Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) 5H-Dibenz(b,f)azepine-5-carboxamide
2) CBZ
3) G-32883
4) Molecular Formula: C15-H12-N2-O
5) CAS 298-46-4

1.2.1) MOLECULAR FORMULA
1) C15H12N2O

Available Forms Sources

A)

1) Carbamazepine is available in a variety of dosage forms, including (Prod Info Tegretol(R)-XR oral extended-release tablets, 2011; Prod Info Tegretol(R) oral chewable tablets, tablets, suspension, 2011):

1) Chewable tablets 100 mg
2) Tablets 200 mg
3) Tablets, extended release 100, 200, 400 mg
4) Capsules, extended release 100, 200, 300 mg
5) Suspension, 100 mg/5 mL

B)

1) Carbamazepine is indicated for the treatment of following conditions: bipolar I disorder (acute manic and mixed episodes), epilepsy (partial, generalized, and mixed types), glossopharyngeal neuralgia, and trigeminal neuralgia (Prod Info Tegretol(R)-XR oral extended-release tablets, 2011; Prod Info Tegretol(R) oral chewable tablets, tablets, suspension, 2011).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Carbamazepine is used as an antiepileptic and for pain disorders and a range of psychiatric diagnoses.
B) PHARMACOLOGY: Carbamazepine and its metabolite decrease repetitive action potential firing in the CNS via sodium channel inactivation.
C) TOXICOLOGY: Toxic effects are due to the drug's anticholinergic activity, sodium channel blockade, CNS depression, and myocardial depressant properties.
D) EPIDEMIOLOGY: Poisoning is common and there are several deaths each year from carbamazepine poisoning.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: Patients may develop hypersensitivity reactions, dystonic reactions, rashes, exacerbation and development of cardiac dysrhythmias, cytopenias, transaminitis, pancreatitis, and the manifestations of mild toxicity with chronic therapy when levels are therapeutic or above the therapeutic range. Adverse reactions are common.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Common initial signs of toxicity are nystagmus, ataxia, hyperreflexia, CNS depression, dystonia, sinus tachycardia, and mild anticholinergic symptoms such as mydriasis, delirium/encephalopathy, and decreased bowel sounds. These symptoms may occur with chronic supratherapeutic serum concentrations or acute overdoses. Patients will commonly experience nausea and vomiting after acute overdose. Less common effects include hepatotoxicity and hyponatremia secondary to syndrome of inappropriate ADH secretion due to vasopressin secretion. These effects are more common with chronic therapy. The onset of symptoms may be delayed 1 to 3 hours following the ingestion of extended release carbamazepine.
2) SEVERE TOXICITY: Manifestations of severe toxicity include coma, seizures, and respiratory depression. Rhabdomyolysis and renal failure may occur rarely following large overdoses. Severe cardiac toxicity generally occurs at doses greater than 60 g and may include decreased myocardial contractility, pulmonary edema, hypotension, dysrhythmias and conduction delays including PR, QRS and QTc prolongation.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Hypothermia may occur following overdose, and hyperthermia may develop as a part of neuroleptic malignant syndrome.

0.2.20)

A) Carbamazepine is classified as FDA pregnancy category D. Craniofacial defects, fingernail hypoplasia, and developmental delays were found in a series of 35 patients whose mothers took only carbamazepine. Human and animal studies indicate that carbamazepine and its epoxide metabolite are found and excreted in breast milk and may affect the nursing child.

0.2.21)

A) At the time of this review, the manufacturer does not report any human carcinogenic potential.

Laboratory Monitoring

A)

B)

C)

D)

E)

F)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment of mild to moderate toxicity is largely supportive. Sinus tachycardia should be treated with fluid resuscitation and benzodiazepines for anticholinergic symptoms. Dystonic reactions can be treated with anticholinergic medications, such as diphenhydramine 25 mg, or benzodiazepines if the patient is also exhibiting signs of anticholinergic toxicity (ie, mydriasis, delirium, flushing, dry mucous membranes, decreased bowel sounds, and urinary retention). Adverse reactions to chronic therapy such as transaminitis or cytopenia should be treated by discontinuation of the medication.

