ORPHENADRINE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Orphenadrine citrate
2) N,N-dimethyl-2-[(2-methylphenyl)phenylmethoxy]ethanamine
3) N,N-dimethyl-2-(o-methyl-alpha-phenylbenzyloxy)ethylamine
4) 2-dimethylaminoethyl 2-methylbenzhydryl ether citrate
5) o-methyldiphenhydramine
6) o-monomethyldiphenhydramine
7) Mephenamine citrate
8) CAS 83-98-7 (orphenadrine)
9) CAS 4682-36-4 (orphenadrine citrate)

Available Forms Sources

1) Orphenadrine is available as 100 mg tablets, 100 mg extended-release tablets, and 30 mg/mL (2 mL ampules each containing 60 mg/ampule of orphenadrine citrate in an aqueous solution in boxes of 6 for IV or IM use) solution for injection (Prod Info NORFLEX IV, IM injection, 2007; Prod Info NORFLEX(TM) extended-release oral tablets, injection, 2006). Orphenadrine (25 mg or 50 mg) is also available in combination with aspirin (385 mg and 770 mg) and caffeine (30 mg or 60 mg) (Prod Info Norgesic(R), orphenadrine, aspirin, caffeine, 2000).

1) Orphenadrine citrate is used as an adjunct with other measures (ie, physical therapy, rest) for the relief of pain associated with acute musculoskeletal conditions (Prod Info NORFLEX IV, IM injection, 2007).
2) Orphenadrine has been used in some countries to treat symptoms of parkinsonism and to alleviate the extrapyramidal syndrome induced by antipsychotics (Saracino et al, 2009).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Orphenadrine citrate is used as an adjunct with other measures (ie, physical therapy, rest) for the relief of pain associated with acute musculoskeletal conditions.
B) PHARMACOLOGY: Orphenadrine is an agent with analgesic and anticholinergic properties. It does not directly relax skeletal muscles in humans.
C) TOXICOLOGY: Anticholinergic effects can develop in overdose. Orphenadrine may also have sodium channel blocking effects similar to the class 1A antiarrhythmics which may be responsible for its proarrhythmic and proconvulsive effects. In some cases, it has been chronically abused for its euphoric effects.
D) EPIDEMIOLOGY: Overdose is rare.
E) WITH THERAPEUTIC USE

1) The following adverse effects may occur following therapeutic use of orphenadrine: dry mouth, lightheadedness, dizziness or syncope, tachycardia, urinary hesitancy or retention, blurred vision, dilatation of pupils, increased ocular tension, weakness, nausea, vomiting, headache, constipation, drowsiness, pruritus, agitation, tremor, and gastric irritation. RARE: Urticaria, dermatoses, hallucinations, anaphylactic reaction (with IM injection).

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Nausea, vomiting, mydriasis, tachycardia, agitation, confusion, hallucinations, urinary retention, and decreased gastrointestinal motility.
2) SEVERE TOXICITY: Hypotension, bradycardia, delirium, ventricular dysrhythmias, respiratory depression, CNS depression, protracted seizures, and hypoglycemia. Metabolic acidosis may develop in patients with dysrhythmias, hypotension, or seizures after an orphenadrine overdose. Renal failure may develop secondary to hypotension or rhabdomyolysis.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Respiratory depression, bradycardia and hypotension may develop following a severe overdose.

0.2.20)

A) Orphenadrine is Pregnancy category C.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive. Sedate patients with benzodiazepines for agitation and delirium. Manage mild hypotension with IV fluids. Mild tachycardia do not require specific treatment.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive. Treat severe hypotension with IV fluids, add dopamine, or norepinephrine if hypotension persists . Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops. If therapy is required, most patients with severe tachycardia respond to sedation with benzodiazepines; a short acting, cardioselective agent such as esmolol may also be used. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Treat hypoglycemia with intravenous dextrose (50 mL of 50% dextrose in adults, 2 to 4 mL/kg of 25% or 10% dextrose in children). Follow blood glucose carefully and repeat as needed. Treat QRS widening or ventricular dysrhythmias with sodium bicarbonate 1 to 2 mEq/kg. Monitor arterial blood gases goal pH 7.45 to 7.55. If dysrhythmias persist follow ACLS protocols. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary. Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
2) HOSPITAL: Late activated charcoal and gastric lavage may be of benefit because of decreased gastrointestinal motility. Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway. Consider gastric lavage in recent, life threatening ingestion, protect airway prior to gastric lavage.

D) AIRWAY MANAGEMENT

1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias, significant CNS and respiratory depression, or severe allergic reactions.

E) ANTIDOTE

1) None

F) VENTRICULAR DYSRHYTHMIAS

1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias, administer 1 to 2 mEq/kg, repeat as needed to maintain blood pH between 7.45 and 7.55. In patients unresponsive to bicarbonate, consider lidocaine.

