Substances Included Synonyms

Therapeutic Toxic Class

A)

B)

Specific Substances

A)

1) 2-Imidazoline, 2-(2,6-dichloroanilino)-
2) 2-(2,6-Dichloroanilino)-2-imidazoline hydrochloride
3) 2-(2,6-Dichlorophenylamino)-2-imidazoline hydrochloride
4) 2,6-Dichloro-N-(imidazolidin-2-ylidene)aniline hydrochloride
5) Clonidin
6) M-5041T
7) St 155
8) Molecular formula: C9-H9-Cl12-N3
9) CAS 4205-90-7 (clonidine)
10) CAS 4205-91-8 (clonidine hydrochloride)
11) CAS 57066-25-8

1) 2-((4-Amino-2,6-dichlorophenyl)imino)-imidazolidine hydrochloride
2) AL 02145
3) p-Aminoclonidine
4) Apraclonidine hydrochloride
5) Aplonidine
6) Molecular formula: C9-H10-Cl12-N4
7) CAS 66711-21-5

1) CAS 75438-57-2

Available Forms Sources

A)

1) CLONIDINE

a) Transdermal patch, extended release: 0.1 mg/24 hr (2.5 mg of clonidine), 0.2 mg/24 hr (5 mg of clonidine), 0.3 mg/24 hr (7.5 mg of clonidine (Prod Info Catapres-TTS(R) transdermal system, 2012).
b) Epidural solution: 0.1 mg/mL, 0.5 mg/mL (Prod Info Duraclon(R) epidural injection solution, 2012).
c) Oral tablet: 0.1 mg, 0.2 mg, 0.3 mg (Prod Info Catapres(R) oral tablets, 2012)
d) Oral tablet, extended release: 0.1 mg and 0.2 mg (Prod Info KAPVAY(R) oral extended-release tablets, 2015).

2) CLONIDINE WITH CHLORTHALIDONE

a) Oral tablet (chlorthalidone-clonidine hydrochloride) 15 mg-0.1 mg, 15 mg-0.2 mg, 15 mg-0.3 mg (Prod Info CLORPRES(R) oral tablets, 2002).

3) Moxonidin is available in Germany as 0.2 milligram, 0.3 milligram and 0.4 milligram tablets (Fachinformation, 1995). Moxonidine is not available in the United States.

B)

1) Clonidine immediate-release tablets and transdermal system are indicated for the treatment of hypertension, alone or in combination with other antihypertensive agents (Prod Info Catapres(R) oral tablets, 2012; Prod Info Catapres-TTS(R) transdermal system, 2012). Clonidine is also available with chlorthalidone for the treatment of hypertension (Prod Info CLORPRES(R) oral tablets, 2002).
2) Clonidine hydrochloride extended-release tablets are indicated as monotherapy and as adjunctive therapy to other stimulant medications for the treatment of attention deficit hyperactivity disorder (ADHD) in children (Prod Info KAPVAY(R) oral extended-release tablets, 2015).
3) Clonidine hydrochloride injection, given as a continuous epidural infusion, is indicated in combination with opioids for the treatment of severe cancer pain that is not adequately relieved by opioid analgesics alone (Prod Info Duraclon(R) epidural injection solution, 2012).
4) Clonidine is used in the treatment of ethanol withdrawal (Baumgartner & Rowen, 1991; Ip Yam et al, 1992) and narcotic opiate withdrawal (Anderson et al, 1997). Clonidine has also been used as an aid in smoking cessation (Glassman et al, 1984; Glassman et al, 1988) and to reduce the craving associated with cocaine withdrawal.
5) An abuse potential for clonidine has been identified in treatment-seeking opiate abusers, particularly those with concurrent cocaine use (Anderson et al, 1997). Chewing of clonidine patches has been reported as a mechanism of abuse in drug-seeking individuals (Fetrow et al, 1994).
6) Clonidine has also been abused in the intentional poisoning of a 3-year-old child in an episode of Munchausen-By-Proxy (Tessa et al, 2001).
7) MOXONIDINE: Moxonidine is an antihypertensive agent. It is a centrally acting imidazoline-I-1 and alpha-2 receptor agonist with up to a 600-fold greater selectivity at imidazole receptor sites than at alpha-2 receptors. Moxonidine is structurally related to clonidine, but results in fewer central side effects (ie, dry mouth, sedation) than clonidine (Prod Info Cynt(R), 1996; Yu & Frishman, 1996; Chrisp & Faulds, 1992).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Used primarily for the treatment of hypertension and attention deficit hyperactivity disorder (ADHD); less often for detoxification from opioid, ethanol, or nicotine.
B) PHARMACOLOGY: Clonidine stimulates the presynaptic alpha-2 receptor in the brain, leading to inhibition of norepinephrine release, and it also stimulates the imidazoline receptor; both of these actions decrease sympathetic outflow.
C) TOXICOLOGY: Stimulation of peripheral postsynaptic alpha-2 receptors after overdose can cause initial transient hypertension. Excessive stimulation of presynaptic alpha-2 receptors in the lower brainstem and medulla decreases plasma norepinephrine concentrations, causing hypotension and bradycardia.
D) EPIDEMIOLOGY: Clonidine ingestion is common, but severe poisoning is rare.
E) WITH THERAPEUTIC USE

1) Confusion, hallucinations, dry mouth, hypotension, nausea, vomiting, constipation, pruritus, contact dermatitis, tinnitus, dizziness, nervousness, and sedation are the most common adverse effects. Atrioventricular block, minor dysrhythmias, Raynaud phenomenon, and congestive heart failure are also reported. Rebound hypertension develops with abrupt withdrawal.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: CNS depression, miosis, heart conduction abnormality, hypertension.
2) SEVERE TOXICITY: Apnea, respiratory depression, coma, bradycardia, hypothermia, hypotension, early transient hypertension.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Mild hypertension may develop early and is usually followed by hypotension. Relative bradycardia is common, although tachycardia may occur. Mild hypothermia and respiratory depression are common in patients with CNS depression.

0.2.20)

A) Clonidine is classified as US Food and Drug Administration (FDA) pregnancy category C. Clonidine does not appear to produce teratogenic effects in animals. Clonidine is excreted into breast milk.

Laboratory Monitoring

A)

B)

C)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) There is no specific treatment. Hypotension should be treated with intravenous boluses of crystalloid. Bradycardia is typically mild and usually doesn't require any treatment. Bradycardia, hypotension and CNS depression often respond to physical stimulation. Naloxone has been used to reverse CNS depression with inconsistent success.

B) MANAGEMENT OF SEVERE TOXICITY

1) Severe bradycardia associated with hypotension and not responsive to physical stimulation should be treated with standard dose of atropine or cardiac pacing. Norepinephrine or dopamine may be beneficial in patients with severe bradycardia and hypotension not responding to physical stimulation, naloxone, intravenous crystalloid, and atropine. Patients with significant CNS and/or respiratory depression should be intubated. If hypertension is severe (associated with end organ effects) and prolonged, treatment should be initiated with an infusion of sodium nitroprusside.

C) DECONTAMINATION

1) PREHOSPITAL: GI decontamination is not recommended because of the potential risk of altered mental status.
2) HOSPITAL: Induced emesis and gastric lavage are not indicated. Activated charcoal binds clonidine and may be given for patients who present early after significant ingestions. Whole bowel irrigation should be used for symptomatic patients who have ingested a clonidine patch.

D) AIRWAY MANAGEMENT

1) Intubate patients with depressed mental status and who are unable to protect their airway and those with significant respiratory depression.

E) ANTIDOTE

1) There is no antidote for clonidine. Although some patients have responded to naloxone (reversal of altered mental status, respiratory depression or apnea, and miosis), not all patients respond. Naloxone should be administered to patients with significant CNS or respiratory depression. Tolazoline (an alpha-2 adrenergic antagonist) has been suggested as an antidote, but there is little clinical experience with its use and most patients do well with supportive care.

F) INTRATHECAL INJECTION

1) Intrathecal overdose of clonidine has not been reported; however, clonidine can be administered intrathecally, therefore the potential for overdose exists. Support blood pressure with fluids and pressors. Intubate and ventilate as needed. Immediately empty the intrathecal pump. Cerebrospinal fluid (CSF) drainage should be performed immediately followed by CSF exchange. Keep the patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers).

G) ENHANCED ELIMINATION

1) Although clonidine has pharmacokinetic characteristics suggesting it is amenable to hemodialysis, there is no clinical experience with its use, and overdose is rarely severe enough to warrant emergent hemodialysis.

H) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic children with inadvertent clonidine tablet ingestions may be monitored at home if the ingestion is: Less than 0.1 mg clonidine for a child 4-years-old or younger, 0.2 mg clonidine or less in a child aged 5 to 8 years, or less than 0.4 mg clonidine in a child older than 8 years of age. Children taking clonidine therapeutically who inadvertently receive no more than double their therapeutic dose may be observed at home if asymptomatic.
2) OBSERVATION CRITERIA: Symptomatic patients, those with deliberate ingestions, children who have chewed or ingested clonidine patches or ophthalmic preparations, and children with tablet ingestions greater than the amounts listed above should be sent to a healthcare facility for observation and treatment. Most patients who ingest clonidine will manifest symptoms rapidly, typically within 30 to 90 minutes, so a 4-hour observation period is adequate for asymptomatic patients. Patients who ingest a clonidine patch may have delayed onset of symptoms. Following ingestion of extended-release formulations, onset of toxicity is expected to be delayed. Peak plasma concentrations of extended-release formulations are reached at about 7 to 8 hours after therapeutic doses; patients should be observed for the development of toxic effects for at least 9 to 14 hours.
3) ADMISSION CRITERIA: Patients who develop even mild toxic effects after ingestion of sustained release formulations should be admitted to a monitored setting as more severe and prolonged toxicity may develop. Patients with bradycardia, CNS depression, respiratory depression, heart block, and hemodynamic instability or other serious symptoms should be admitted to an intensive care setting.

I) PITFALLS

1) Hypertension may occur early in the clinical course and always is transient and self limited; it should not be treated except in the rare circumstance where severe hypertension is causing end organ effects. Small volumes of ophthalmic preparations can cause severe toxicity (5 mL of 1% apraclonidine drops contains 25 mg apraclonidine). Crushing, breaking or chewing extended release formulations can result in toxicity due to rapid absorption of the entire dose.

J) PHARMACOKINETICS

1) Clonidine is well absorbed following oral ingestion; bioavailability is nearly 100%, the elimination half life is 6 to 24 hours; approximately 50% of the drug is excreted unchanged in the urine. Binding to plasma protein is 20% to 40% and the volume of distribution is about 1 to 2 L/kg.
2) IMMEDIATE-RELEASE: Plasma concentrations peak at 1 to 3 hours.
3) EXTENDED-RELEASE: Plasma concentrations peak at 6.5 to 7.8 hours.

K) DIFFERENTIAL DIAGNOSIS

1) The differential diagnosis should consider other causes of bradycardia, heart block, altered mental status, and hypotension, including overdose with calcium channel antagonists, beta-blockers, or digoxin, and medical causes such as acute myocardial infarction or hypoxia.

Range Of Toxicity

A)

1) Adults have survived acute ingestions as high as 100 mg. Mild toxicity may occur at just above the therapeutic range.

