, 2, 3, or 4 mg/day) for the treatment of ADHD (n=513) compared with 4% of those receiving placebo (n=149) in two short-term, randomized, double-blind, parallel-group studies. Dizziness was dose-related and attributed to study discontinuation for approximately 1% of patients. Approximately 1% of patients discontinued study treatment due to dizziness (Prod Info INTUNIV(R) oral extended-release tablets, 2011a).
    b) Dizziness occurred in 12%, 2%, 8%, and 15% of patients receiving immediate-release guanfacine at daily doses of 0.5 mg (n=60), 1 mg (n=61), 2 mg (n=60), and 3 mg (n=59), respectively, compared with 8% in patients receiving placebo (n=59) in a dose-response monotherapy study. Dizziness was one of the most common reasons cited for study discontinuation (Prod Info guanfacine hcl oral tablets, 2007).
    E) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Convulsions were reported in pediatric patients treated with guanfacine extended release (ER) tablets during short-term controlled and long-term open-label studies (Prod Info INTUNIV(R) oral extended-release tablets, 2011a).
    F) FEELING IRRITABLE
    1) WITH THERAPEUTIC USE
    a) Irritability was reported in 6% of children and adolescents (age range, 6 to 17 years) receiving guanfacine extended release (ER) tablets as monotherapy for ADHD (n=513) compared with 4% of those receiving placebo (n=149) in two, short-term, randomized, double-blind, parallel-group studies (Prod Info INTUNIV(R) oral extended-release tablets, 2011a).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) MENTAL STATUS CHANGES
    a) Altered mental status, including drowsiness, lethargy, and somnolence, has been reported.
    2) CNS EFFECTS
    a) Disturbed equilibrium, piloerection, rhythmic tremors and seizures have been demonstrated in laboratory animals.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain, including upper and lower pain was reported in 11% of children and adolescents (age range, 6 to 17 years) receiving guanfacine extended release (ER) tablets as monotherapy for ADHD (n=513) compared with 9% of those receiving placebo (n=149) in two, short-term, randomized, double-blind, parallel-group studies. Abdominal pain appeared to be dose-related (Prod Info INTUNIV(R) oral extended-release tablets, 2011).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea was reported in 6% of children and adolescents (age range, 6 to 17 years) receiving guanfacine extended release (ER) tablets as monotherapy for ADHD (n=513) compared with 2% of adolescents receiving placebo (n=149) in two, short-term, randomized, double-blind, parallel-group studies (Prod Info INTUNIV(R) oral extended-release tablets, 2011a).