G) TORSADES DE POINTES

1) Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia. Avoid class Ia (eg, quinidine, disopyramide, procainamide), class IC (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol).

H) HYPERSENSITIVITY REACTION

1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.

I) PHYSOSTIGMINE

1) Use of physostigmine has been associated with reversal of CNS toxicity and ventricular dysrhythmias after orphenadrine. It should be used only with extreme caution, as its use in the setting of severe tricyclic antidepressant overdose (also sodium channel blocking agents) has been associated with abrupt cardiovascular collapse. Anticholinergic effects are likely to recur within 30 to 60 minutes because of its short duration of action. ADULT: 2 mg IV at a slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min if severe symptoms recur. For patients with prolonged anticholinergic delirium consider a continuous infusion, start at 2 mg/hr and titrate to effect. CHILD: 0.02 mg/kg by slow IV injection, at a rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAXIMUM DOSAGE: 2 mg total.

J) ENHANCED ELIMINATION

1) It is unknown if hemodialysis would be effective in overdose.

K) PATIENT DISPOSITION

1) HOME CRITERIA: There is no data to support home management in children; toddlers have developed severe toxicity after ingestion of 300 mg and fatal toxicity after 400 mg. Asymptomatic adults with inadvertent ingestion of an extra dose can be managed at home.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions and symptomatic patients should be sent to a healthcare facility for observation for 6 to 8 hours. Patients that remain asymptomatic can be discharged.
3) ADMISSION CRITERIA: Patients with significant persistent central nervous system toxicity (ie, hallucinations, somnolence, delirium, coma), or persistent tachycardia should be admitted. Patients with evidence of significant CNS (eg, coma, seizures, delirium) or cardiovascular toxicity should be admitted to an intensive care setting.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

L) PITFALLS

1) Physostigmine should generally be used only with extreme caution. While it may reverse anticholinergic effects, they will generally recur within 30 to 45 minutes. In addition, as orphenadrine has cardiotoxic sodium channel blocking effects similar to tricyclic antidepressants, and the use of physostigmine has been associated with abrupt deterioration in the setting of TCA overdose. antidepressant overdose. Anticholinergic toxicity may be prolonged secondary to decreased gastrointestinal motility leading to prolonged absorption.

M) PHARMACOKINETICS

1) Tmax: 2 to 4 hours after ingestion. Metabolism: hepatic. Excretion: approximately 60% of a dose is excreted in the urine in 72 hours. Elimination half-life: 14 hours; 30 to 40 hours after repeated doses.

N) DIFFERENTIAL DIAGNOSIS

1) Anticholinergic poisoning from other substances, sympathomimetic poisoning (should have less mydriasis, usually no visual hallucinations, usually have moist skin), CNS infection, or ethanol/benzodiazepine/barbiturate withdrawal.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Respiratory depression, bradycardia and hypotension may develop following a severe overdose.

3.3.2)

A) WITH POISONING/EXPOSURE

1) RESPIRATORY DEPRESSION develops in severe overdose, usually in association with seizures or ventricular dysrhythmias (Gill & Sowerby, 1975; Bennett & Kohn, 1976; Stoddart et al, 1968; Clarke et al, 1985).

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPERTHERMIA: Mild hyperthermia may develop as an anticholinergic effect (Mendelson, 1975a).
2) HYPOTHERMIA: Mild hypothermia has also been reported (Bozza-Marrubini et al, 1977; Gill & Sowerby, 1975).

3.3.4)

A) WITH POISONING/EXPOSURE

1) HYPOTENSION may develop in severe overdoses (Stoddart et al, 1968; Gill & Sowerby, 1975; Clarke et al, 1985).

3.3.5)

A) WITH POISONING/EXPOSURE

1) TACHYCARDIA is a common anticholinergic effect (Stoddart et al, 1968; Mendelson, 1975a; Bennett & Kohn, 1976; Danze & Langdorf, 1991).
2) BRADYCARDIA has been reported with severe overdose (Gill & Sowerby, 1975; Clarke et al, 1985).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) MYDRIASIS is a common anticholinergic effect (Prod Info NORFLEX IV, IM injection, 2007; Garza et al, 2000; Stoddart et al, 1968; Gill & Sowerby, 1975; Mendelson, 1975a; Bennett & Kohn, 1976).
2) Blurred vision, dilatation of pupils, and increased ocular tension may occur with therapeutic use of orphenadrine (Prod Info NORFLEX IV, IM injection, 2007).

Cardiovascular

3.5.2)

A) TACHYCARDIA

1) WITH THERAPEUTIC USE

a) Tachycardia and palpitations may occur with therapeutic doses of orphenadrine (Prod Info NORFLEX IV, IM injection, 2007).