B)

1) As little as 0.1 mg has produced toxicity in children. Toddlers have developed toxicity after chewing a single used clonidine patch or ingesting small volumes of ophthalmic preparations.

C)

Clinical Effects

Cardiovascular

3.5.2)

A) CARDIOVASCULAR FINDING

1) WITH POISONING/EXPOSURE

a) Overdoses often result in initial, reversible hypertension followed by hypotension and bradycardia. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias (Prod Info clonidine hcl oral tablets, 2006). Signs of cardiovascular toxicity were noted in 79% of children following clonidine ingestions ranging from 0.2 to 10.2 mg in a retrospective study (Wiley et al, 1990):

INCIDENCE (%)	FINDING
30	Dysrhythmia
53	Bradycardia
0	Cardiac Arrest
38	Hypotension
21	Hypertension

B) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Hypotension has been reported after therapeutic use and ingestion of clonidine patches in children (Broderick-Cantwell, 1999; Kraft, 1998; Dockstader et al, 1993; Klein, 1991) .

2) WITH POISONING/EXPOSURE

a) INCIDENCE: Hypotension occurs frequently (12% to 50% of children in several case series and 32% of adolescents and adults) and may be severe and prolonged, but generally blood pressure returns to normotensive levels within 24 hours (Spiller et al, 2005; Kappagoda et al, 1998; Kraft, 1998; Nichols et al, 1997; Whelan & Dearlove, 1995; Bamshad & Wasserman, 1990; Fiser et al, 1990; Conner & Watanabe, 1979; Stein & Volans, 1978).

1) In a pediatric case series of acute-on-chronic or chronic exposures to clonidine, the most common effects in symptomatic children were lethargy (80%), bradycardia (17%), hypotension (15%), and respiratory depression (5%) (Klein-Schwartz et al, 2001). Ingestion of apraclonidine ophthalmic drops produced hypotension in a 2-year-old child (Everson et al, 1999).

b) CASE REPORT: A 2-year-old boy presented to the emergency department with a several hour history of lethargy following a suspected ingestion of clonidine tablets. At presentation, he was hypotensive (68/51 mmHg; reference systolic 75 mmHg), with depressed respirations (18 breaths/min; reference range 30 to 50 breaths/min), and miotic pupils. Neurologic exam indicated hypotonia and an ECG demonstrated first-degree heart block. Over the next hour post-admission, the patient's miosis and CNS depression worsened, necessitating intubation. A trial of naloxone was administered of which the patient was unresponsive. A urine toxicology screen, obtained 2 hours post-presentation, indicated high concentrations of clonidine. With supportive therapy, including IV atropine and IV fluids, the patient recovered and was discharged approximately 48 hours later (Ahmad et al, 2015).
c) ONSET: Hypotension will usually occur within the first several hours postingestion (within 30 minutes, with peak effect in 2 to 4 hours) (Lusthof et al, 2000; Artman & Boerth, 1983; Dollery et al, 1976; Pettinger, 1975).
d) Hypotension has been reported after ingestion and therapeutic use of clonidine patches in children (Broderick-Cantwell, 1999; Kraft, 1998; Dockstader et al, 1993; Klein, 1991).
e) CASE REPORT: Sustained hypotension occurred after an inadvertent soft tissue injection during an implantable drug delivery device refill. It was estimated the patient received a 90-day dose (18 mg) all at once. The patient experienced hypertension within minutes of the exposure, but then developed hypotension which lasted approximately 3 days. She recovered after being treated with vasopressors and standard care (Johnson et al, 2011).
f) RETROSPECTIVE REVIEW: According to a retrospective chart review from the National Poison Data System between January 2000 to December 2011, identifying 27,825 clonidine non-patch unintentional exposures in children 12 years of age or less (median age: 4 years), hypotension was reported in 8.5% of patients (Wang et al, 2014).

1) The review also identified 220 clonidine patch unintentional exposures (median age: 2 years), with ingestion of the patches reported in 141 patients (64%) . Hypotension was reported in 9.5% of patients (n=220) (Wang et al, 2014).

C) BRADYCARDIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Bradycardia has been reported after therapeutic use of a 5-mg clonidine patch in a 13-year-old (Dockstader et al, 1993) and after accidental overdose of a clonidine patch in a 15-year-old (Broderick-Cantwell, 1999).

2) WITH POISONING/EXPOSURE

a) Bradycardia frequently accompanies hypotension. In one study, bradycardia developed in 8 of 11 toddlers (73%) who were being managed for clonidine intoxication (Fiser et al, 1990). Bradycardia occurred after an inadvertent soft tissue injection during an implantable drug delivery device refill. It was estimated the patient received a 90-day dose (18 mg) all at once. The patient experienced bradycardia within minutes of the exposure, which persisted for approximately 3 days. She recovered after being treated with vasopressors and standard care (Johnson et al, 2011).
b) Bradycardia, defined as a heart rate of less than 75 beats/min in children aged 0 to 4 years and less than 60 beats/min in children 5 to 12 years, occurred in 10 of 81 younger children (14%) and 3 of 32 older children (9%) in a prospective study of clonidine poisoning (Spiller et al, 2005). However, in another case series, bradycardia developed in 50% of 14 pediatric patients who experienced clonidine poisoning (Erickson & Duncan, 1998). Bradycardia may be profound (Lusthof et al, 2000; Fetrow et al, 1994).
c) CASE REPORT/DERMAL EXPOSURE: A 6-year-old girl developed bradycardia (54 beats/min) following inadvertent clonidine patch administration; she presumed the patch was a "band-aid" (Killian et al, 1997).
d) CASE REPORT: Profound bradycardia (30 beats/min) with hypotension (70/40 mmHg) was reported in a 40-year-old man after he intentionally chewed his clonidine 2 mg sustained-release patch (Fetrow et al, 1994).
e) CASE SERIES: Bradycardia developed in 33 of 80 children (41%) in a retrospective case series of clonidine overdose (Nichols et al, 1997).
f) CASE SERIES: Bradycardia was reported in 11 of 24 children (46%) with clonidine poisoning (Sinha & Cranswick, 2004).
g) CASE REPORT: Persistent bradycardia (heart rate 60) and several episodes of apnea were reported in a 2-year-old child following ingestion of 5 cc of apraclonidine ophthalmic drops. The child recovered following symptomatic therapy (Everson et al, 1999).
h) CASE REPORTS: Bradycardia was reported in 2 children (a 21-month-old and a 2-year-old) who ingested apraclonidine ophthalmic drops. The 21-month-old boy ingested an unknown amount of apraclonidine and developed bradycardia, with a pulse rate of 72 beats/min approximately 9.5 hours postingestion. The 2-year-old girl ingested approximately 25 mg of apraclonidine and developed bradycardia, with a pulse rate of 60 beats/min 2 hours postingestion. Both patients recovered with supportive care (Rangan et al, 2008).
i) RETROSPECTIVE REVIEW: According to a retrospective chart review from the National Poison Data System between January 2000 to December 2011, identifying 27,825 clonidine non-patch unintentional exposures in children 12 years of age or less (median age: 4 years), bradycardia was reported in 10.2% of patients (Wang et al, 2014).

1) The review also identified 220 clonidine patch unintentional exposures (median age: 2 years), with ingestion of the patches reported in 141 patients (64%) . Bradycardia was reported in 17.3% of patients (n=220) (Wang et al, 2014).

j) CASE SERIES: A 6-year retrospective observational case series of pediatric clonidine exposures, reported to a poison center, identified 458 cases of clonidine as a single agent ingestion in pediatric patients less than 12 years of age. The ingested clonidine dose was reported in 315 of the 458 cases with a median dose of 0.2 mg (range 0.05 to 6 mg). Lethargy with bradycardia with or without hypotension was reported in 338 (74%) of the 458 patients (Lewis et al, 2015).
k) CASE REPORT: A 17-year-old girl intentionally ingested 2.4 mg of clonidine and 1500 mg buPROPion. Initially, she developed somnolence, miosis, and bradycardia (heart rate 39 beats/min). Over the next several hours, she was continually monitored and received supportive care. Approximately 23 hours post-ingestion, the patient developed tachycardia (peak heart rate 126 beats/minute), nausea, anxiety, mydriasis, and a generalized tonic-clonic seizure that lasted approximately 3 to 4 minutes. Over the next 8 hours, she continued to be tachycardic, hypertensive, and tremulous. With supportive care, her signs and symptoms resolved approximately 31 hours post-ingestion and, 2 days post-ingestion, she was discharged without sequelae to a psychiatric facility. It is suspected that manifestations of clonidine toxicity initially appeared, masking the toxic effects of buPROPion. Following the clearance of clonidine from the patient, buPROPion toxicity was then unmasked (Phillips et al, 2015).

D) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) INCIDENCE: Transient hypertension may also occur but is less frequent than hypotension (2% to 34% of children in several case series and 11% of adolescents and adults) (Spiller et al, 2005; Kappagoda et al, 1998; Nichols et al, 1997; Fiser et al, 1990; Stein & Volans, 1978). Hypertension occurred after an inadvertent soft tissue injection during an implantable drug delivery device refill. It was estimated the patient received a 90-day dose (18 mg) all at once. The patient experienced hypertension within minutes of the exposure, but then developed sustained hypotension which lasted approximately 3 days. She recovered after being treated with vasopressors and standard care (Johnson et al, 2011).
b) Hypertension developed in 27 of 80 children (34%) in a retrospective case series of clonidine overdose (Nichols et al, 1997). Hypertension, defined as a systolic blood pressure of greater than 110 mmHg or a diastolic blood pressure of greater than 75 mmHg, developed in 4 out of 81 children (5%) aged 0 to 4 years old with clonidine poisoning (Spiller et al, 2005).
c) In a study of 25 pediatric patients, hypertension was seen in 44%; some cases may be attributable to anxiety in the emergency department setting (Bamshad & Wasserman, 1990).
d) DURATION: Hypertension is usually transient. A blood pressure of 140/90 mmHg was seen in a 9-month-old 6 hours after the child ingested clonidine 1.95 mg (Yagupsy & Gorodischer, 1983). Hypertension persisted for 10 to 12 hours in 1 pediatric patient (Bamshad & Wasserman, 1990).
e) Three patients (24 months old, 21 months old, and 20 months) developed hypertension (114/70 mmHg, 160/128 mmHg, 160/110 mmHg) after being given atropine and naloxone for clonidine ingestion (Gremse et al, 1986).
f) Following a single-dose suicidal ingestion of clonidine (4.5 to 10.5 mg), a 28-year-old woman with renal failure presented with progressive drowsiness and a blood pressure of 210/150 mmHg (Lilja et al, 1984).