Reproductive

    3.20.1) SUMMARY
    A) Guanfacine is classified as FDA pregnancy category B. In animal studies, maternal death, reduced weight gain, abortion, and postimplantation loss were observed at higher dosages.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RABBITS: No evidence of teratogenicity was observed in rabbits administered doses up to 5 mg/kg/day on days 6 through 18 of gestation (Griffith & Grauwiler, 1974a).
    2) RATS: No evidence of teratogenicity was observed in rats administered doses up to 10 mg/kg/day on days 6 through 15 of gestation (Griffith & Grauwiler, 1974a).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified guanfacine hydrochloride as FDA pregnancy category B (Prod Info guanfacine HCl oral tablets, 2015; Prod Info INTUNIV(R) oral extended release tablets, 2014).
    2) This drug should only be administered to a pregnant woman if clearly needed (Prod Info guanfacine HCl oral tablets, 2015; Prod Info INTUNIV(R) oral extended release tablets, 2014).
    3) While there is no information on the effects of guanfacine during labor and delivery, it not recommended for the treatment of acute hypertension associated with toxemia of pregnancy (Prod Info guanfacine HCl oral tablets, 2015).
    B) ANIMAL STUDIES
    1) RABBITS: Maternal death, reduced weight gain, abortion, and postimplantation loss were observed in rabbits administered 1 or 5 mg/kg/day doses. No embryotoxic effects were observed (Griffith & Grauwiler, 1974a).
    2) RATS: Guanfacine has been shown to cross the placenta in rats (Prod Info guanfacine HCl oral tablets, 2015; Prod Info INTUNIV(R) oral extended release tablets, 2014). No maternal effects were seen and the perinatal and postnatal development and health of the offspring were normal when rats were administered oral 2 and 4 mg/kg/day doses from day 15 of gestation through day 21 of lactation. Reduced maternal weight gain and fetal weight were observed at 3 and 10 mg/kg/day doses on days 6 through 15 of gestation; however, no embryo lethal effects were reported. Maternal death and reduced litter size, fetal weight, and offspring survival rates were observed at 8 mg/kg/day doses (Griffith, 1974e).
    3) RATS, RABBITS: No evidence of fetal harm has been observed in rabbits and rats administered doses up to 20 and 70 times the maximum recommended human dose (MRHD), respectively (Prod Info guanfacine HCl oral tablets, 2015; Prod Info INTUNIV(R) oral extended release tablets, 2014). Maternal toxicity and reduced fetal survival were observed in rabbits and rats at doses 13.5 times and greater than the MRHD, respectively (Prod Info guanfacine HCl oral tablets, 2015; Prod Info INTUNIV(R) oral extended release tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Exercise caution when administering guanfacine to a woman who is breastfeeding (Prod Info guanfacine HCl oral tablets, 2015; Prod Info INTUNIV(R) oral extended release tablets, 2014). If a guanfacine-treated woman continues to nurse, the infant should be observed for sedation and somnolence (Prod Info INTUNIV(R) oral extended release tablets, 2014).
    B) ANIMAL STUDIES
    1) RATS: Guanfacine has been shown to be excreted in the milk of rats (Prod Info guanfacine HCl oral tablets, 2015; Prod Info INTUNIV(R) oral extended release tablets, 2014).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) RATS: No adverse effects on fertility were observed in male or female rats administered doses up to 22 times the maximum recommended human dose, based on mg/m(2) (Prod Info guanfacine HCl oral tablets, 2015; Prod Info INTUNIV(R) oral extended release tablets, 2014).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) LACK OF EFFECT
    1) Studies in laboratory animals found no evidence of carcinogenicity at doses greater than 150 times the maximum human recommended dose (USPDI, 1991).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs frequently. Evaluate for CNS or respiratory depression. Institute continuous cardiac monitoring and obtain an ECG.
    B) Routine laboratory studies are not needed unless otherwise indicated.
    4.1.2) SERUM/BLOOD
    A) OTHER
    1) No routine lab work (CBC, electrolytes, urinalysis) is needed unless otherwise indicated.

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) All patients with lethargy, altered mental status, bradycardia, hypo- or hypertension require observation (frequent monitoring of vital signs and ECG) for a minimum of 24 hours due to the long half-life of this medication (VanDyke et al, 1990).
    1) CASE REPORT: A teenager ingested 25 mg of immediate-release guanfacine alone and initially developed hypertension about 8 hours after ingestion, followed by orthostatic hypotension and syncope and an ECG showed a prolonged QTc interval of 593 ms that developed about 30 hours after exposure. She recovered with supportive care; vasopressors were not needed (Minns et al, 2010).
    6.3.1.2) HOME CRITERIA/ORAL
    A) Home management in a young child is not indicated, since respiratory and CNS depression can occur following a single 1 mg dose. All children with a history of ingestion should be evaluated in a medical facility.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All pediatric ingestions, adolescents/adults who are symptomatic after inadvertent ingestions, and patients with a deliberate self-harm ingestion should be sent to a healthcare facility for evaluation and treatment. If patients develop lethargy, they should be observed for the development of more serious events (ie, coma, bradycardia and hypotension) for up to 24 hours due to a potential delayed onset of hypotension.
    1) IMMEDIATE RELEASE: Monitor for at least 6 hours (time to peak plasma concentration is 1 to 4 hours; average 2.6 hours after a single oral dose (Prod Info Tenex(R) oral tablets, 2013)) .
    2) EXTENDED RELEASE: Monitor for at least 8 to 14 hours (time to peak plasma concentration is 6 hours (range: 4 to 8 hours) after a therapeutic dose) (Prod Info INTUNIV(R) oral extended release tablets, 2013)) and admit if signs or symptoms of toxicity develop.
    3) If a patient develops lethargy, they should be observed for the development of more serious events (ie, coma, bradycardia and hypotension) for up to 24 hours due to a potential delayed onset of hypotension (Prod Info INTUNIV(R) oral extended release tablets, 2013).