2) WITH POISONING/EXPOSURE

a) Tachycardia is a common anticholinergic effect (Prod Info NORFLEX IV, IM injection, 2007; Dilaveris et al, 2001; Garza et al, 2000; Stoddart et al, 1968; Mendelson, 1975a; Bennett & Kohn, 1976; Danze & Langdorf, 1991).
b) CASE REPORT: A 3-year-old boy developed agitation and visual hallucinations following ingestion of no more than two 100-mg orphenadrine tablets. An ECG revealed sinus tachycardia with evidence of right bundle branch block (Garza et al, 2000).

B) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension may develop in severe overdoses (Stoddart et al, 1968; Gill & Sowerby, 1975; Clarke et al, 1985).
b) CASE REPORT: A 23-month-old girl developed coma, status epilepticus, hypotension, and acidosis after ingesting 300 milligrams of orphenadrine. She recovered with supportive care (Gill & Sowerby, 1975).
c) CASE REPORT: A 40-year-old man developed seizures, hypotension, severe acidosis, and bradycardia that deteriorated to asystole after ingesting an unknown amount of orphenadrine. Complications included rhabdomyolysis, renal failure, transient hyperphosphatemia and hyperuricemia. He survived with aggressive supportive care (Clarke et al, 1985).
d) CASE REPORT: A 2-year-old developed coma, status epilepticus and hypotension after ingesting 60 orphenadrine (50 milligram) tablets. He was treated with supportive care and hemodialysis. During dialysis he developed ventricular tachycardia which converted with propranolol. He gradually recovered over a period of 5 days (Stoddart et al, 1968).

C) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) Bradycardia has been reported with severe overdose (Gill & Sowerby, 1975; Clarke et al, 1985).
b) CASE REPORT: A 40-year-old man developed seizures, hypotension, severe acidosis, and bradycardia that deteriorated to asystole after ingesting an unknown amount of orphenadrine. Complications included rhabdomyolysis, renal failure, transient hyperphosphatemia and hyperuricemia. He survived with aggressive supportive care (Clarke et al, 1985).

D) TORSADES DE POINTES

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 48-year-old woman developed recurrent polymorphic ventricular tachycardia (torsades de pointes) after ingesting 210 mg of haloperidol and 1400 mg of orphenadrine (Henderson et al, 1991).

E) VENTRICULAR TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT/PEDIATRIC: A 2.5-year-old girl (estimated weight 12 kg) developed ataxia, severe agitation, refractory seizures, and a period of ventricular tachycardia 4 hours after ingestion of 400 mg orphenadrine, which responded to a lidocaine bolus followed by a continuous infusion. Recovery was complete (Van Herreweghe et al, 1999).
b) CASE REPORT/PEDIATRIC: A 3-year-old boy developed recurrent episodes of wide complex tachycardia (rate 180 beats/minute, QRS duration 0.18 seconds) after orphenadrine overdose. After converting to sinus rhythm he had premature ventricular contractions with couplets and triplets (Danze & Langdorf, 1991).
c) CASE REPORT/PEDIATRIC: An 18-month-old child developed hypoglycemia, status epilepticus and ventricular tachycardia after ingesting an unknown quantity of orphenadrine (Bozza-Marrubini et al, 1977).
d) CASE REPORT/PEDIATRIC: A 2-year-old developed coma, status epilepticus, and ventricular tachycardia after ingesting approximately 50 orphenadrine (50 milligrams) tablets. He was treated with supportive care and dialysis and survived neurologically intact (Stoddart et al, 1968).
e) CASE REPORT: Non-sustained ventricular tachycardia developed in a 57-year-old woman after 7 days of treatment with orphenadrine 35 milligrams twice daily for management of musculoskeletal pain. The patient was also taking a daily dose of propafenone 600 mg as maintenance therapy for a history of atrial fibrillation. She initially presented with complaints of frequent palpitations accompanied by dizziness. A 12-lead electrocardiogram revealed sinus rhythm and a maximum QT interval within normal limits (383 milliseconds); however, 24-hour Holter monitoring revealed frequent, brief episodes of atrial tachycardia and non-sustained ventricular tachycardia. Orphenadrine was discontinued, and 1 week later, a follow-up Holter recording showed sinus rhythm without evidence of any dysrhythmia (Dilaveris et al, 2001).

F) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 40-year-old man developed severe bradycardia followed by asystolic cardiac arrest after orphenadrine overdose (Clarke et al, 1985).
b) CASE REPORT: A 6-year-old boy was brought to the hospital in cardiac arrest after orphenadrine overdose. He was successfully resuscitated but sustained anoxic brain injury (Bozza-Marrubini et al, 1977).

Respiratory

3.6.2)

A) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) Respiratory depression may develop in severe overdose, usually in association with seizures or ventricular dysrhythmias (Gill & Sowerby, 1975; Bennett & Kohn, 1976; Stoddart et al, 1968; Clarke et al, 1985).