1) 16 hours later, blood pressure was 140/100 mmHg and plasma clonidine level was 4.7 ng/mL.

g) CASE REPORT: Hypertensive crisis and myocardial infarction occurred following an inadvertent subcutaneous overdose of clonidine (12.2 mg) and hydromorphone (48.3 mg). The patient had a history of hypertension (medically controlled) and breast cancer. She was treated symptomatically; on day 5 hypotension developed and she was given dopamine, with eventual return to baseline pressure. At the initial overdose, clonidine acted peripherally to stimulate alpha-adrenergic receptors, leading to vasoconstriction and increased blood pressure (Frye & Vance, 2000).
h) CASE REPORTS: Three patients (a 54-year-old man, a 71-year-old man, and a 77-year-old woman), treated with clonidine intrathecally, via a pump, for severe lower back pain, developed severe hypertension (blood pressure ranging from 192/143 to 220/156 mmHg) following needle dislocation during the refill procedure, inadvertently causing extravasation of the clonidine into a subcutaneous pocket. The dose of clonidine that had leaked ranged from 3 mg to 22 mg. The 77-year-old woman also developed left ventricular failure and pulmonary edema secondary to her severe hypertension. All 3 patients recovered without sequelae following intensive supportive therapy (Perruchoud et al, 2012).
i) MECHANISM: Hypertension is believed to be secondary to peripheral alpha-adrenergic agonist effects.
j) CASE REPORT/MOXONIDINE: A 17-year-old woman presented with hypertension (165/100 mmHg) approximately 4 hours after intentionally ingesting 60 moxonidine 0.2-mg tablets. With supportive care, her blood pressure stabilized in the range of 100 to 105/60 to 75 mmHg (Magdalan et al, 2008).

E) ATRIOVENTRICULAR BLOCK

1) WITH POISONING/EXPOSURE

a) Dysrhythmias including atrioventricular (AV) block, complete heart block, and Wenckebach block have been reported (Ahmad et al, 2015; Williams et al, 1977). Large overdoses can result in reversible cardiac conduction defects or dysrhythmias (Prod Info clonidine hcl oral tablets, 2006).
b) CASE REPORT: A 22-year-old woman with systemic lupus erythematosus, mild renal insufficiency, and severe systemic hypertension developed a transient high-grade AV block after inadvertently receiving clonidine hydrochloride 18.8 mg over 4 days; an ECG revealed a 2:1 AV block. The ECG readings progressed to complete AV block that lasted several hours; clonidine was discontinued. A junctional supraventricular rhythm without apparent atrial activity then developed, followed by AV nodal Wenckebach block for several days. Readings returned to normal 6 days after the first dysrhythmia was detected. No hypotension was associated with the overdose, and no hemodynamic compromise was noted with the complete AV block (Williams et al, 1977).

F) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A heart rate of 144 beats/min was noted in a 2-year-old boy who ingested an unknown amount of clonidine and presented with diaphoresis and lethargy with intermittent delirium (Fiser et al, 1990).

G) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Following a massive inadvertent subcutaneous overdose of clonidine (12.2 mg) and hydromorphone (48.3 mg), a 62-year-old woman developed hypertensive crisis and anterior myocardial infarction, confirmed on cardiac catheterization. The patient had a history of hypertension (medically controlled) and breast cancer. Following symptomatic therapy, the patient improved (Frye & Vance, 2000).

H) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) RETROSPECTIVE REVIEW: According to a retrospective chart review from the National Poison Data System between January 2000 to December 2011, identifying 27,825 clonidine non-patch unintentional exposures in children 12 years of age or less (median age: 4 years), cardiac arrest occurred in 7 patients (Wang et al, 2014).

Respiratory

3.6.2)

A) RESPIRATORY FINDING

1) WITH POISONING/EXPOSURE

a) Signs of respiratory system effects were noted in 36% of children following clonidine ingestions ranging from 0.2 to 10.2 mg in a retrospective study (Wiley et al, 1990):

INCIDENCE (%)	FINDING
21	Apnea
17	Respiratory depression

B) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) Respiratory depression has been reported in 7% to 54% of children in several case series and 5% of adolescents and adults following clonidine overdose (Spiller et al, 2005; Sinha & Cranswick, 2004; Nichols et al, 1997; Bamshad & Wasserman, 1990; Fiser et al, 1990; Wiley et al, 1990; Stein & Volans, 1978) and following ingestion of apraclonidine ophthalmic drops (Everson et al, 1999). Respiratory depression usually responds to tactile stimulation (Rangan et al, 2008).
b) CASE REPORT: Respiratory failure occurred at 60 and 75 minutes postingestion of clonidine 10 mg in a set of 34-month-old twin girls (Maggi et al, 1986).
c) CASE SERIES: Respiratory depression requiring mechanical ventilation occurred in 8 of 113 pediatric clonidine poisonings (7%) in a prospective study (Spiller et al, 2005).
d) RETROSPECTIVE REVIEW: According to a retrospective chart review from the National Poison Data System between January 2000 to December 2011, identifying 27,825 clonidine non-patch unintentional exposures in children 12 years of age or less (median age: 4 years), respiratory depression, cyanosis, and respiratory arrest occurred in 717 (2.6%), 14 (0.1%), and 68 (0.2%) patients, respectively (Wang et al, 2014).

1) The review also identified 220 clonidine patch unintentional exposures (median age: 2 years), with ingestion of the patches reported in 141 patients (64%). Respiratory symptoms were reported in 7 of the 220 patients (3.2%) (Wang et al, 2014).

e) CASE REPORT: A 2-year-old boy presented to the emergency department with a several hour history of lethargy following a suspected ingestion of clonidine tablets. At presentation, he was hypotensive (68/51 mmHg; reference systolic 75 mmHg), with depressed respirations (18 breaths/min; reference range 30 to 50 breaths/min), and miotic pupils. Neurologic exam indicated hypotonia and an ECG demonstrated first-degree heart block. Over the next hour post-admission, the patient's miosis and CNS depression worsened, necessitating intubation. A trial of naloxone was administered of which the patient was unresponsive. A urine toxicology screen, obtained 2 hours post-presentation, indicated high concentrations of clonidine. With supportive therapy, including IV atropine and IV fluids, the patient recovered and was discharged approximately 48 hours later (Ahmad et al, 2015).

C) APNEA

1) WITH POISONING/EXPOSURE

a) Irregular respirations with intermittent apneic episodes may occur (Fiser et al, 1990; Grabert et al, 1979).
b) CASE REPORT: Several episodes of apnea over a 3-hour period, requiring intubation, were reported in a 2-year-old child following ingestion of 5 cc of apraclonidine ophthalmic drops (Everson et al, 1999).
c) CASE REPORTS: Intermittent apnea occurred in 2 children (a 21-month-old and a 2-year-old) following ingestion of apraclonidine ophthalmic drops. The 21-month-old boy ingested an unknown amount of apraclonidine ophthalmic drops and subsequently developed shallow respirations with a respiratory rate that decreased to 11 breaths/min with an oxygen saturation of 92% on room air. The patient's respiratory rate gradually normalized with periodic tactile stimulation. The 2-year-old girl ingested approximately 25 mg of apraclonidine ophthalmic drops and subsequently experienced intermittent apneic episodes over the next 3 hours, requiring mechanical ventilation. With supportive care, the patient's condition improved, and she was extubated within 11 hours postingestion (Rangan et al, 2008).

D) HYPERVENTILATION

1) WITH POISONING/EXPOSURE

a) Hyperventilation (40 breaths/min) was reported in the initial presentation of a 5-year-old child following a 1000-fold overdose of 50 mg. Rapid progression to respiratory depression occurred, with respirations of 5 to 8 breaths/min and 15- to 20-second apneic periods. The child recovered following naloxone administration and supportive care (Romano & Dinh, 2001).

E) PULMONARY EDEMA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Pulmonary edema due to left cardiac failure secondary to the development of hypertensive crisis (220/156 mmHg) was reported in a 77-year-old woman following inadvertent extravasation of intrathecal clonidine into a subcutaneous pocket because of the needle in the intrathecal pump that had dislocated during the refill procedure. The dose of clonidine that had leaked into the subcutaneous pocket was 22 mg (18 mL). With intensive supportive therapy, the patient recovered without sequelae (Perruchoud et al, 2012).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM FINDING

1) WITH POISONING/EXPOSURE

a) Common effects of overdose include impaired consciousness, hypotonia, hyporeflexia, miosis, and hypothermia (Prod Info clonidine hcl oral tablets, 2006). In a pediatric case series of acute-on-chronic or chronic exposures to clonidine, the most common effects in symptomatic children were lethargy (80%), bradycardia (17%), hypotension (15%), and respiratory depression (5%) (Klein-Schwartz et al, 2001). Signs of CNS effects were noted in 94% of children following clonidine ingestions ranging from 0.2 to 10.2 mg in a retrospective study (Wiley et al, 1990):

INCIDENCE (%)	FINDING
4.3	Coma
10.8	Extensor Babinski response
28	Hyporeflexia
17	Hypotonia
11	Irritability
94	Lethargy
26	Miosis
4.3	Mydriasis
8.5	Pupils, unresponsive

b) CASE REPORT: A 2-year-old boy presented to the emergency department with a several hour history of lethargy following a suspected ingestion of clonidine tablets. At presentation, he was hypotensive (68/51 mmHg; reference systolic 75 mmHg), with depressed respirations (18 breaths/min; reference range 30 to 50 breaths/min), and miotic pupils. Neurologic exam indicated hypotonia and an ECG demonstrated first-degree heart block. Over the next hour post-admission, the patient's miosis and CNS depression worsened, necessitating intubation. A trial of naloxone was administered of which the patient was unresponsive. A urine toxicology screen, obtained 2 hours post-presentation, indicated high concentrations of clonidine. With supportive therapy, including IV atropine and IV fluids, the patient recovered and was discharged approximately 48 hours later (Ahmad et al, 2015).
c) CASE SERIES: A 6-year retrospective observational case series of pediatric clonidine exposures, reported to a poison center, identified 458 cases of clonidine as a single agent ingestion in pediatric patients less than 12 years of age. The ingested clonidine dose was reported in 315 of the 458 cases with a median dose of 0.2 mg (range 0.05 to 6 mg). Lethargy with bradycardia with or without hypotension was reported in 338 (74%) of the 458 patients (Lewis et al, 2015).