Monitoring

    A) Monitor vital signs frequently. Evaluate for CNS or respiratory depression. Institute continuous cardiac monitoring and obtain an ECG.
    B) Routine laboratory studies are not needed unless otherwise indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital GI decontamination is generally not warranted because of the risk of 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) MONITORING OF PATIENT
    1) Monitor vital signs frequently. Evaluate for CNS or respiratory depression. Institute continuous cardiac monitoring and obtain an ECG.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) In a review of the literature, peak hypotensive effects were delayed up to 8 to 12 hours after therapeutic ingestion (Minns et al, 2010).
    2) 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.
    3) Hypotension may respond also to isoproterenol or naloxone.
    4) 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).
    5) 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).
    6) ISOPROTERENOL
    a) ISOPROTERENOL INDICATIONS
    1) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
    2) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
    3) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    4) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    7) NALOXONE
    a) Naloxone may be useful in treating hypotension, CNS depression, and apnea. Guanfacine does not directly stimulate opiate receptors, but may cause release of an endogenous opiate through central alpha stimulation.
    b) DOSE: Initial: Adult or Pediatric: 0.4 to 2 mg (5 ampules) IV. Repeat as needed.
    c) No data exists on the dose required to reverse guanfacine toxicity. Doses of 0.8 to 2 mg have been effective in some cases of clonidine overdose.
    d) CASE REPORT: A 4-year-old boy with ADHD and taking the standard formulation of guanfacine for 7 months and tolerating it well, developed increased sleepiness after being started on the extended release (ER) formulation. Thirty-eight hours after the last ER dose, the patient was admitted to the ED with somnolence and an unstable Glasgow Coma Scale (GCS) of 12 to 14. Bradycardia and hypotension were also noted. A toxicology screen was negative, and a head CT was normal. Naloxone (0.1 mg/kg) was given and the GCS improved to 15; however, repeated doses were needed to maintain alertness and a normal GCS. A continuous infusion of naloxone (1.8 mg/h) was administered for 6 hours and gradually weaned over 15 hours. The child was discharged to home the following day with no sequelae (Tsze & Dayan, 2012).
    C) BRADYCARDIA
    1) ATROPINE
    a) ATROPINE/DOSE
    1) 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).
    2) 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.
    a) There is no minimum dose (de Caen et al, 2015).
    b) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    D) HYPERTENSIVE EPISODE
    1) Hypertension is likely to be transient and generally should not be treated. The risk of prolonged hypotension merits a conservative approach to therapy. Nitroprusside is rapidly reversible and may be used to treat LIFE-THREATENING hypertension.
    2) DOSE: Administer 0.5 to 10 mcg/min IV; adjust rate based upon patient response.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Guanfacine is not dialyzable. Guanfacine has a plasma protein binding of 70% (immediate or extended release) (Prod Info INTUNIV(R) oral extended-release tablets, 2011; Prod Info guanfacine hcl oral tablets, 2007) and a high volume of distribution (mean 6.3 L/kg) (Prod Info guanfacine hcl oral tablets, 2007).
    2) Guanfacine clearance by dialysis is only 15% of the total drug clearance in healthy subjects (Kirch & Ohnhaus, 1983).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. An adult ingested 60 mg of guanfacine and developed severe drowsiness and bradycardia (45 bpm). A teenager ingested 25 mg and initially developed hypertension, followed by orthostatic hypotension that developed about 30 hours after exposure. She recovered with supportive care. A toddler developed lethargy, bradycardia and hypotension after ingesting 4 mg (0.33 mg/kg).
    B) THERAPEUTIC DOSE: ANTIHYPERTENSIVE: IMMEDIATE RELEASE: ADULT: Initial dose: 1 mg recommended at bedtime; range: 1 to 3 mg daily. PEDIATRIC: ATTENTION DEFICIT HYPERACTIVITY DISORDER: EXTENDED RELEASE: Children 6 years of age and older: Initial dose: 1 mg once daily; maintenance: 1 to 4 mg once daily as a monotherapy or as an adjunctive therapy in combination with a psychostimulant.