B) MANAGEMENT OF SEVERE TOXICITY

1) MANAGEMENT OF SEVERE TOXICITY: Supportive care is the mainstay of treatment. Specific interventions based on the system of toxicity are as follows:

a) CNS: Mental status depression may require airway protection. Coma should be treated with airway management and supportive care. Seizures should be treated with benzodiazepines as first-line therapy followed by barbiturates or propofol. Agitated patients should be treated with benzodiazepines, large doses may be required.
b) CARDIOVASCULAR: Hypotension should be treated with isotonic fluids. If unresponsive to 2 or more liters of fluid, vasopressor agents, such as norepinephrine or phenylephrine, should be administered. In rare cases, cardiopulmonary bypass or aortic balloon pump may be used to maintain perfusion while carbamazepine is metabolized. QRS widening (progressive widening on serial ECGs or a single ECG with a QRS duration longer than 140 msec) should be treated with sodium bicarbonate boluses of 50 mEq (CHILD: 1 to 2 mEq/kg of sodium bicarbonate) until the QRS narrows. The serum pH should be maintained between 7.4 and 7.55.
c) RESPIRATORY: Intubation and mechanical ventilation should be considered for respiratory depression.
d) GASTROINTESTINAL: Severe nausea and vomiting should be treated with antiemetics, preferably agents without additional anticholinergic activity (eg, ondansetron).
e) RENAL: Urinary retention is due to anticholinergic effects and should be treated with catheterization. Urine output should be maintained above 30 mL/hr because the metabolites are primarily renally cleared. Acute renal failure is due to hypotension or rhabdomyolysis and should be treated with liberal fluid administration.

C) DECONTAMINATION

1) PREHOSPITAL: Because of the risk of CNS depression and subsequent aspiration, prehospital decontamination should generally be avoided.
2) HOSPITAL: Activated charcoal should be considered in asymptomatic patients who are likely to have medication remaining in their GI tract, or in symptomatic patients who have a secure airway. Whole bowel irrigation may be considered for patients with severe toxicity involving ingestion of a large amount of a sustained release formulation. Gastric lavage may be considered for very large overdoses (on the order of 40 g or more) presenting early, though airway protection should be considered prior to the procedure.

D) AIRWAY MANAGEMENT

1) May be necessary for airway protection in cases of prominent CNS depression, seizures or significant respiratory depression.

E) ANTIDOTE

1) There is no specific antidote for carbamazepine toxicity.

F) ENHANCED ELIMINATION

1) MULTIPLE DOSE ACTIVATED CHARCOAL (MDAC) increases clearance of carbamazepine, but it has not been shown to improve clinical outcomes. If MDAC is initiated, 50 g of activated charcoal without sorbitol should be administered every 4 to 6 hours for a total of 24 hours; MDAC should NOT be continued in a patient who develops an ileus.
2) HEMOPERFUSION or HIGH FLUX HEMODIALYSIS may be useful in acutely decreasing serum concentrations in a severe, life-threatening overdose.

G) PATIENT DISPOSITION

1) HOME CRITERIA: All suicide attempts should be referred to a health care facility. Asymptomatic patients with inadvertent ingestion of therapeutic doses may be observed at home.
2) OBSERVATION CRITERIA: Patients with deliberate or large ingestions should be observed for at least 6 to 8 hours (OR 12 to 24 hours if a sustained release formulation is ingested), until serial carbamazepine concentrations have clearly peaked and are declining due to erratic absorption of the drug. Patients who develop significant symptoms should be admitted.
3) ADMISSION CRITERIA: Patients with severe toxicity or those that are not able to ambulate safely should be admitted until symptoms resolve.
4) CONSULT CRITERIA: A toxicologist should be consulted for patients with severe toxicity

H) PITFALLS

1) Failure to observe patients long enough following overdose (observe until at least 2 serum concentrations are declining prior to discharge). Giving activated charcoal to a patient with a large overdose without airway protection may be complicated by seizures or aspiration. Failure to control the airway early in large overdoses may lead to aspiration.

I) PHARMACOKINETICS

1) Carbamazepine is lipid soluble, slowly and unpredictably absorbed and reaches peak plasma concentrations in 4 to 8 hours. It is metabolized primarily by CYP 3A4 yielding an active metabolite, carbamazepine 10,11 epoxide. It is a potent 3A4 inducer leading to lower concentrations of many drugs, including its own. This auto-induction means doses must be adjusted approximately 1 month after initiation of therapy.

J) TOXICOKINETICS

1) Absorption can be prolonged as long as 24 hours after a large overdose or an ingestion of a sustained-release formulation. Toxicity typically resolves within 48 hours; however, large ingestions with prolonged absorption may have a longer course.