B) ALTERED MENTAL STATUS

1) WITH POISONING/EXPOSURE

a) Drowsiness, somnolence, ataxia, impaired consciousness, and coma are frequently seen. Overdose may result in the rapid development of CNS depression. The frequency of CNS depression is usually higher in children than adults. Seizures may rarely occur following large overdoses (Phillips et al, 2015; Rangan et al, 2008; Prod Info clonidine hcl oral tablets, 2006; Spiller et al, 2005; Romano & Dinh, 2001; Frye & Vance, 2000).
b) INCIDENCE: Impaired consciousness was seen in 85% to 96% of children in several case series and 78% of adults (Nichols et al, 1997; Roberge et al, 1996; Ryan, 1996; Matyunas et al, 1995; Bamshad & Wasserman, 1990; Fiser et al, 1990; Wiley et al, 1990; Stein & Volans, 1978). Impaired consciousness was reported in 10 pediatric poisonings (71%) in a case series (Erickson & Duncan, 1998) and in 77 pediatric poisonings (96%) in another (Nichols et al, 1997). In a prospective series of 113 pediatric clonidine poisonings, 81 of patients (72%) developed drowsiness and lethargy, and 7 (6%) became comatose (Spiller et al, 2005). Lethargy was reported following ingestion of 5 cc of apraclonidine ophthalmic drops in a child (Everson et al, 1999).
c) CASE SERIES: Drowsiness/coma was reported in 11 of 24 children (46%) with clonidine poisoning. Glasgow Coma Scale (GCS) scores ranged from 9 to 15 following ingestion of estimated clonidine doses of 250 mcg to 9000 mcg. There appeared to be little correlation between the estimated clonidine dose and the patient's GCS score, with an estimated clonidine dose of 500 mcg associated with a GCS score of 9 as compared with an estimated clonidine dose of 2000 mcg associated with GCS scores ranging from 10 to 15 (Sinha & Cranswick, 2004).
d) DURATION: Consciousness is usually regained within 24 to 36 hours of the ingestion (Lusthof et al, 2000; Erickson & Duncan, 1998; Fiser et al, 1990; Conner & Watanabe, 1979).
e) CASE REPORT: A 6-year-old girl was found somnolent and later became obtunded, responding only to forceful stimuli following inadvertent clonidine patch administration; the child thought the patch was a "band-aid." The child had been applying and removing the patch from one of her extremities during an afternoon visit at her grandparents. A qualitative urine screen was positive for clonidine. The child made a complete recovery within 18 hours following supportive care only (Killian et al, 1997).
f) Significant CNS toxicity has resulted from transdermal clonidine patches in pediatric patients. Symptoms have included irritability, decreased food intake, somnolence (Reed & Hamburg, 1986), and drowsiness progressing to lethargy and obtundation (Killian et al, 1997; Klein, 1991). These symptoms were often accompanied by bradycardia, hypotension, miosis, and gasping respiration (Corneli et al, 1989). Exposure has followed chewing or sucking on discarded patches (Caravati & Bennett, 1988), with one patch found adhering to the midportion of the hard palate (Klein, 1991). Patches have been inadvertently transferred from an adult to a child's back while sharing his parent's bed (Reed & Hamburg, 1986).

1) Recovery generally occurs with conservative supportive therapy within 6 to 24 hours (Klein, 1991; Reed & Hamburg, 1986), although in cases of delayed recognition of clonidine as causative, more aggressive treatment with systemic antidotes, pressor agents, and gastric lavage has been needed (Killian et al, 1997; Caravati & Bennett, 1988).

g) CASE SERIES/PEDIATRIC: Three pediatric patients developed extreme somnolence after inadvertently receiving a 100-fold overdose of epidural clonidine (concentration prepared was 200 mcg/mL instead of the prescribed 2 mcg/mL). The patients then underwent their surgical procedures without incident. During and after surgery, there was no evidence of respiratory depression, and vital signs remained stable. All 3 patients recovered within 24 hours and were discharged home on the first postoperative day (Meyer & Cambray, 2008).
h) RETROSPECTIVE REVIEW: According to a retrospective chart review from the National Poison Data System between January 2000 to December 2011, identifying 27,825 clonidine non-patch unintentional exposures in children 12 years of age or less (median age: 4 years), CNS depression, drowsiness/lethargy, and coma were reported in 45.3%, 44.2%, and 1.1% of patients, respectively (Wang et al, 2014).

1) The review also identified 220 clonidine patch unintentional exposures (median age: 2 years), with ingestion of the patches reported in 141 patients (64%) . CNS depression was reported in 48.6% of patients (n=220) (Wang et al, 2014).

C) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headache was reported in 2 boys (ages 9 and 10, respectively) following inadvertent compounding errors in which the first child received a concentration of 2168.6 mcg/mL (an 87-fold dosing error) for 1 dose. The second patient ingested capsules that contained 0.198 mg of clonidine, a 10-fold dose difference. Both patients developed other CNS effects (eg, ataxia, dysarthria, followed by lethargy, somnolence) and bradycardia, which are typical of clonidine toxicity. Both recovered completely (Suchard & Graeme, 2002).

D) HYPOREFLEXIA

1) WITH POISONING/EXPOSURE

a) Hypotonia, hyporeflexia, and seizures have been reported (Fiser et al, 1990; Mendoza & Medalie, 1979; Hunyor et al, 1975). However, seizures are rare (Grabert et al, 1979; Williams et al, 1977).

E) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Hypoxic-ischemic encephalopathy (seen on serial cranial MRI examinations) with permanent mental regression was reported in a 3-year-old boy following clonidine poisoning in Munchausen by proxy. Prior to this event, the boy had had several lethargic episodes during hospitalizations when the mother was present. Hypothermia, respiratory depression, and arterial hypotension also occurred during some of these episodes (Tessa et al, 2001).

F) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures are rarely observed with clonidine poisoning (Grabert et al, 1979; Williams et al, 1977).
b) CASE REPORT/MOXONIDINE: A 17-year-old patient presented with a severe headache, dry mouth, drowsiness, and hypertension (165/100 mmHg) approximately 4 hours following intentional ingestion of 60 moxonidine 0.2-mg tablets. Two hours postpresentation, the patient experienced a tonic-clonic seizure that was successfully treated with intravenous diazepam; however, another seizure occurred 1 hour later and was treated with intravenous clonazepam. No other seizures were observed, and the patient recovered with normalization of her blood pressure (Magdalan et al, 2008).

Gastrointestinal

3.8.2)

A) DIARRHEA

1) WITH POISONING/EXPOSURE

a) Diarrhea may occur following clonidine overdose in children (Wiley et al, 1990).

Dermatologic

3.14.2)

A) PALE COMPLEXION

1) WITH POISONING/EXPOSURE

a) Pallor has been reported (Lusthof et al, 2000; Fiser et al, 1990; Stein & Volans, 1978).
b) CASE REPORT: Cool extremities and pale skin color were reported in a set of 34-month-old twin girls who ingested a total dose of 10 mg clonidine (Maggi et al, 1986).

B) CONTACT DERMATITIS

1) WITH THERAPEUTIC USE

a) Allergic contact dermatitis develops in 5% to 30% of patients wearing the transdermal patch (Burris, 1987).

C) APPLICATION SITE REACTION

1) WITH THERAPEUTIC USE

a) A pseudolymphoma was reported at the application site of a clonidine patch. Following an intralesional triamcinolone injection, the lesion involuted (Shelley & Shelley, 1997).

Reproductive

3.20.1)

A) Clonidine is classified as US Food and Drug Administration (FDA) pregnancy category C. Clonidine does not appear to produce teratogenic effects in animals. Clonidine is excreted into breast milk.

3.20.2)

A) ANIMAL STUDIES

1) MICE, RATS: No human studies of pregnancy outcomes after exposure to clonidine have been published, and there have been no reports of outcomes after inadvertent exposure during pregnancy. During animal studies, rabbits administered oral doses of clonidine up to 3 times the maximum recommended human dose (MRHD) showed no evidence of teratogenicity or embryotoxicity (Prod Info KAPVAY(R) oral extended-release tablets, 2014; Prod Info Catapres(R) oral tablets, 2012; Prod Info Catapres-TTS(R) transdermal system, 2012).

3.20.3)

A) PREGNANCY CATEGORY

1) Clonidine is classified as US Food and Drug Administration (FDA) pregnancy category C (Prod Info KAPVAY(R) oral extended-release tablets, 2014; Prod Info Catapres-TTS(R) transdermal system, 2012; Prod Info Catapres(R) oral tablets, 2012; Prod Info Duraclon(R) epidural injection solution, 2012)
2) Clonidine should be used during pregnancy only if the need outweighs the potential risk to the fetus (Prod Info KAPVAY(R) oral extended-release tablets, 2014; Prod Info Catapres-TTS(R) transdermal system, 2012; Prod Info Duraclon(R) epidural injection solution, 2012)

B) ANIMAL STUDIES

1) MICE, RATS: During animal studies, rabbits administered oral doses of clonidine up to 3 times the maximum recommended human dose (MRHD) showed no evidence of teratogenicity or embryotoxicity. In rats, administration of clonidine as low as one-third the MRHD for 2 months prior to mating was associated with increased resorption. Increased resorption was not observed in dams treated on gestation days 6 to 15 administered the same or higher doses of clonidine. Clonidine doses approximately 40 times the MRHD in mice and rats treated on gestation days 1 to 14 resulted in increased resorption (Prod Info KAPVAY(R) oral extended-release tablets, 2014; Prod Info Catapres(R) oral tablets, 2012; Prod Info Catapres-TTS(R) transdermal system, 2012; Prod Info Duraclon(R) epidural injection solution, 2012).

3.20.4)

A) BREAST MILK

1) Clonidine is secreted into breast milk. The manufacturer recommends using caution when administering clonidine to breastfeeding women (Prod Info KAPVAY(R) oral extended-release tablets, 2014; Prod Info Catapres(R) oral tablets, 2012; Prod Info Catapres-TTS(R) transdermal system, 2012; Prod Info Duraclon(R) epidural injection solution, 2012). Clonidine may also decrease maternal prolactin secretion (Hell & Wernze, 1988).

3.20.5)

A) ANIMAL STUDIES

1) Fertility was unaffected in male and female rats administered clonidine at doses of 150 mcg/kg. However, at doses of 500 to 2000 mcg/kg, female fertility was adversely affected (Prod Info KAPVAY(R) oral extended-release tablets, 2014; Prod Info Catapres-TTS(R) transdermal system, 2012; Prod Info Duraclon(R) epidural injection solution, 2012)

Summary Of Exposure

A)

B)

C)

D)

E)

1) Confusion, hallucinations, dry mouth, hypotension, nausea, vomiting, constipation, pruritus, contact dermatitis, tinnitus, dizziness, nervousness, and sedation are the most common adverse effects. Atrioventricular block, minor dysrhythmias, Raynaud phenomenon, and congestive heart failure are also reported. Rebound hypertension develops with abrupt withdrawal.

F)

1) MILD TO MODERATE TOXICITY: CNS depression, miosis, heart conduction abnormality, hypertension.
2) SEVERE TOXICITY: Apnea, respiratory depression, coma, bradycardia, hypothermia, hypotension, early transient hypertension.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Mild hypertension may develop early and is usually followed by hypotension. Relative bradycardia is common, although tachycardia may occur. Mild hypothermia and respiratory depression are common in patients with CNS depression.

3.3.2)

A) WITH POISONING/EXPOSURE

1) Apnea, bradypnea, and irregular respiration were noted in 6 of 11 toddlers (54%) managed for clonidine intoxication. Amount ingested ranged from 0.06 to 0.57 mg/kg. (Fiser et al, 1990).
2) Respiratory depression requiring mechanical ventilation was noted in 7 of 81 children (9%) aged 0 to 4 years and 1 of 25 children (4%) aged 5 to 8 years in a prospective series of pediatric clonidine poisoning cases (Spiller et al, 2005).

3.3.3)

A) WITH POISONING/EXPOSURE

1) Hypothermia may occur within 1 hour of the ingestion and may last as long as 48 hours, but it is usually mild and resolves spontaneously within 6 to 8 hours (Romano & Dinh, 2001; Lusthof et al, 2000; Roberge et al, 1996; Fiser et al, 1990; Artman & Boerth, 1983; Hunyor et al, 1975) .
2) Hypothermia occurred in 5 of 11 toddlers (45%) who ingested 0.03 to 0.19 mg/kg in a study (Fiser et al, 1990). Hypothermia occurred in 18 of 80 children (23%) in a retrospective case series (Nichols et al, 1997) and in 4 of 16 children (25%) in another retrospective case series (Kappagoda et al, 1998). However, there were no cases of hypothermia recorded in a recent prospective case series of 113 pediatric clonidine poisonings (Spiller et al, 2005).
3) CASE REPORT: A case of severe hypothermia (core rectal temperature 84 degrees F) resulting in a misdiagnosis of death was reported in a 39-year-old woman after an intentional clonidine overdose. The patient recovered after 3 days of supportive care (Quail & Shannon, 2001).