Therapeutic Dose

    7.2.1) ADULT
    A) ANTIHYPERTENSIVE
    1) IMMEDIATE-RELEASE TABLETS: Initial dose of 1 mg orally at bedtime may be titrated to 2 mg/day orally; adverse reactions increase significantly with doses above 3 mg/day (Prod Info Tenex(R) oral tablets, 2013).
    B) ATTENTION DEFICIT HYPERACTIVE DISORDER
    1) EXTENDED-RELEASE TABLETS: Initial dose, 1 mg orally daily; adjust in increments of no more than 1 mg weekly (Prod Info INTUNIV(R) oral extended-release tablets, 2015).
    2) ADMINISTRATION: Swallow tablets whole; do NOT crush, chew, or break tablets (Prod Info INTUNIV(R) oral extended-release tablets, 2015).
    7.2.2) PEDIATRIC
    A) ANTIHYPERTENSIVE
    1) UNDER 12 YEARS
    a) IMMEDIATE-RELEASE TABLETS: The safety and efficacy guanfacine immediate release formulation has not been established in children less than 12 years of age (Prod Info Tenex(R) oral tablets, 2013).
    2) 12 YEARS AND OLDER
    a) IMMEDIATE-RELEASE TABLETS: Initial dose of 1 mg orally at bedtime may be titrated to 2 mg/day orally; adverse reactions increase significantly with doses above 3 mg/day (Prod Info Tenex(R) oral tablets, 2013).
    B) ATTENTION DEFICIT HYPERACTIVITY DISORDER
    1) UNDER 6 YEARS
    a) EXTENDED RELEASE TABLETS: The safety and efficacy of guanfacine extended release formulation has not been established in children less than 6 years of age (Prod Info INTUNIV(R) oral extended-release tablets, 2015).
    2) 6 YEARS TO 12 YEARS
    a) EXTENDED-RELEASE TABLETS: Initial dose, 1 mg orally daily; adjust in increments of no more than 1 mg weekly; MAX: 4 mg/day (Prod Info INTUNIV(R) oral extended-release tablets, 2015).
    b) ADMINISTRATION: Swallow tablets whole; do NOT crush, chew, or break tablets (Prod Info INTUNIV(R) oral extended-release tablets, 2015).
    3) 13 TO 17 YEARS
    a) EXTENDED-RELEASE TABLETS: Initial dose, 1 mg orally daily; adjust in increments of no more than 1 mg weekly; MAX: 7 mg/day (Prod Info INTUNIV(R) oral extended-release tablets, 2015).
    b) ADMINISTRATION: Swallow tablets whole; do NOT crush, chew, or break tablets (Prod Info INTUNIV(R) oral extended-release tablets, 2015).