K) DIFFERENTIAL DIAGNOSIS

1) Ingestions of other anticholinergic agents may yield similar clinical signs and symptoms. Sympathomimetic toxicity may look clinically indistinguishable from carbamazepine toxicity though the neuromuscular effects such as nystagmus may be more prominent with carbamazepine. Serotonin syndrome may have similar vital sign abnormalities and CNS depression though the hyperreflexia is more pronounced in serotonin syndrome. Other antiepileptic agents (ie, phenytoin or valproic acid) can lead to CNS depression and nystagmus though these agents do not tend to have the cardiovascular toxicity associated with carbamazepine overdose.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) ADVERSE EFFECTS: Patients may develop hypersensitivity reactions, dystonic reactions, rashes, exacerbation and development of cardiac dysrhythmias, cytopenias, transaminitis, pancreatitis, and the manifestations of mild toxicity with chronic therapy when levels are therapeutic or above the therapeutic range. Adverse reactions are common.

F)

1) MILD TO MODERATE TOXICITY: Common initial signs of toxicity are nystagmus, ataxia, hyperreflexia, CNS depression, dystonia, sinus tachycardia, and mild anticholinergic symptoms such as mydriasis, delirium/encephalopathy, and decreased bowel sounds. These symptoms may occur with chronic supratherapeutic serum concentrations or acute overdoses. Patients will commonly experience nausea and vomiting after acute overdose. Less common effects include hepatotoxicity and hyponatremia secondary to syndrome of inappropriate ADH secretion due to vasopressin secretion. These effects are more common with chronic therapy. The onset of symptoms may be delayed 1 to 3 hours following the ingestion of extended release carbamazepine.
2) SEVERE TOXICITY: Manifestations of severe toxicity include coma, seizures, and respiratory depression. Rhabdomyolysis and renal failure may occur rarely following large overdoses. Severe cardiac toxicity generally occurs at doses greater than 60 g and may include decreased myocardial contractility, pulmonary edema, hypotension, dysrhythmias and conduction delays including PR, QRS and QTc prolongation.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Hypothermia may occur following overdose, and hyperthermia may develop as a part of neuroleptic malignant syndrome.

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPOTHERMIA may occur following acute overdose and last up to 10 hours (De Zeeuw et al, 1979; Lehrman & Bauman, 1981; Sullivan et al, 1981; Kulling P, Skoog G & Holmay T et al, 1994).
2) HYPERTHERMIA may develop as a part of the neuroleptic malignant syndrome (NMS) (O'Griofa & Voris, 1991), but is not always present in carbamazepine-induced NMS (Coulter & Corrigan, 1991; Dalkin & Lee, 1990).

a) Temperature of 104.5 degrees F was reported after a massive carbamazepine overdose complicated by status epilepticus (Spiller & Carlisle, 2002).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) MYDRIASIS, unresponsive or sluggish response to light, may develop following acute overdose (De Zeeuw et al, 1979; Low et al, 1996; Vree et al, 1997; Cordova & Lee, 2000; Duzova et al, 2001; De Rubeis & Young, 2001; Fleischman & Chiang, 2001).
2) EXTRAOCULAR MOTION ABNORMALITIES have been reported following overdoses. An 18-month-old child was reported to have nonreactive, 2-mm pupils bilaterally, and positive doll's eye response following an overdose (Schuerer et al, 2000).

a) Nystagmus is common (Sullivan et al, 1981; Soman et al, 1994; Bridge et al, 1994; Stremski et al, 1995). Ophthalmoplegia has been reported (Mullally, 1982; Noda & Umezaki, 1982; Spiller & Durbin, 1991).

1) In a case series of 14 children with mild to moderate intoxications, the most common sign of overdose was nystagmus (8/14 children had nystagmus and drowsiness; 4/14 had nystagmus and ataxia) (Lifshitz et al, 2000).

b) Oculogyric crisis has been reported (Berchou & Rodin, 1979).
c) Complete external ophthalmoplegia was reported in a 45-year-old woman whose blood carbamazepine level was 29 mg/L. After the blood level declined to 5.7 mg/L and below, this sign completely resolved (Ng et al, 1991).

3.4.4)

A) WITH POISONING/EXPOSURE

1) CASE REPORT: Hearing loss was experienced by a 34-year-old woman 6 days following a suicide attempt with carbamazepine 36 g. Along with hearing loss, she had tinnitus and described sounds as distorted. Her symptoms resolved after 2 weeks (de la Cruz & Bance, 1999).