B) SUFFOCATING

1) WITH POISONING/EXPOSURE

a) Aspiration pneumonitis may develop in patients with CNS depression or seizures and an unprotected airway (Stoddart et al, 1968; Gill & Sowerby, 1975).

C) PULMONARY HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An 18-month-old boy developed pulmonary congestion on x-ray, hypoxia and bloody pulmonary secretions 24 hours after severe orphenadrine overdose (Bozza-Marrubini et al, 1977). Hemorrhagic pulmonary edema was found at autopsy.

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH THERAPEUTIC USE

a) Light-headedness, drowsiness, dizziness or syncope, and weakness may occur with therapeutic use of orphenadrine (Prod Info NORFLEX IV, IM injection, 2007).

2) WITH POISONING/EXPOSURE

a) CNS depression is common. In mild cases weakness and lethargy are reported (Prod Info NORFLEX IV, IM injection, 2007; Pincus & Ike, 1992).
b) Coma may develop in cases with severe toxicity (Stoddart et al, 1968; Gill & Sowerby, 1975; Danze & Langdorf, 1991).
c) CASE REPORT: A 23-month-old girl developed coma, status epilepticus, hypotension, and acidosis after ingesting 300 mg of orphenadrine. She recovered with supportive care (Gill & Sowerby, 1975).
d) CASE REPORT: A 2-year-old developed coma, status epilepticus and hypotension after ingesting 60 orphenadrine (50 mg) tablets. He was treated with supportive care and hemodialysis. During dialysis he developed ventricular tachycardia which converted with propranolol. He gradually recovered over a period of 5 days (Stoddart et al, 1968).
e) CASE REPORT: A schizophrenic patient developed only confusion (Glasgow Coma Scale 15) after ingesting 1000 mg of orphenadrine. Following supportive care, he recovered completely (Saracino et al, 2009).

B) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures and status epilepticus have been reported in children and adults with overdose (Stoddart et al, 1968; Gill & Sowerby, 1975; Clarke et al, 1985; Danze & Langdorf, 1991).
b) CASE REPORT: A 23-month-old girl developed coma, status epilepticus, hypotension, and acidosis after ingesting 300 milligrams of orphenadrine. She recovered with supportive care (Gill & Sowerby, 1975).
c) CASE REPORT: A 2-year-old developed coma, status epilepticus and hypotension after ingesting 60 orphenadrine (50 milligram) tablets. He was treated with supportive care and hemodialysis. During dialysis he developed ventricular tachycardia which converted with propranolol. He gradually recovered over a period of 5 days (Stoddart et al, 1968).
d) CASE REPORT: A 3-year-old boy developed seizures and a wide complex tachycardia believed to be ventricular tachycardia after ingesting an unknown quantity of orphenadrine. His dysrhythmia was resistant to cardioversion and lidocaine but converted to sinus rhythm with physostigmine. He recovered uneventfully with supportive care (Danze & Langdorf, 1991a).
e) CASE REPORT: Seizures refractory to rectal diazepam (0.5 mg/kg), intramuscular clonazepam (0.08 mg/kg), and intravenous phenytoin (100 mg) were reported in a 2.5-year-old 12 kg girl following ingestion of 400 mg orphenadrine. Seizures ceased after endotracheal intubation and intravenous diazepam 10 mg (Van Herreweghe et al, 1999).

C) EUPHORIA

1) WITH THERAPEUTIC USE

a) Orphenadrine has mood elevating effects at therapeutic doses (Prod Info NORFLEX IV, IM injection, 2007; Bassi et al, 1986).

2) WITH POISONING/EXPOSURE

a) It has been chronically abused for its euphoric effects (Prod Info NORFLEX IV, IM injection, 2007; Shariatmadari, 1975; Snyder et al, 1976; Schifano et al, 1988).

D) DYSKINESIA

1) WITH THERAPEUTIC USE

a) Bucco-linguo-masticatory dyskinesias and akathisia have been reported in patients with parkinsonism taking therapeutic doses (Birket-Smith, 1974).

2) WITH POISONING/EXPOSURE

a) Ataxia has been reported in overdose (Pincus & Ike, 1992).
b) CASE REPORT: A 2.5-year-old girl who ingested 400 mg orphenadrine hydrochloride developed ataxia, confusion, and episodes of severe agitation (Van Herreweghe et al, 1999).

E) HEADACHE

1) WITH THERAPEUTIC USE

a) Headache may occur with therapeutic use of orphenadrine (Prod Info NORFLEX IV, IM injection, 2007).

F) PSYCHOMOTOR AGITATION

1) WITH THERAPEUTIC USE

a) Agitation may occur with therapeutic use of orphenadrine (Prod Info NORFLEX IV, IM injection, 2007).