Maximum Tolerated Exposure

    A) ADULT
    1) Higher daily doses in adults have been used, but adverse reactions increase significantly with doses above 3 mg/day of the immediate release formulation (Prod Info guanfacine hcl oral tablets, 2007).
    2) CASE REPORT: A 25-year-old woman presented with severe drowsiness and bradycardia (45 beats/min) after intentionally ingesting 60 mg of guanfacine. She recovered with supportive care (Prod Info guanfacine hcl oral tablets, 2007).
    3) CASE REPORT: An 18-year-old man, with history of acute lymphoblastic leukemia, hydromorphone dependency, intermittent cocaine abuse and depression, developed bradycardia and prolonged hypotension after taking 6 1 mg guanfacine tablets. Treatment with dopamine (5 mcg/kg/min titrated up to 20 mcg/kg/min) was required for 7 days. Guanfacine levels were 0.934 ng/mL, 0.142 ng/mL, and undetectable at 2, 5, and 8 days postingestion, respectively. The authors speculated that this patient had prolonged hypotension despite low guanfacine levels, possibly due to the synergy of guanfacine with prescribed medications (paroxetine, methadone, clonazepam, trimethoprim/sulfamethoxazole, fluconazole, and gabapentin; a course of cytarabine, etoposide, vincristine, and methotrexate one week prior to admission) (Muller et al, 2002).
    B) PEDIATRIC
    1) CASE REPORT: A 16-year-old girl with a history of Tourette's syndrome intentionally ingested 25 mg of guanfacine immediate-release to help control her tics. Eight hours after exposure she informed her family and was taken to the hospital with an elevated blood pressure (BP 123-144/81-110 mmHg) and was observed for several hours. She was given a dose of activated charcoal and remained normotensive and was discharged 2 hours later. Approximately 30 hours after exposure she developed near syncopal episodes and became hypotensive (BP 97/57 mmHg at home) and was readmitted with orthostatic hypotension (lying BP 104 /50 mmHg; standing BP 67/30 mmHg). She remained alert and oriented. An ECG showed normal sinus rhythm with a QTc interval of 593 ms. A toxicology screen was negative. She was treated with intravenous saline only. Approximately 60 hours after exposure her vital signs were normal and the ECG showed a QTc interval of 511 ms. She was discharged to home with no further symptoms (Minns et al, 2010).
    2) CASE REPORT: Ingestion of approximately 4 mg (0.33 mg/kg) of guanfacine in a 2-year-old (12 kg) toddler resulted in lethargy, hypotension, and bradycardia, which normalized within 24 hours (Prod Info guanfacine hcl oral tablets, 2007; VanDyke et al, 1990).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The principal mechanism of action of guanfacine appears to be stimulation of central alpha2-adrenergic receptors in regions of the cardiovascular system. It is not a CNS stimulant (Prod Info INTUNIV(R) oral extended release tablets, 2013).
    B) Stimulation of these receptors causes a reduction of sympathetic nerve impulses from the vasomotor center to the heart and blood vessels, resulting in reduced peripheral vascular resistance and heart rate (Prod Info INTUNIV(R) oral extended-release tablets, 2011) and, consequently, lower blood pressure.
    C) IMMEDIATE RELEASE vs. EXTENDED RELEASE: The 2 formulations of guanfacine have different pharmacokinetics; therefore a dose substitution on a mg for mg basis is not the same and will result in differences in exposure (Prod Info INTUNIV(R) oral extended release tablets, 2013).
    D) CHILDREN: Younger children (ages 6-12 years) had higher exposure to guanfacine compared to adolescents (ages 13-17 years) and adults. Following multiple doses of extended-release (4 mg) guanfacine, the Cmax was 10 ng/mL compared to 7 ng/mL and the AUC was 162 ng h/mL compared to 116 ng h/mL in children (ages 6-12) and adolescents (ages 13-17), respectively. The events appear attributable to the lower body weight of young children compared to adolescents and adults (Prod Info INTUNIV(R) oral extended release tablets, 2013).

Physicochemical

Physical Characteristics

    A) White to off-white crystalline powder that is relatively highly soluble in methanol (greater than 30 mg/mL), slightly soluble in acetone, and sparingly soluble in water (approximately 1 mg/mL) and alcohol (Prod Info INTUNIV(TM) extended-release oral tablets, 2009).