3.3.4)

A) WITH POISONING/EXPOSURE

1) Hypotension occurs frequently following clonidine ingestion (Fiser et al, 1990; Corneli et al, 1989) . In a prospective study of 113 children with clonidine poisoning, 10 (9%) developed hypotension, defined as systolic blood pressure of less than 80 mmHg (Spiller et al, 2005).
2) Hypertension may initially occur following overdose. It is generally transient and followed by a more profound hypotension (Prod Info clonidine hcl oral tablets, 2006).
3) CASE REPORT: A 2-year-old boy and a 19-month-old girl presented with systolic blood pressures of 140 and 130 mmHg, respectively, on initial examination for clonidine intoxication (Fiser et al, 1990).
4) Hypertension developed in 27 of 80 children (34%) in a retrospective case series of clonidine overdose (Nichols et al, 1997). Hypertension, defined as a systolic blood pressure of greater than 110 mmHg or a diastolic blood pressure of greater than 75 mmHg, developed in 4 out of 81 children (5%) aged 0 to 4 years old with clonidine poisoning (Spiller et al, 2005).

3.3.5)

A) WITH POISONING/EXPOSURE

1) Bradycardia is common. Bradycardia, defined as a heart rate of less than 75 beats/min in children aged 0 to 4 years and less than 60 beats/min in children 5 to 12 years, occurred in 10 of 81 younger children (14%) and 3 of 32 older children (9%) in a prospective study of clonidine poisoning (Spiller et al, 2005). Bradycardia developed in 8 of 11 toddlers (73%) managed for clonidine intoxication (Fiser et al, 1990).
2) Bradycardia developed in 33 of 80 children (41%) in a retrospective case series of clonidine overdose (Nichols et al, 1997).
3) Tachycardia has been reported to occur following an overdose.
4) CASE REPORT: A heart rate of 144 beats/min was noted in a 2-year-old boy who ingested an unknown amount of clonidine and presented with diaphoresis and lethargy with intermittent delirium (Fiser et al, 1990).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) Miotic pupils that may be unresponsive to light are common (Phillips et al, 2015; Ahmad et al, 2015; Fetrow et al, 1994; Grant & Schuman, 1993; Conner & Watanabe, 1979). Miosis was reported in 45% to 56% of pediatric patients who ingested clonidine in several case series (Nichols et al, 1997; Bamshad & Wasserman, 1990; Fiser et al, 1990).

3.4.6)

A) WITH POISONING/EXPOSURE

1) Dry mouth has been reported following clonidine and moxonidine ingestions (Magdalan et al, 2008; Wiley et al, 1990).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Clonidine is not routinely detected by the urine drug screen, and the serum level is not clinically useful.
B) Evaluation of respiratory function with pulse oximetry and cardiac function with ECG and frequent vital signs are important.
C) Most patients with mild symptoms do not require additional testing.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Serum clonidine levels are not readily available at most institutions.

4.1.3)

A) SPECIFIC SUBSTANCE

1) A qualitative urine assay for clonidine by thin layer chromatography is available (Nichols et al, 1997).

4.1.4)

A) OTHER

1) ECG

a) Institute continuous cardiac monitoring and obtain an ECG in all symptomatic patients.

2) OTHER

a) Monitor pulse oximetry or arterial blood gases in patients who are demonstrating CNS depression or decreased respiratory rates.

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients who develop even mild toxic effects after ingestion of sustained release formulations should be admitted to a monitored setting as more severe and prolonged toxicity may develop. Patients with bradycardia, CNS depression, respiratory depression, heart block, and hemodynamic instability or other serious symptoms should be admitted to an intensive care setting.
B) Intensive care monitoring is frequently required in children. Invasive blood pressure monitoring, supplemental oxygen, or artificial ventilation may be required in severe cases (Heidemann & Sarnaik, 1990).

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic children 4 years of age or younger with unintentional ingestions of less than 0.1 mg of clonidine may be observed at home(Spiller et al, 2005). Those ingesting 0.1 mg or more should be referred to a medical facility for activated charcoal and observation (Spiller et al, 2005; Stein & Volans, 1978; Bamshad & Wasserman, 1990).
B) Asymptomatic children aged 5 to 8 years with unintentional ingestions of 0.2 mg or less may be observed at home; those with ingestions of more than 0.2 mg, or with intentional ingestions, should be referred to a medical facility for activated charcoal and observation(Spiller et al, 2005).
C) Asymptomatic children older than 8 years of age with unintentional ingestions of less than 0.4 mg clonidine may be observed at home. Those with ingestions of 0.4 mg or more, or with intentional ingestions, should be referred to a medical facility for activated charcoal and observation(Spiller et al, 2005).
D) Children who are taking clonidine therapeutically, and receive no more than a double therapeutic dose, can be safely managed at home with close follow-up by a poison control center (Matthews & Courtemanche, 1999).

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Eddy and Howell (2003) suggested that all children with a clonidine ingestion above the therapeutic dose (0.002-0.005 mg/kg) should be evaluated by a physician (Eddy & Howell, 2003). However, Spiller et al (2005) recommended direct medical evaluation for all children 4 years and younger with an unintentional clonidine ingestion greater than 0.1 mg, for all children 5 to 8 years old with an ingestion greater than 0.2 mg clonidine, and for all children older than 8 years with an ingestion greater than 0.4 mg clonidine (Spiller et al, 2005). Any symptomatic patient and those with deliberate ingestions should be referred to a medical facility.
B) Most patients who ingest clonidine will manifest symptoms rapidly, typically within 30 to 90 minutes, so a 4-hour observation period is adequate for asymptomatic patients. Patients who ingest a clonidine patch may have delayed onset of symptoms.

1) Toxic effects appeared in one patient (2%, n=47) as late as 4 hours after ingestion in a retrospective study (Wiley et al, 1990).
2) In a prospective case series, involving toxic clonidine ingestions in 113 children, all patients who eventually developed toxicity (hypotension, bradycardia, CNS depression, respiratory depression) were symptomatic within 4 hours of ingestion, suggesting that an observation period of 4 hours post-ingestion may be sufficient to detect severe effects in patients (Spiller et al, 2005).

C) Patients who have not developed evidence of toxicity after 4 hours of observation and adequate decontamination may be discharged after psychiatric evaluation as appropriate.
D) EXTENDED-RELEASE: Following ingestion of extended-release formulations, onset of toxicity is expected to be delayed. Peak plasma concentrations of extended-release formulations are reached at about 7 to 8 hours after therapeutic doses; patients should be observed for the development of toxic effects for at least 9 to 14 hours.

Monitoring

A)

B)

C)

Oral Exposure

6.5.1)

A) Prehospital gastrointestinal decontamination is not recommended because of the potential risk of altered mental status. With dermal exposure, remove clonidine patches and wash exposed skin.

6.5.2)

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).

B) WHOLE BOWEL IRRIGATION

1) Whole bowel irrigation (WBI) has been reported as treatment for a clonidine patch ingestion in a pediatric patient. After 4 hours of WBI the child passed a clonidine patch in the rectal effluent (Henretig et al, 1995).

a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.

1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.

b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.

6.5.3)

A) MONITORING OF PATIENT

1) Clonidine is not routinely detected by the urine drug screen and the serum level is not clinically useful.
2) Evaluation of respiratory function with pulse oximetry and cardiac function with ECG and frequent vital signs are important.
3) Most patients with mild symptoms do not require additional testing.

B) AIRWAY MANAGEMENT

1) Endotracheal intubation and ventilation may be indicated in the presence of apnea, coma, depressed respirations, or hypotonia during the first 24 hours following ingestion of clonidine (Wiley et al, 1990).

C) NALOXONE

1) Naloxone has been reported to reverse effects of clonidine overdose symptoms, however results have been very inconsistent. In a few studies the response rate was approximately 50% (Wang et al, 2014; Bamshad & Wasserman, 1990; Fiser et al, 1990), and in one pediatric case series 84% (n=80) demonstrated no response to naloxone (Nichols et al, 1997).
2) CASE REPORTS

a) Improvement in mental status, respirations, or respiratory drive associated with naloxone administration was noted in 16% of patients in a retrospective study (Wiley et al, 1990).

1) Naloxone administered in doses of 0.01 to 0.25 mg/kg to children following clonidine ingestions ranging from 0.2 to 10.2 mg produced definite improvement in mental status, respirations, or respiratory drive that was temporally associated with naloxone administration in 16% (3/19) of patients.
2) Mental status improved within 90 minutes of naloxone administration in 21% (4/19) of patients.
3) No detectable response occurred in 63% (12/19) of patients administered naloxone.
4) More patients required intubation in the group who received naloxone (26% - 5/19) than patients who received no naloxone (4% - 1/28).
5) Possible differences in severity of intoxication between the naloxone group and control group was not addressed.

b) Three studies (North et al, 1981; Kulig et al, 1982; Bamshad & Wasserman, 1990) have reported clonidine induced apnea and coma responding to naloxone 0.8 to 2 mg in children and adults.
c) Hypotension and bradycardia responded to administration of 2.4 mg in an opiate withdrawal patient who ingested 3 mg of clonidine (Weigel et al, 1988).
d) Administration of 2 mg of naloxone to a comatose woman who had ingested 9 mg of clonidine, resulted in increased pulse and respiratory rate, awakening from coma, and reversal of miosis.

1) An additional 4 mg of naloxone resulted in further improvement, which was maintained by use of a continuous infusion of 0.8 mg/hour (Wedin & Edwards, 1989).

e) Niemann et al (1986) reported on the use of clonidine for hypertensive urgencies, which result in hypotension that was managed successfully with 2 mg naloxone by intravenous bolus (Niemann et al, 1986).

1) A fourth study (Banner et al, 1983) using doses up to 0.1 mg/kg, failed to show reversal of toxic effects.

f) Eight of 11 children with clonidine intoxication received naloxone and only 50% of them had immediate improvement in sensorium (Fiser et al, 1990).

1) Naloxone was given once to as much as 4 times to antagonize 0.02 to 0.57 mg/kg of clonidine. Total doses of naloxone administered ranged from 0.02 to 0.07 mg/kg.
2) Two of the patients became hypotensive after naloxone administration, 1 became hypertensive, 1 became bradycardic, and 3 had further respiratory depression, with 1 requiring intubation and ventilatory support.
3) A six-year-old girl (20.9 kg) who was inadvertently exposed (dermal) to a clonidine patch, was given a total of 2.8 mg of IV naloxone over 15 minutes with no apparent improvement in her mental status (obtunded) (Killian et al, 1997). The patient made a complete recovery with supportive care only.

g) Wasserman (1989) reports an 80% effectiveness with naloxone, but with responses varying from one to all opioid depressive signs and symptoms. The author advocates early use of naloxone and often in large doses, 5 to 10 mg (Wasserman, 1989).