G) TREMOR

1) WITH THERAPEUTIC USE

a) Tremor may occur with therapeutic use of orphenadrine (Prod Info NORFLEX IV, IM injection, 2007).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea, vomiting, and gastric irritation may occur following orphenadrine use (Prod Info NORFLEX IV, IM injection, 2007).

2) WITH POISONING/EXPOSURE

a) Nausea and vomiting may develop in overdose due to anticholinergic effects (Prod Info NORFLEX IV, IM injection, 2007; Stoddart et al, 1968; Bennett & Kohn, 1976).

B) DRUG-INDUCED ILEUS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 16-year-old girl developed abdominal pain and distension as a result of gastric dilatation 3 days after overdose with amitriptyline, orphenadrine and flurazepam (How & Strachan, 1976).

C) CONSTIPATION

1) WITH THERAPEUTIC USE

a) Constipation is a common anticholinergic side effect (Prod Info NORFLEX IV, IM injection, 2007; Bassi et al, 1986).
b) CASE REPORT: A 77-year-old man developed abdominal distension and vomiting associated with a fecal impaction which occurred while taking therapeutic doses of orphenadrine (Daggett & Ibrahim, 1976).

2) WITH POISONING/EXPOSURE

a) Constipation may also occur in overdose (Prod Info NORFLEX IV, IM injection, 2007).

D) APTYALISM

1) WITH THERAPEUTIC USE

a) Dry mouth is an anticholinergic effect that may occur with therapeutic use (Prod Info NORFLEX IV, IM injection, 2007; Gill & Sowerby, 1975; Bennett & Kohn, 1976; Bassi et al, 1986).

2) WITH POISONING/EXPOSURE

a) Dry mouth is an anticholinergic effect that may occur in overdose (Prod Info NORFLEX IV, IM injection, 2007; Gill & Sowerby, 1975; Bennett & Kohn, 1976; Bassi et al, 1986).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An 18-month-old child developed hepatomegaly and elevated transaminase levels (SGOT 290 U/L, SGPT 236 U/L) after severe orphenadrine overdose complicated by ventricular dysrhythmias and status epilepticus. An autopsy demonstrated central and medio-lobular hepatic necrosis (Bozza-Marrubini et al, 1977).

Genitourinary

3.10.2)

A) RETENTION OF URINE

1) WITH THERAPEUTIC USE

a) Urinary retention is an anticholinergic effect that may occur with therapeutic use (Prod Info NORFLEX IV, IM injection, 2007; Bozza-Marrubini et al, 1977; Bassi et al, 1986).

2) WITH POISONING/EXPOSURE

a) Urinary hesitancy and retention are anticholinergic effects that may occur in overdose (Bozza-Marrubini et al, 1977; Bassi et al, 1986).

B) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 40-year-old man with severe orphenadrine toxicity after an overdose developed seizures, cardiac arrest, rhabdomyolysis, and acute renal failure 24 hours after ingestion (Clarke et al, 1985).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis may develop in patients with dysrhythmias, hypotension, or seizures after an orphenadrine overdose (Gill & Sowerby, 1975; Clarke et al, 1985).
b) CASE REPORT: A 23-month-old girl developed coma, status epilepticus, hypotension, and acidosis after ingesting 300 mg of orphenadrine. She recovered with supportive care (Gill & Sowerby, 1975).
c) CASE REPORT: A 40-year-old man developed seizures, hypotension, severe acidosis, and bradycardia that deteriorated to asystole after ingesting an unknown amount of orphenadrine. Complications included rhabdomyolysis, renal failure, transient hyperphosphatemia and hyperuricemia. He survived with aggressive supportive care (Clarke et al, 1985).

Hematologic

3.13.2)

A) BLOOD COAGULATION PATHWAY FINDING

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An 18-month-old child developed a coagulopathy after severe orphenadrine overdose complicated by ventricular dysrhythmias and status epilepticus (Bozza-Marrubini et al, 1977).

Dermatologic

3.14.2)

A) FLUSHING

1) WITH THERAPEUTIC USE

a) Dry flushed skin may develop as an anticholinergic effect at therapeutic doses (Prod Info NORFLEX IV, IM injection, 2007; Bozza-Marrubini et al, 1977; Bassi et al, 1986; Danze & Langdorf, 1991).

2) WITH POISONING/EXPOSURE

a) Dry flushed skin may develop as an anticholinergic effect in overdose (Bozza-Marrubini et al, 1977; Bassi et al, 1986; Danze & Langdorf, 1991).

B) URTICARIA

1) WITH THERAPEUTIC USE

a) Urticaria or other dermatoses may rarely occur following orphenadrine use (Prod Info NORFLEX IV, IM injection, 2007).