Molecular Weight

    A) 282.55 (Prod Info INTUNIV(TM) extended-release oral tablets, 2009)

References

General Bibliography

    1) Carchman SH, Crowe JT, & Wright GJ: Steady state plasma levels and pharmacokinetics of guanfacine in patients with normal renal function. Clin Pharmacol Ther 1985b; 37:186.
    2) Carchman SH: A Comparison of the Bioavailability and Pharmacokinetics of AHR-4458 After Oral and Intravenous Administration. Robins Report No. 84-0573 (Jan 25), 1985a.
    3) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    4) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    5) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    6) Fontane E & Shiber J: A somnolent 2-year-old boy with a hyperactive brother. Pediatr Emerg Care 2013; 29(9):1033-1036.
    7) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    8) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    9) Griffith R & Grauwiler J: BS 100-141: A Teratological Study in Rats, AH Robins, Richmond, VA, 1974a.
    10) Griffith RW: BS 100-141: postnatal study in rats, AH Robins, Richmond, VA, 1974e.
    11) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    12) Jerie P & Lasance A: Long-term efficacy and tolerance of the antihypertensive agent guanfacine. J Clin Pharmacol Ther Toxicol 1984; 22(3):170-174.
    13) Jerie P: Clinical experience with guanfacine in long-term treatment of hypertension. Part II: adverse reactions to guanfacine. Br J Clin Pharmacol 1980a; 10(suppl 1):157S-164S.
    14) Jerie P: Long-term evaluations of therapeutic efficacy and safety of guanfacine. Am J Cardiol 1986; 57:55E-59E.
    15) Jerie P: Long-term evaluations of therapeutic efficacy and safety of guanfacine. Am J Cardiol 1986a; 57(9):55E-59E.
    16) Kiechel JR: Pharmacokinetics and metabolism of guanfacine in man: a review. Br J Clin Pharmacol 1980; (Suppl 1):22S-32S.
    17) King A, Harris P, Fritzell J, et al: Syncope in children with Tourette's syndrome treated with guanfacine. Mov Disord 2006; 21(3):419-420.
    18) Kirch W & Ohnhaus EE: The elimination of guanfacine, a central acting antihypertensive agent in normal and impaired renal function in patients undergoing haemodialysis treatment. Arch Pharmacol 1983; 322(Suppl):R131.
    19) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    20) McGrath J & Klein-Schwartz W: Analysis of guanfacine exposures in children <19 years old reported to poison centers. J Toxicol Clin Toxicol 2001; 39(5):494.
    21) Minns AB , Clark RF , & Schneir A : Guanfacine overdose resulting in initial hypertension and subsequent delayed, persistent orthostatic hypotension. Clin Toxicol (Phila) 2010; 48(2):146-148.
    22) Muller AA, Ishimine P, Henretig FM, et al: Prolonged hypotension in acute guanfacine overdose. J Toxicol Clin Toxicol 2002; 40(3):352.
    23) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    24) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    25) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
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    27) Product Information: INTUNIV(R) oral extended release tablets, guanfacine oral extended release tablets. Shire US Inc. (per FDA), Wayne, PA, 2013.
    28) Product Information: INTUNIV(R) oral extended release tablets, guanfacine oral extended release tablets. Shire US Inc. (per FDA), Wayne, PA, 2014.
    29) Product Information: INTUNIV(R) oral extended-release tablets, guanfacine oral extended-release tablets. Shire US Inc (per FDA), Wayne, PA, 2011.
    30) Product Information: INTUNIV(R) oral extended-release tablets, guanfacine oral extended-release tablets. Shire US Inc. (per FDA), Wayne, PA, 2015.
    31) Product Information: INTUNIV(R) oral extended-release tablets, guanfacine oral extended-release tablets. Shire US Inc., Wayne, PA, 2011a.
    32) Product Information: INTUNIV(TM) extended-release oral tablets, guanfacine extended-release oral tablets. Shire Pharmaceuticals, Inc, Wayne, PA, 2009.
    33) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    34) Product Information: TENEX(R) oral tablets, guanfacine hcl oral tablets. Reddy Pharmaceuticals,LLC, Bridgewater, NJ, 2006.
    35) Product Information: Tenex(R) oral tablets, guanfacine HCl oral tablets. Promius Pharma, LLC (per FDA), Bridgewater, NJ, 2013.
    36) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    37) Product Information: guanfacine HCl oral tablets, guanfacine HCl oral tablets. Mylan Pharmaceuticals Inc. (per DailyMed), Morgantown, WV, 2015.
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