1) Naloxone is most effective at reversing respiratory depression, somewhat helpful at lessening the "paradoxical hypertensive" effect and least effective against hypotension.

h) CASE SERIES: A 6-year retrospective observational case series of pediatric clonidine exposures, reported to a poison center, identified 458 cases of clonidine as a single agent ingestion in pediatric patients less than 12 years of age. The ingested clonidine dose was reported in 315 of the 458 cases with a median dose of 0.2 mg (range 0.05 to 6 mg). Lethargy with bradycardia with or without hypotension was reported in 338 (74%) of the 458 patients. Naloxone was administered to 58 patients (13%). Of the 58 patients who received naloxone, an improvement in blood pressure and/or mental status was reported in 37 (64%) patients (Lewis et al, 2015).
i) CASE REPORT/LACK OF EFFECT: A 2-year-old boy presented to the emergency department with a several hour history of lethargy following a suspected ingestion of clonidine tablets. At presentation, he was hypotensive with depressed respirations and miotic pupils. Neurologic exam indicated hypotonia and an ECG demonstrated first-degree heart block. Over the next hour post-admission, the patient's miosis and CNS depression worsened, necessitating intubation. A trial of naloxone 0.1 mg/kg was intravenously administered of which the patient was unresponsive. A urine toxicology screen, obtained 2 hours post-presentation, indicated high concentrations of clonidine. With supportive therapy, including IV atropine and IV fluids, the patient recovered and was discharged approximately 48 hours later (Ahmad et al, 2015).

3) DOSE

a) ADULT: The most frequently recommended initial naloxone dose for opioid overdose in a consensus of experts (Consensus, 1985) was as follows:

1) 0.4 to 2 mg intravenous bolus in both children and adults. This dose can also be given intralingually in the absence of intravenous access (Maio et al, 1987) or intratracheally.

b) Single doses of up to 24 mg have been given without adverse effect (Evans et al, 1973).

4) NEONATE

a) Small doses (10 to 30 micrograms/kilogram [0.01 to 0.03 milligram/kilogram] intravenously) have been successful in the setting of exposure via maternal administration of narcotics or administration to neonates in therapeutic doses for anesthesia (Wiener et al, 1977; Welles et al, 1984; Fischer & Cook, 1974; Brice et al, 1979).
b) Naloxone may have a longer half-life (3 hours) in neonates (Moreland et al, 1980; Brice et al, 1979); however, the route of administration in these studies (umbilical vein) may have resulted in prolonged absorption and a spuriously prolonged half-life.
c) The American Academy of Pediatrics recommends a neonatal dose of 0.1 milligram/kilogram (100 micrograms/kilogram) intravenously or intratracheally (AAP, 1989).
d) MANUFACTURER RECOMMENDED DOSE - The package insert recommends an initial pediatric dose of 0.01 milligram/kilogram (10 microgram/kilogram) followed by 0.1 milligram/kilogram (100 micrograms/kilogram) if clinical improvement is not optimum.

5) PEDIATRIC

a) The recommended INITIAL DOSE of naloxone in the pediatric patient is 0.01 milligram/kilogram/dose (10 micrograms/kilogram/dose) intravenously and may be repeated at 2 to 3 minute intervals according to desired patient response (Rowe, 1987; Wiley et al, 1990).
b) Rogers (1989) advises the use of ten times the initial dose, 0.1 milligram/kilogram [100 micrograms/kilogram] intravenously, if there is no observed response to the initial dose within 2 to 3 minutes (Rogers, 1989).
c) A continuous naloxone INTRAVENOUS INFUSION has been used to reverse clonidine-induced unconsciousness in a pediatric patient.

1) The recommended initial intravenous infusion rate is 5 micrograms/kilogram/hour, titrated to desired patient response (Cook, 1987; Rogers, 1989).

d) USUAL DOSE: The most frequently recommended initial naloxone dose for opioid overdose in a consensus of experts (Consensus, 1985) was as follows: 0.4 to 2 milligrams intravenous bolus in both children and adults.

1) This dose can also be given intralingually in the absence of intravenous access (Maio et al, 1987) or intratracheally.

e) The American Academy of Pediatrics recommends a dose of 0.1 milligram/kilogram [100 micrograms/kilogram] intravenously or intratracheally for children aged neonates to 5 years (or 20 kilograms). In older children a minimum dose of 2 milligrams is recommended (AAP, 1989).
f) MANUFACTURER RECOMMENDED DOSE - The package insert recommends an initial pediatric dose of 0.01 milligram/kilogram (10 micrograms/kilogram) IV, IM, or SubQ followed by 0.1 milligram/kilogram (100 micrograms/kilogram) if clinical improvement is not optimum (Prod Info NARCAN(R) injection, 2003).
g) WARNING: It has been reported that severe hypertension requiring management with phentolamine has followed the administration of naloxone in several pediatric clonidine overdoses.

1) Caution should be exercised when administering naloxone to the pediatric patient (Gremse et al, 1986).

6) ADVERSE EFFECTS: There have been a few cases of hypertension following administration of naloxone in overdose by clonidine.

a) The relationship between naloxone administration and later development of hypertension is unclear since hypertension of a similar nature and time course has been seen without naloxone administration (Yagupsy & Gorodischer, 1983).
b) Patients should have their blood pressure monitored during administration (Gremse et al, 1986).

7) MECHANISM: Naloxone has been used in an effort to treat clonidine overdose because:

a) Opiate overdose symptoms and clonidine overdose symptoms are similar in many respects.
b) Animal studies show a decrease in hypotensive effects when naloxone is used in a clonidine overdose (Farsang & Kunos, 1979).
c) Withdrawal of either agent may be reversed by the administration of the other (Thoolen et al, 1981).
d) There may be a subset of hyperadrenergic, hypertensive patients in which the antihypertensive effect of clonidine involves a naloxone-reversible inhibition of central sympathetic outflow, probably mediated by the release of an endogenous opioid (Farsang, 1984).

D) 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) NALOXONE

a) Hypotension and bradycardia have responded to naloxone (Weigel et al, 1988).

4) TOLAZOLINE

a) Although tolazoline is reported to reverse bradycardia and hypotension secondary to clonidine (Amery, 1970) the efficacy in treating symptoms of clonidine overdose is not consistent (Prod Info Catapres(R), clonidine hydrochloride, 2001; Anderson et al, 1981).
b) Tolazoline should be reserved for those patients who do not respond to fluids, dopamine, or atropine.
c) Tolazoline can be associated with toxic effects including marked hypertension, cardiac dysrhythmias and tachycardia (Conner & Watanabe, 1979; Mendoza & Medalie, 1979; Schieber & Kaufman, 1981).
d) The cardiovascular response to tolazoline is not always predictable. Tolazoline is given at a dose of 10 milligrams intravenously and repeated every 5 to 10 minutes as needed up to a maximum of 40 milligrams.

E) BRADYCARDIA

1) Bradycardia following clonidine overdosage may not be symptomatic and may not require treatment. Bradycardia and hypotension may respond to atropine alone in patients with heart rates below 60 (Prod Info Catapres(R), clonidine hydrochloride, 2001; Mathew et al, 1981).
2) Atropine produced no effect on respirations or mental status (Wiley et al, 1990).
3) 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).

F) HYPERTENSIVE EPISODE

1) Management of hypertension secondary to clonidine warrants great caution due to the transient nature of the episode. Generally no treatment is necessary. Aggressive therapy with hypotensive agents such as diazoxide may result in profound and prolonged hypotension (Anderson et al, 1981).
2) For life threatening hypertension, nitroprusside or phentolamine are preferred, with nitroglycerin or labetalol as alternatives.

a) SODIUM NITROPRUSSIDE/INDICATIONS

1) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

b) SODIUM NITROPRUSSIDE/DOSE

1) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

c) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION

1) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

d) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

1) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

e) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS

1) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

f) PHENTOLAMINE/INDICATIONS

1) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).

g) PHENTOLAMINE/ADULT DOSE

1) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
2) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).

h) PHENTOLAMINE/PEDIATRIC DOSE

1) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).

i) PHENTOLAMINE/ADVERSE EFFECTS

1) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).

j) CAUTION

1) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).

k) NITROGLYCERIN/INDICATIONS

1) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).

l) NITROGLYCERIN/ADULT DOSE

1) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).

m) NITROGLYCERIN/PEDIATRIC DOSE

1) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

n) CASE REPORT: A 77-year-old woman, who was receiving clonidine intrathecally, via a pump, for treatment of severe low back pain, developed severe hypertension (220/156 mmHg) and cardiogenic pulmonary edema following needle dislocation during the pump refill procedure, inadvertently causing extravasation of the clonidine into a subcutaneous pocket. The dose of clonidine that had leaked was 22 mg (18 mL). The patient recovered without sequelae following supportive therapy, including a continuous nitrates infusion with a maximum rate of 0.2 mg/kg, oral amlodipine, and repeated IV bolus dose of phentolamine 1 mg (Perruchoud et al, 2012).

3) Sublingual nifedipine was used to treat hypertension following a clonidine overdose (Dire & Kuhns, 1988). Blood pressure decreased over 45 minutes, but it is unclear if nifedipine altered the natural course of the paradoxical hypertension.

a) Additionally, the longer duration of action of nifedipine makes it a less favorable choice.

G) VENTRICULAR ARRHYTHMIA

1) Cardiac dysrhythmias should be treated with standard antiarrhythmic drugs, if necessary.

H) SEIZURE

1) Seizures may rarely occur following overdose.
2) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

3) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

4) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

5) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

6) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

7) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

I) EXPERIMENTAL THERAPY

1) YOHIMBINE

a) Yohimbine, a CNS alpha-2 adrenergic antagonist, has been used for treatment of clonidine overdose. Approximately 7 hours after ingestion of 1.5 mg clonidine, a 20-year-old woman with hypotension and sinus bradycardia was given 5.4 mg yohimbine orally, after naloxone and nalmefene were given with no discernible clinical effects. One hour later she was more responsive and alert with an increased blood pressure of 106/52 mmHg and a normal sinus rhythm (Roberge et al, 1996).

1) Drawbacks to using yohimbine may include: lack of access to intravenous form; use in the setting of chronic clonidine dosing, with possible precipitation of withdrawal symptoms; and use of yohimbine during the hypertensive phase of overdose possibly precipitating a hypertensive crisis.

Dermal Exposure

6.9.1)

A) Remove clonidine patches and wash exposed skin.

6.9.2)

A) ACUTE ALLERGIC REACTION

1) Allergic contact dermatitis occurs in 5% to 30% of patients wearing the transdermal patch (Burris, 1987). Transdermal therapy should be discontinued in these patients.

B) SKIN ABSORPTION

1) Bradycardia and hypotension have been reported after ingestion or therapeutic use of clonidine patches in children (Dockstader et al, 1993; Klein, 1991; Kraft, 1998) and in adults (Fetrow et al, 1994). Remove the patch and wash the exposed area thoroughly.

C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

A)

1) Although clonidine has pharmacokinetic characteristics suggesting it is amenable to hemodialysis, there is no clinical experience with its use, and overdose is rarely severe enough to warrant emergent hemodialysis.