C) ITCHING OF SKIN

1) WITH THERAPEUTIC USE

a) Pruritus may occur following orphenadrine use (Prod Info NORFLEX IV, IM injection, 2007).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 40-year-old man with severe orphenadrine overdose complicated by seizures and cardiac arrest developed rhabdomyolysis and acute renal failure (Clarke et al, 1985).

Endocrine

3.16.2)

A) HYPOGLYCEMIA

1) WITH THERAPEUTIC USE

a) Hypoglycemia has been reported in an adult diabetic taking therapeutic doses of chlorpromazine and orphenadrine (Buckle & Guillebaud, 1967).

2) WITH POISONING/EXPOSURE

a) Hypoglycemia has been reported in children after overdoses (Bozza-Marrubini et al, 1977).

Immunologic

3.19.2)

A) ANAPHYLAXIS

1) WITH THERAPEUTIC USE

a) Anaphylactic reaction may rarely occur with orphenadrine IM injection (Prod Info NORFLEX IV, IM injection, 2007).

Reproductive

3.20.1)

A) Orphenadrine is Pregnancy category C.

3.20.3)

A) PREGNANCY CATEGORY

1) Orphenadrine is Pregnancy category C (Prod Info NORFLEX(TM) extended-release oral tablets, injection, 2006).

3.20.4)

A) BREAST MILK

1) There are no data available on the excretion of orphenadrine in human breast milk (Briggs et al, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Obtain an ECG, and institute continuous cardiac monitoring.
B) Monitor vital signs, arterial blood gases, and mental status following significant overdose.
C) Monitor blood glucose, serum electrolytes, renal function, and CPK levels following significant overdose.

Methods

1) In one study, orphenadrine plasma concentrations were obtained using high-pressure liquid chromatography (HPLC) with diode array detection (at 220 nm) and a novel solid-phase extraction procedure. This method had better precision and extraction yields, and lower costs than the reported LC or GC with a mass spectrometry detector (Saracino et al, 2009).
2) Orphenadrine concentrations can be determined in biological fluids by high-pressure liquid chromatography (HPLC-UV), gas liquid chromatography, or liquid chromatography with mass detection (Saracino et al, 2009; Beckett & Khan, 1971; Ellison et al, 1971).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with significant persistent central nervous system toxicity (ie, hallucinations, somnolence, delirium, coma), or persistent tachycardia should be admitted. Patients with evidence of significant CNS (eg, coma, seizures, delirium) or cardiovascular toxicity should be admitted to an intensive care setting.

6.3.1.2) HOME CRITERIA/ORAL

A) There is no data to support home management in children; toddlers have developed severe toxicity after ingestion of 300 mg and fatal toxicity after 400 mg. Asymptomatic adults with inadvertent ingestion of an extra dose can be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate ingestions and symptomatic patients should be sent to a healthcare facility for observation for 6 to 8 hours. Patients that remain asymptomatic can be discharged.

Monitoring

Oral Exposure

6.5.1)

A) Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.

6.5.2)

A) SUMMARY

1) Late activated charcoal and gastric lavage may be of benefit because of decreased gastrointestinal motility. Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway. Consider gastric lavage in recent, life threatening ingestion, protect airway prior to gastric lavage.

B) 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).

C) GASTRIC LAVAGE

1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

3) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

4) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

5) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

6.5.3)

A) MONITORING OF PATIENT

1) Obtain an ECG, and institute continuous cardiac monitoring.
2) Monitor vital signs, arterial blood gases, and mental status following significant overdose.
3) Monitor blood glucose, serum electrolytes, renal function, and CPK levels following significant overdose.

B) VENTRICULAR ARRHYTHMIA

1) SUMMARY

a) Obtain and ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias, administer 1 to 2 mEq/kg, repeat as needed to maintain blood pH between 7.45 and 7.55. In patients unresponsive to bicarbonate, consider lidocaine.

2) CONTRAINDICATIONS

a) Quinidine, disopyramide, and procainamide are contraindicated as their effects on myocardial conduction are similar to that of other sodium blocking drugs.

3) SODIUM BICARBONATE

a) Because orphenadrine has sodium blocking properties (Desaphy et al, 2009; Clark, 1993), dysrhythmias may respond to administration of sodium bicarbonate (Clark, 1993). An initial dose of 1 mEq/kg is appropriate, repeated as needed with careful monitoring of blood pH.

4) LIDOCAINE

a) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

b) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

c) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

C) TORSADES DE POINTES

1) SUMMARY

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

2) MAGNESIUM SULFATE

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

3) OVERDRIVE PACING

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

4) POTASSIUM REPLETION

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

5) ISOPROTERENOL

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

6) OTHER DRUGS

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

7) AVOID

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

D) TACHYCARDIA

1) Most patients respond to sedation with benzodiazepines.
2) TACHYCARDIA SUMMARY

a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
c) ESMOLOL/ADULT LOADING DOSE

1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).

d) ESMOLOL/ADULT MAINTENANCE DOSE

1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).

e) CAUTION

1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).

E) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

F) SEIZURE

1) 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).

2) 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 .

3) 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).

4) 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, 2009; Chin et al, 2008).

5) 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).

6) 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).

G) HYPOGLYCEMIA

1) Correct with intravenous dextrose, 50 mL of 50% dextrose in adults, 2 to 4 milliliters/kilogram of 25% or 10% dextrose in children. Follow blood glucose carefully and repeat as needed.

H) PHYSOSTIGMINE

1) Physostigmine has been used successfully to reverse the CNS toxicity associated with orphenadrine intoxication (Snyder et al, 1976).
2) Physostigmine was used to convert ventricular tachycardia to sinus rhythm in a 3-year-old with an orphenadrine overdose (Danze & Langdorf, 1991).
3) Some authors feel that the decrease in heart rate induced by physostigmine might worsen orphenadrine-induced cardiotoxicity (Sangster et al, 1977a).
4) Physostigmine should be used only with extreme caution, as its use in the setting of severe tricyclic antidepressant overdose (also sodium channel blocking agents) has been associated with abrupt cardiovascular collapse
5) PHYSOSTIGMINE/INDICATIONS

a) Physostigmine is indicated to reverse the CNS effects caused by clinical or toxic dosages of agents capable of producing anticholinergic syndrome; however, long lasting reversal of anticholinergic signs and symptoms is generally not achieved because of the relatively short duration of action of physostigmine (45 to 60 minutes) (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). It is most often used diagnostically to distinguish anticholinergic delirium from other causes of altered mental status (Frascogna, 2007; Shannon, 1998).
b) Physostigmine should not be used in patients with suspected tricyclic antidepressant overdose, or an ECG suggestive of tricyclic antidepressant overdose (eg, QRS widening). In the setting of tricyclic antidepressant overdose, use of physostigmine has precipitated seizures and intractable cardiac arrest (Stewart, 1979; Newton, 1975; Pentel & Peterson, 1980; Frascogna, 2007).

6) DOSE

a) ADULT: BOLUS: 2 mg IV at slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min, if severe symptoms recur (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). INFUSION: For patients with prolonged anticholinergic delirium, a continuous infusion of physostigmine may be considered. Starting dose is 2 mg/hr, titrate to effect (Eyer et al, 2008)
b) CHILD: 0.02 mg/kg by slow IV injection, at a rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAXIMUM DOSAGE: 2 mg total (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
c) AVAILABILITY: Physostigmine salicylate is available in 2 mL ampules, each mL containing 1 mg of physostigmine salicylate in a vehicle containing sodium metabisulfite 0.1%, benzyl alcohol 2%, and water (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).

7) CAUTIONS

a) Relative contraindications to the use of physostigmine are asthma, gangrene, diabetes, cardiovascular disease, intestinal or urogenital tract mechanical obstruction, peripheral vascular disease, cardiac conduction defects, atrioventricular block, and in patients receiving choline esters and depolarizing neuromuscular blocking agents (decamethonium, succinylcholine). It may cause anaphylactic symptoms and life-threatening or less severe asthmatic episodes in patients with sulfite sensitivity (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
b) Too rapid IV administration of physostigmine has resulted in bradycardia, hypersalivation leading to respiratory difficulties, and possible seizures (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).

8) ATROPINE FOR PHYSOSTIGMINE TOXICITY

a) Atropine should be available to reverse life-threatening physostigmine-induced, toxic cholinergic effects (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008; Frascogna, 2007). Atropine may be given at half the dose of previously given physostigmine dose (Daunderer, 1980).

I) RHABDOMYOLYSIS

1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

J) ACUTE ALLERGIC REACTION

1) SUMMARY

a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.

2) BRONCHOSPASM

a) ALBUTEROL

1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

3) CORTICOSTEROIDS

a) Consider systemic corticosteroids in patients with significant bronchospasm.
b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).

4) MILD CASES

a) DIPHENHYDRAMINE

1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).

5) MODERATE CASES

a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).

6) SEVERE CASES

a) EPINEPHRINE

1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).

7) AIRWAY MANAGEMENT

a) OXYGEN: 5 to 10 liters/minute via high flow mask.
b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

8) MONITORING

a) CARDIAC MONITOR: All complicated cases.
b) IV ACCESS: Routine in all complicated cases.

9) HYPOTENSION

a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.

1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).

10) H1 and H2 ANTIHISTAMINES

a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).

1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).

b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).

11) DYSRHYTHMIAS

a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.

12) OTHER THERAPIES

a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

K) EXPERIMENTAL THERAPY

1) TETRAHYDROAMINACRINE: It has been used to reverse orphenadrine-induced hallucinosis (Mendelson, 1975a; Mendelson, 1975b).