Abstracts

Case Reports

A)

1) A case of acute intoxication in a 60-year-old woman who ingested clonidine 20 mg has been reported. The patient showed bradycardia, hypotonia, systemic hypertension, and peripheral vasoconstriction. She was treated with atropine and sodium nitroprusside. There was no recurrence and the patient recovered in 8 days (Marruecos et al, 1983).
2) A 28-year-old man ingested clonidine 100 mg and was initially hypertensive (200/140 mmHg), bradycardic (heart rate 30), and disoriented. The hypertensive phase lasted 24 hours and was followed by a hypotensive phase for 48 hours. Peak serum level was 230 ng/mL. Elimination half-life after the first day was 12.2 hours. The patient recovered (Domino et al, 1986).
3) TOPICAL clonidine (total clonidine content 5 mg) patch therapy for opiate withdrawal was placed on a 33-year-old man during hospitalization. On day 4 the patient chewed and swallowed the patch, leading to intoxication approximately 12 hours later. Acutely, his pulse was 41 beats/min, speech was slurred, and he was disoriented. Atropine and naloxone were administered during transfer to an acute emergency care hospital. At admission, pulse had dropped to 32 beats/min, blood pressure was 110/70 mmHg, and respirations were regular at 16 breaths/min.

a) Supportive care was limited to 4 IM doses of haloperidol for agitation. Heart rate did not exceed 48 beats/min over his 60-hour hospital stay, although he did remain normotensive. Serial clonidine serum levels were drawn; admission levels of 9 ng/mL declined to 1.4 ng/mL at discharge (Raber & Finkelstein, 1993).

B)

1) A girl aged 1 year 9 months ingested a single tablet of clonidine 0.3 mg. She became drowsy and unconscious with bradycardia and severe hypotension. Bradycardia was antagonized promptly by atropine, and blood pressure was corrected by giving IV fluids. The level of consciousness fluctuated for 6 to 8 hours from alertness to unconsciousness. Serum concentrations were only about 2 times higher than adult mean therapeutic values (Neuvonen et al, 1979).
2) A 16-month-old girl ingested 23 clonidine 0.2 mg tablets (0.44 mg/kg). She was lethargic on examination and experienced bradycardia and hypoventilation that progressed to apnea. Atropine IV for 2 doses increased her heart rate and respiratory rate. Blood pressure was 173/116 mmHg with recurrent bradycardia.

a) Tolazoline 10 mg IV was given. Blood pressure fell to 80 mmHg systolic, and normal saline and albumin were given for normalization of blood pressure. Tolazoline was considered by the authors as the drug of choice because of its ability to reverse peripheral and central effects of clonidine. The potential hypotensive effect of tolazoline should be anticipated (Schieber & Kaufman, 1981).

3) A 9-month-old boy became pale and lethargic 1.5 hours after sucking on a Catapres-TTS-2(R) patch which had been worn for 5 days by an adult and then discarded. His blood pressure dropped to 38 mmHg systolic 3.5 hours after exposure, and a dopamine infusion for 6 hours was required to maintain blood pressure. He recovered in 24 hours (Caravati & Bennett, 1988).
4) A 12-month-old was found unarousable in her crib by parents and subsequently brought to the emergency room. The patient was lethargic but arousable, with temperature of 100.1 degrees F, blood pressure 80/40 mmHg, pulse 72 beats/min, respiration 22 breaths/min, and pupils were miotic but reactive.

a) Upon physical exam, a transdermal clonidine patch containing clonidine 2.5 mg was discovered firmly attached to the midportion of her hard palate. Upon removal of the patch and with supportive care, the patient was fully alert 10 hours later. No bradycardia, hypotension, or hypertension were noted during the brief hospitalization (Klein, 1991).

5) A 3.5-year-old, 15-kg, child presented with drowsiness approximately 30 minutes after ingesting 10 to 20 tablets of clonidine 0.2 mg. He became comatose with pinpoint pupils and no response to pain. Temperature was 35.6 degrees C rectally; heart rate, 60 beats/min and regular; blood pressure, 90 mmHg systolic palpatory; respirations, 30 breaths/min, shallow and regular (Pai & Lipsitz, 1976).

a) Administration of atropine sulfate 0.2 mg IV resulted in a prompt increase of heart rate to 120 beats/min; the pupils dilated and the light reflex returned. Repeated doses of atropine were given to keep the heart rate above 100 beats/min. Continuous ECG monitoring showed sinus bradycardia without heart block or arrhythmia. The patient remained hypothermic for 4 hours. Over the next 6 to 8 hours his level of consciousness gradually improved and 36 hours after ingestion, he was totally free from the effects of the drug.

6) A case of clonidine toxicity in a 2.5-year-old girl who ingested an indeterminate number of 0.1-mg tablets orally in a single dose has been reported. The patient developed marked hypotension, drowsiness, pupil constriction, bradycardia, hypothermia, hyporeflexia, and bradypnea. Therapy was initiated with tolazoline 15 mg IV at 15-minute intervals. Addition of fluids and a thermal blanket were used for treatment. The patient was discharged the following day with all symptoms normal except for fluctuating pulse (Mendoza & Medalie, 1979).
7) A 2-year-old girl developed bradycardia (75 beats/min), hypotension (90/50 mmHg), miosis (2 mm), lethargy, and gasping respiration following an exposure to a discarded clonidine-containing transdermal patch. Her condition returned to normal over 16 hours without specific treatment. Clonidine levels at 24 hours postingestion were 30 nmol/L (Corneli et al, 1989).
8) A 3.5-year-old, 15-kg child presented with drowsiness approximately 30 minutes after ingesting 10 to 20 tablets of clonidine 0.2 mg. He became comatose with pinpoint pupils and no response to pain. Temperature was 35.6 degrees C rectally; heart rate was 60 beats/min and regular; blood pressure was 90 mmHg systolic palpatory; and respiration was 30 breaths/min, shallow and regular (Pai & Lipsitz, 1976).

a) Atropine sulfate 0.2 mg IV resulted in a prompt increase of heart rate to 120 beats/min; the pupils dilated and the light reflex returned. Repeated doses of atropine were given to keep the heart rate above 100 beats/min. Continuous ECG monitoring showed sinus bradycardia without heart block or arrhythmia. The patient remained hypothermic for 4 hours. Over the next 6 to 8 hours his level of consciousness gradually improved, and 36 hours after ingestion, he was totally free from the effects of the drug.

Range Of Toxicity

Summary

A)

1) Adults have survived acute ingestions as high as 100 mg. Mild toxicity may occur at just above the therapeutic range.

B)

1) As little as 0.1 mg has produced toxicity in children. Toddlers have developed toxicity after chewing a single used clonidine patch or ingesting small volumes of ophthalmic preparations.

C)

Therapeutic Dose

7.2.1)

A) ROUTE OF ADMINISTRATION

1) TABLET: Initial dose is 0.1 mg twice daily (morning and bedtime). The normal therapeutic range is 0.2 to 0.6 mg/day in divided doses. Maximum therapeutic dose is 2.4 mg/24 hours (Prod Info Catapres(R) oral tablets, 2012).
2) EXTENDED-RELEASE TABLET: The initial dose is 0.1 mg at bedtime. The dose may be titrated to a maximum of 0.4 mg/day; doses should be given twice a day (in the morning and at bedtime) with either an equal or higher dose at bedtime. Because the tablet is extended-release, the dose must be swallowed whole and NOT crushed, cut, or chewed (Prod Info KAPVAY(TM) oral extended-release tablets, 2013).
3) TRANSDERMAL: Apply 1 patch to a hairless area of intact skin on upper arm or chest, once every 7 days. The initial dose delivers 0.1 mg/day (the patch contains 2.5 mg), which may be increased to a maximum of 0.6 mg/day (2 patches of 0.3 mg/day, each containing 7.5 mg) (Prod Info Catapres-TTS(R) transdermal system, 2012).
4) INJECTION: The recommended starting dose of clonidine injection is 30 mcg/hour given as a continuous epidural infusion. The dose may be titrated up or down depending on the clinical response and occurrence of adverse effects. Clinical experience with dosage rates greater than 40 mcg/hour is limited (Prod Info Duraclon(R) epidural injection solution, 2012).
5) CLONIDINE DIVERSION AND ABUSE: Recreational clonidine abuse may be increasing. The intention is to give the user a "blind drunk" effect or to provide a "booster" in conjunction with heroin to make the effects last longer (Anderson et al, 1997; Fetrow et al, 1994).

a) Clonidine 0.3 mg tablet appears to be the preferred dose (Tschirgi, 1990), although patch chewing has also been reported (Fetrow et al, 1994).

7.2.2)

A) DISEASE STATE

1) HYPERTENSION

a) An initial pediatric dose of clonidine 5 to 10 mcg/kg/day (0.005 to 0.01 mg/kg/day) divided in 2 to 3 doses (Rocchini, 1984) up to a maximum of 0.9 mg/day (Rocchini, 1984; Reisman & Selden, 1982) has been reported. Most children will demonstrate an initial response to clonidine 3 to 5 mcg/kg/day (0.003 to 0.005 mg/kg/day). Since clonidine may produce sedation, a larger evening dose and smaller morning dose may diminish the sedation experienced and may be helpful for school-aged children (Pruitt, 1981).
b) ORAL IMMEDIATE-RELEASE TABLETS: According to the manufacturer, safety and effectiveness have not been established in pediatric patients (Prod Info Catapres(R) oral tablets, 2012).
c) TRANSDERMAL PATCH: Safety and effectiveness have not been established in pediatric patients (Prod Info Catapres-TTS(R) transdermal system, 2012).

2) ATTENTION DEFICIT HYPERACTIVITY DISORDER

a) CHILDREN 6 TO 17 YEARS OLD: The initial dose of extended-tablets is 0.1 mg ORALLY at bedtime. The dose may be titrated to a maximum of 0.4 mg/day; doses should be given twice a day (in the morning and at bedtime) with either an equal or higher dose at bedtime. Because the tablet is extended-release, the dose must be swallowed whole and NOT crushed, cut, or chewed (Prod Info KAPVAY(TM) oral extended-release tablets, 2013).

3) SEVERE INTRACTABLE PAIN FROM CANCER UNRESPONSIVE TO EPIDURAL OR SPINAL OPIATES

a) PATIENTS OLD ENOUGH TO TOLERATE PLACEMENT AND MANAGEMENT OF EPIDURAL CATHETER: Recommended starting dose is 0.5 mcg/kg/hour as a continuous epidural infusion and adjusted with caution based on clinical response (Prod Info Duraclon(R) epidural injection solution, 2012).

Minimum Lethal Exposure

A)

1) A 37-year-old man with a history of diabetes, pancreatitis, and longstanding drug abuse was found unconscious after ingesting an unknown number of clonidine hydrochloride tablets at an unknown time (Litovitz et al, 1989).

a) He went into cardiac arrest after gastric lavage was begun, and naloxone 0.4 mg and tolazoline hydrochloride 10 mg were administered.