Enhanced Elimination

1) It is unknown if hemodialysis would be effective in overdose.

Abstracts

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) ORAL

1) 100 mg orally twice daily (Prod Info orphenadrine citrate oral extended-release tablets, 2012)

B) PARENTERAL

1) One 2 mL vial (60 mg) IV or IM; may repeat every 12 hours (Prod Info orphenadrine citrate intravenous injection, intramuscular injection, 2012).

7.2.2)

A) The safety and efficacy of orphenadrine have not been established in pediatric patients (Prod Info orphenadrine citrate oral extended-release tablets, 2012; Prod Info orphenadrine citrate intravenous injection, intramuscular injection, 2012).

Minimum Lethal Exposure

1) Based on a review of orphenadrine toxicity, the minimum lethal dose was between 2 to 3 grams for adults; however, it appears to be variable and unpredictable (Prod Info NORFLEX IV, IM injection, 2007; Prod Info NORFLEX(TM) extended-release oral tablets, injection, 2006).
2) In a series of 10 fatal cases, the mean amount of orphenadrine ingested by the 6 adults was 22 mg/kg and the mean amount ingested by the 4 children was 72 mg/kg (Bozza-Marrubini et al, 1977).
3) Death has been reported in children ingesting as little as 400 mg of orphenadrine (Garza et al, 2000).

Maximum Tolerated Exposure

1) A schizophrenic patient developed only confusion (Glasgow Coma Scale 15) after ingesting 1000 mg of orphenadrine. Following supportive care, he recovered completely. Orphenadrine blood concentrations were 375 ng/mL and 254 ng/mL 30 hours and 60 hours postingestion, respectively (Saracino et al, 2009).
2) Mild anticholinergic effects have been reported in elderly adults after doses of 400 and 800 mg (Pincus & Ike, 1992).
3) A 24-year-old man developed confusion, tachycardia, mydriasis and decreased pain response after ingesting 5 grams of orphenadrine; he recovered uneventfully (Furlanut et al, 1985).
4) Ingestions of 1000 to 4500 mg have produced typical anticholinergic effects in young adults (Bozza-Marrubini et al, 1977).
5) A 23-month-old child developed seizures, hypotension, respiratory depression, metabolic acidosis, and aspiration pneumonia after ingesting 300 mg. She recovered with supportive care (Gill & Sowerby, 1975).
6) A 62-year-old woman developed hypothermia, hypokalemia, severe dysrhythmias and cardiac arrest after ingesting 3900 mg. She survived with aggressive supportive care (Bozza-Marrubini et al, 1977).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) GENERAL

a) A therapeutic blood level is below 0.2 mg/L (200 ng/mL) (Saracino et al, 2009; Clarke et al, 1985).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) Toxic effects may occur with blood concentrations greater than 500 ng/mL. Concentrations greater than 5000 ng/mL can be lethal (Saracino et al, 2009). However, it can be lower in children. In one case report, an 18-month-old ingested an unknown amount of orphenadrine, and died despite aggressive supportive care. A blood level 30 hours after ingestion revealed an orphenadrine concentration of 4 mcg/mL (4000 ng/mL) (Bozza-Marrubini et al, 1977).
2) Postmortem blood concentrations have ranged from 7 mg/L (7000 ng/mL) to 33 mg/L (33,000 ng/mL) (Clarke et al, 1985).
3) CASE REPORTS

a) A schizophrenic patient developed only confusion (Glasgow Coma Scale 15) after ingesting 1000 mg of orphenadrine. Following supportive care, he recovered completely. Orphenadrine blood concentrations were 375 ng/mL and 254 ng/mL 30 hours and 60 hours postingestion, respectively (Saracino et al, 2009).
b) A 40-year-old man developed seizures, hypotension, severe acidosis, and bradycardia that deteriorated to asystole after ingesting an unknown amount of orphenadrine. Complications included rhabdomyolysis, renal failure, and transient hyperphosphatemia and hyperuricemia. He survived with aggressive supportive care. Orphenadrine concentration in his blood upon presentation was 16.2 mg/mL (Clarke et al, 1985).
c) An 18-month-old child developed coma, status epilepticus, hypoglycemia, ventricular tachycardia, hepatic injury, coagulopathy, and hemorrhagic pulmonary edema after ingesting an unknown amount of orphenadrine. He died despite aggressive supportive care. A blood level 30 hours after ingestion revealed an orphenadrine concentration of 4 mcg/mL (4000 ng/mL) (Bozza-Marrubini et al, 1977).
d) Blood levels in two other children were 12.3 mcg/mL (12,300 ng/mL) and 5.1 mcg/mL (5100 ng/mL) (Gill & Sowerby, 1975).

Pharmacology Toxicology

Pharmacologic Mechanism

General Bibliography

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