Maximum Tolerated Exposure

A)

1) As little as 0.1 mg has produced toxic effects in children (Bamshad & Wasserman, 1990; Stein & Volans, 1978).
2) Symptoms have been reported in children following doses of 0.025 to 3 mg (Wedin et al, 1990; Stein & Volans, 1978).
3) In a prospective series, 113 children aged 6 months to 11 years old ingested clonidine; the dose was known in 90 of the poisonings (80%). None of the 61 children (68%) who ingested less than 0.3 mg developed coma, respiratory depression, or hypotension (Spiller et al, 2005).
4) A set of 34-month-old twin girls survived an accidental ingestion of clonidine 10 mg (Maggi et al, 1986).
5) Nine-month-old infants have become floppy, hyporeflexic (Hamblin & Martin, 1987), and hypotensive (Caravati & Bennett, 1988) after putting used 2.5-mg transdermal clonidine patches in their mouths.
6) A 5-year-old child survived the ingestion of approximately 50 mg. The child initially developed hyperventilation and later, bradycardia, hypothermia, miosis, CNS depression, and dry mucous membranes (Romano & Dinh, 2001).
7) A 2-year-old child survived the ingestion of 3.6 mg (Stein & Volans, 1978).
8) A 6-year-old girl developed bradycardia (54 beats/min) and somnolence progressing to obtundation following inadvertent clonidine patch administration. She thought the patch was a "band-aid." Her clinical signs and symptoms improved over 18 hours with supportive care only (Killian et al, 1997).
9) An 11-year-old boy with Tourette syndrome, who was taking clonidine 25 mcg 3 times daily, took an intentional overdose of 168 of the 25-mcg tablets (4.2 mg). He developed a marked decrease in blood pressure within 4 hours that returned to normal after 24 hours. Aggressive and abusive behavior that was unresponsive to midazolam developed. He was given chlorpromazine, fell asleep, and was discharged 24 hours later behaving normally (Whelan & Dearlove, 1995).
10) A 2-year-old child developed lethargy, persistent bradycardia, and several episodes of apnea over 3 hours that required intubation, following ingestion of apraclonidine 5-mL ophthalmic drops (Everson et al, 1999).
11) A 10-year-old boy received clonidine 3 mg in a dosing error. He subsequently developed a blood pressure of 84/30 mmHg and a pulse of 80 beats/min, required fluid resuscitation, and was discharged after 24 hours of observation (Spiller et al, 2005).
12) A 2-year-old girl developed persistent bradycardia and several episodes of intermittent apnea that required mechanical ventilation after she ingested 5 mL of 1% apraclonidine ophthalmic drops (estimated total dose ingested 25 mg). The patient recovered with supportive care (Rangan et al, 2008).
13) CASE SERIES: Three pediatric patients developed extreme somnolence after inadvertently receiving a 100-fold overdose of epidural clonidine (concentration prepared was 200 mcg/mL instead of the prescribed 2 mcg/mL; dose was 200 mcg/kg). During and after surgery, there was no evidence of respiratory depression, and vital signs remained stable. All 3 patients recovered within 24 hours (Meyer & Cambray, 2008).
14) CASE SERIES: A 6-year retrospective observational case series of pediatric clonidine exposures, reported to a poison center, identified 458 cases of clonidine as a single agent ingestion in pediatric patients less than 12 years of age. The ingested clonidine dose was reported in 315 of the 458 cases with a median dose of 0.2 mg (range 0.05 to 6 mg). Lethargy with bradycardia with or without hypotension was reported in 338 (74%) of the 458 patients (Lewis et al, 2015).
15) A 17-year-old girl intentionally ingested 2.4 mg of clonidine and 1500 mg buPROPion. Initially, she developed somnolence, miosis, and bradycardia (heart rate 39 beats/min). Over the next several hours, she was continually monitored and received supportive care. Approximately 23 hours post-ingestion, the patient developed tachycardia (peak heart rate 126 beats/minute), nausea, anxiety, mydriasis, and a generalized tonic-clonic seizure that lasted approximately 3 to 4 minutes. Over the next 8 hours, she continued to be tachycardic, hypertensive, and tremulous. With supportive care, her signs and symptoms resolved approximately 31 hours post-ingestion and, 2 days post-ingestion, she was discharged without sequelae to a psychiatric facility. It is suspected that manifestations of clonidine toxicity initially appeared, masking the toxic effects of buPROPion. Following the clearance of clonidine from the patient, buPROPion toxicity was then unmasked (Phillips et al, 2015).

B)

1) Adults have survived acute ingestions of 16.8 mg, 11.25 mg, and 4.8 mg with alcohol. A 22-year-old who was accidentally administered 18.8 mg developed conduction defects which resolved (Williams et al, 1977).
2) A 28-year-old man accidentally ingested clonidine 100 mg in powdered form; 57 mg was removed by lavage. He developed hypertension followed by hypotension, and he recovered in 4 days (Domino et al, 1986).
3) As much as 8 mg of clonidine solution was added to alcoholic beverages to sedate victims in robbery attempts. One victim developed hypotension, bradycardia, hypothermia, cyanosis, and impaired consciousness; hospitalization and symptomatic treatment resulted in recovery (Lusthof et al, 2000).
4) INJECTION: CLONIDINE: Bradycardia, hypertension followed by hypotension occurred after an inadvertent soft tissue injection during an implantable drug delivery device refill. It was estimated the patient received 18,000 mcg (a 90 day dose) all at once. Her symptoms lasted approximately 3 days. She recovered after being treated with vasopressors and standard care(Johnson et al, 2011)
5) CASE REPORTS: Three patients (a 54-year-old man, a 71-year-old man, and a 77-year-old woman), treated with clonidine intrathecally, via a pump, for severe lower back pain, developed severe hypertension (blood pressure ranging from 192/143 to 220/156 mmHg) following needle dislocation during the refill procedure, inadvertently causing extravasation of the clonidine into a subcutaneous pocket. The dose of clonidine that had leaked ranged from 3 mg to 22 mg. The 77-year-old woman also developed left ventricular failure and pulmonary edema secondary to the severe hypertension. All 3 patients recovered without sequelae following intensive supportive therapy (Perruchoud et al, 2012).
6) MOXONIDINE: A 17-year-old woman experienced a severe headache, dry mouth, drowsiness, hypertension, and tonic-clonic seizures after intentionally ingesting 60 moxonidine 0.2-mg tablets. With supportive care, the patient recovered (Magdalan et al, 2008).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) Across studies, peak plasma concentrations for extended-release clonidine were 50% lower compared with immediate-release. Peak concentrations of extended-release formulations occurred about 5 hours later than immediate-release formulations (Prod Info KAPVAY(TM) oral extended-release tablets, 2013).
2) PEAK CONCENTRATIONS

a) IMMEDIATE RELEASE: ORAL: The mean peak plasma concentration of clonidine hydrochloride following 3 single doses of 0.1 mg (n=15) was 443 picogram (pg)/mL (Prod Info KAPVAY(TM) oral extended-release tablets, 2013).
b) EXTENDED-RELEASE: ORAL: The mean peak plasma concentration of clonidine hydrochloride following 3 single doses of Kapvay (TM) 0.1 mg (n=14) was 258 picogram (pg)/mL (Prod Info KAPVAY(TM) oral extended-release tablets, 2013). The mean peak plasma concentration following single doses of Nexiclon XR (TM) 0.17 mg was 0.49 nanogram (ng)/mL (Prod Info NEXICLON(TM) XR extended-release oral tablets, 2010).
c) TRANSDERMAL: Mean plasma concentrations of 0.39, 0.84, and 1.12 ng/mL were reported for the transdermal system sizes of 3.5, 7, 10.5 cm(2), respectively (MacGregor et al, 1985).

3) TIME TO PEAK CONCENTRATION

a) IMMEDIATE RELEASE: ORAL: Peak plasma levels are reached at about 1 to 3 hours (Prod Info Catapres(R) oral tablets, 2012). Following 3 single doses of immediate-release clonidine hydrochloride 0.1 mg (n=15), the mean time to peak concentration was 2.07 hours (Prod Info KAPVAY(TM) oral extended-release tablets, 2013).
b) EXTENDED-RELEASE: ORAL: Following 3 single doses of Kapvay (TM) 0.1 mg (n=14), the mean time to peak concentration was 6.5 hours (Prod Info KAPVAY(TM) oral extended-release tablets, 2013). The mean time to peak plasma concentration following single doses of Nexiclon XR (TM) 0.17 mg was 7.8 hours (Prod Info NEXICLON(TM) XR extended-release oral tablets, 2010).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORTS

a) ADULT

1) A 28-year-old man took 100 mg; gastric lavage removed 57 mg. The plasma concentration peaked at 230 nanograms/mL (ng/mL) within the first hour. The elimination half-life was 12.2 hours, after the first day (Domino et al, 1986).
2) In a patient who took 4.8 mg and alcohol, the following blood levels were observed at 4, 6, and 8 hours after ingestion: 6, 5.25, and 4.9 ng/mL (Moore & Phillipi, 1976).
3) A 33-year-old man chewed and swallowed a 5-mg topical patch (TTS-2(R)). Approximately 12 hours later, serum level was 9 ng/mL. At discharge, approximately 60 hours later, serum level had fallen to 1.4 ng/mL (Raber & Finkelstein, 1993).
4) An adult man had a plasma clonidine level of 19 mcg/L following ingestion of an unknown quantity of clonidine (estimated as high as 8 mg) (Lusthof et al, 2000).

b) PEDIATRIC

1) In a case series (n=7) of overdoses, initial plasma clonidine levels ranged from 2.05 to 15.69 ng/mL and did not correlate with clinical findings (ingested doses ranged from 0.2 to 0.72 mg/kg) (Wasserman et al, 1992).
2) A 9-month-old infant presented to the hospital with lethargy, bradycardia, and periodic apnea after sucking on a clonidine patch. The infant's serum clonidine level was 11 mg/mL (therapeutic, 0.5 to 4.5 mg/mL). The infant recovered following supportive therapy (Kraft, 1998).
3) Seventeen hours after a 5-year-old child ingested approximately 50 mg of clonidine, a serum concentration of 64 ng/mL was reported (Romano & Dinh, 2001).
4) PLASMA LEVEL CORRELATION TO CLINICAL SIGNS: In one pediatric case series, plasma concentrations of clonidine did NOT relate to clinical findings (Wasserman et al, 1992).

Toxicity Information

7.7.1)

A) LD50- (ORAL)MOUSE:

1) 108 mg/kg (RTECS, 2001)

B) LD50- (ORAL)RAT:

1) 67300 mcg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

A)

1) Other effects of clonidine include alpha agonist and antagonist activity.
2) A direct action on renal adrenergic receptors which inhibit the renin-angiotensin-aldosterone system may also add to the antihypertensive action (DeRoos, 1998). Renal blood flow and glomerular filtration rate remain essentially unchanged.

B)

C)

D)

Toxicologic Mechanism

A)

B)

Physicochemical

Physical Characteristics

A)

Molecular Weight

A)

Animal Toxicology

Clinical Effects

11.1.9)

A) When clonidine 300 mcg was injected into pregnant ewes, maternal and fetal serum glucose increased, uterine blood flow decreased, intra-amniotic pressure increased, and maternal and fetal oxygenation decreased (Eisenach et al, 1988).

1) Maternal and fetal blood pressure were unaffected; heart rate decreased.

Range Of Toxicity

11.3.2)

A) SHEEP

1) A blood level of under 1 nanogram/mL did not produce adverse effects in either fetus or mother when clonidine was given to pregnant ewes (Eisenach et al, 1988).

References

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CLONIDINE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Cardiovascular

Respiratory

Neurologic

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Dermatologic

Reproductive

Summary Of Exposure

Vital Signs

Heent

Monitoring Parameters Levels

Life Support

Patient Disposition

Monitoring

Oral Exposure

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Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

Clinical Effects

Range Of Toxicity

General Bibliography