Cardiovascular

3.5.2)

A) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Cardiovascular effects are inconsistent and are usually not clinically significant (Apfelbaum et al, 1995). Effects reported include sinus tachycardia (common), sinus bradycardia, sinus dysrhythmia and prolonged PR, QRS, and QTc intervals (Perez & Wiley, 2005; Sullivan et al, 1981; Kasarskis et al, 1992; Hojer et al, 1993; Bridge et al, 1994; Stremski et al, 1995; Apfelbaum et al, 1995).
b) CASE SERIES

1) A retrospective study (n=12), found no dysrhythmias with acute toxicity in patients with levels less than 40 mcg/m(Larsen & Caravati, 1991) .
2) PEDIATRIC: No cases of clinically significant cardiac dysrhythmias were reported in a retrospective series of 56 pediatric carbamazepine overdoses(Doyon & Zorc, 1999). QRS prolongation was commonly reported in these patients (37.1% of children younger than 6 years old and 33.3% of children 6 to 18 years old).

c) CASE REPORTS

1) Following the deliberate ingestion of 2 bottles of carbamazepine syrup (exact dose unknown), a 9-year-old girl was reported to have a heart rate ranging between 80 to 140 beats per minute with wide QRS complexes and atrial plus ventricular extrasystoles. Hypokalemia developed, and blood pressure dropped to 85/50 mmHg at 5 hours after emergency department admission (Razik & Shahzadi, 1998).
2) Thirteen hours after an acute overdose, a 27-year-old man developed atrial fibrillation, wide-complex tachycardia, and asystole. Resuscitation was unsuccessful (Mordel et al, 1998).
3) An 18-year-old woman experienced cardiac arrest following status epilepticus that was resistant to amobarbital dosing. Resuscitation was initially successful, but seizure activity continued and she experienced a myocardial infarction and ventricular fibrillation leading to asystole. Further resuscitation efforts were unsuccessful (Spiller & Carlisle, 2002).
4) Following a 20-g ingestion, a 56-year-old man initially developed neurological effects followed by cardiac arrest, preceded by several hours of bradycardia, 2.5 days after hospital admission. Resuscitation was successful. First-degree AV block was present continuously for 24 hours after resuscitation (Vree et al, 1997).
5) A 41-year-old woman was found unresponsive by her husband, in the presence of multiple empty medication bottles, including valproic acid and carbamazepine. At the arrival of emergency personnel, the patient was in asystole, but had a return of spontaneous circulation approximately 20 minutes after initiation of resuscitative efforts. At arrival to the emergency department, the patient was tachycardic (97 beats/min) and hypotensive (78/44 mmHg), with a Glasgow Coma Scale score of 3, fixed pupils, and an absence of gag, cough, or corneal reflexes. An ECG revealed incomplete right bundle branch block and a prolonged QTc interval (519 msec). Laboratory data demonstrated metabolic acidosis, elevated serum creatinine, elevated liver enzymes, mild coagulopathy, and serum valproic acid and carbamazepine concentrations of 57.9 mcg/mL (normal 50 to 125 mcg/mL) and 57.8 mcg/mL (normal 4 to 12 mcg/mL), respectively. Supportive treatment and multiple dose activated charcoal was started; however, due to her continued hemodynamic instability and a progressive increase in her carbamazepine levels, continuous venovenous hemofiltration (CVVH) was initiated approximately 15 hours post-presentation. Gradually, the patient's blood pressure stabilized and she was started on conventional hemodialysis with continued intermittent sessions of CVVH. However, an anoxic brain injury had occurred, and the patient died on hospital day 10 (Smollin et al, 2016).

B) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Severe hypotension has been reported following overdose; it is not common, but is indicative of severe poisoning (Smollin et al, 2016; Gary et al, 1981; Tibballs, 1992; Kulling P, Skoog G & Holmay T et al, 1994; Bridge et al, 1994; Razik & Shahzadi, 1998; Mordel et al, 1998; Faisy et al, 2000; Cordova & Lee, 2000; Fleischman & Chiang, 2001; Spiller, 2001). A massive overdose resulted in death due to respiratory and circulatory failure (De Rubeis & Young, 2001).

C) MYOCARDIAL DYSFUNCTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Decreased myocardial contractility, hypotension, and pulmonary edema were reported in 2 children with severe carbamazepine toxicity (Tibballs, 1992).
b) CASE REPORT: Left ventricular failure, diagnosed with the aid of echocardiography, was reported in 2 separate cases of massive carbamazepine overdose in 2 adults with no previous history of cardiac disorders. Global hypokinesis was also reported. Both patients recovered following symptomatic therapy (Faisy et al, 2000).
c) CASE REPORT: A 26-year-old man developed severe cardiogenic shock after overdose with 32 grams slow release carbamazepine and 600 units of insulin. Despite volume expansion, epinephrine and norepinephrine infusions, he had refractory hypotension, oliguria, pulmonary edema, and an ejection fraction of 20%. He was treated with extracorporeal life support for 6 days and survived with recovery of neurologic and cardiac function (Megarbane et al, 2006).

D) MYOCARDITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 13-year-old boy died as a result of a hypersensitivity reaction to carbamazepine. Death was attributed to eosinophilic myocarditis with uncontrollable dysrhythmias. Serum carbamazepine levels were reported to be 9.4 mg/L when signs/symptoms first began (Salzman et al, 1997).

Respiratory

3.6.2)

A) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) Respiratory depression requiring mechanical ventilation may occur (Perez & Wiley, 2005; Drenck & Risbo, 1980; Sullivan et al, 1981; Bridge et al, 1994; Stremski et al, 1995; Low et al, 1996; Wilschut FA et al, 1997; Bertram et al, 1998; Razik & Shahzadi, 1998; Faisy et al, 2000). Acute respiratory distress syndrome (ARDS) has occurred after overdose; it is rare, but has resulted in a fatality (De Rubeis & Young, 2001). Respiratory acidosis has been reported (Razik & Shahzadi, 1998).
b) Apnea has occurred one hour after ingestion and has lasted intermittently for 36 hours (Lehrman & Bauman, 1981).
c) CASE REPORT: Recurrent respiratory failure occurred in a 36-year-old woman following 2 episodes of intentional carbamazepine overdose. The first hospitalization required mechanical ventilation with an open lung biopsy revealing acute interstitial pneumonia. Supportive therapy was given and the patient was discharged on day 19; lung function was within normal limits at 3 months (Wilschut FA et al, 1997).

1) 15 months later during the second hospitalization, the same respiratory symptoms were present which required mechanical ventilation for 10 days; corticosteroids were given. The patient was successfully extubated and discharged; she was lost to follow-up (Wilschut FA et al, 1997).

d) CASE REPORT: A 31-year-old woman, with a history of bipolar disorder, intentionally ingested approximately 10 g of extended-release carbamazepine tablets, and subsequently became unresponsive with hypotension and respiratory failure, necessitating intubation and mechanical ventilation. Despite administration of IV fluids and decontamination with activated charcoal, the patient remained unresponsive, with a carbamazepine level of 26 mg/mL approximately 20 hours post-ingestion. Continuous venovenous hemodiafiltration (CVVHDF) was then started. After 26 hours of CVVHDF, the patient's carbamazepine level decreased to 10 mcg/mL, she regained consciousness and was extubated. Over the next several days, the patient continued to remain stable and was discharged with outpatient psychiatric follow-up (Narayan et al, 2014).

B) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Acute lung injury (pulmonary edema) has been reported in children with severe toxicity (Tibballs, 1992).
b) CASE REPORT: Pulmonary edema developed 48 hours postingestion of an overdose of carbamazepine and nitrazepam in a 23-year-old man (Kitson & Wauchob, 1988).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) Common signs and symptoms include lethargy, slurred speech, and variable degree of coma (Smollin et al, 2016; Bridge et al, 1994; Stremski et al, 1995; Low et al, 1996; Razik & Shahzadi, 1998; Vree et al, 1997; de Antonio et al, 2001; Fleischman & Chiang, 2001; Duzova et al, 2001); cyclic coma may occur, possibly due to delayed absorption (De Zeeuw et al, 1979; Howard et al, 1990; Sullivan et al, 1981; Weaver et al, 1988). Delayed onset of coma may occur following overdose of controlled-release carbamazepine (Graudins et al, 2001).
b) DURATION: The time to complete neurological recovery in 5 children with acute or acute-on-chronic overdose ranged from 9 to 36 hours in 4 children treated with multiple-dose charcoal and 48 hours in one child not treated with charcoal (Wason et al, 1992).
c) CASE REPORTS/CHILD: Approximately 30 minutes after the ingestion of unknown quantities of carbamazepine suspension (100 mg/5 mL, maximum possible dose of 7 g; 350 mL), two toddlers (a 3.5-year-old girl and a 2.5-year-old boy) developed lethargy and difficulty standing. The girl developed coma, tachycardia, and significant respiratory depression that required endotracheal intubation. Approximately 10 hours after arrival, she self-extubated. Neurological exam revealed nystagmus, ataxia, and dysmetria during recovery. The second patient developed lethargy and tachycardia. Neurological exam revealed nystagmus and ataxia without focal abnormalities. Both patients recovered within 24 hours. Initial carbamazepine levels were 36.6 and 22.7 mg/L (therapeutic range 4 to 12 mg/L), respectively (Perez & Wiley, 2005).
d) CASE REPORT/CHILD: A 7-year-old boy with a 2-year history of epilepsy that was treated with carbamazepine presented to the emergency department comatose 6 hours after ingesting ten 200-mg (100 mg/kg) carbamazepine tablets. A neurologic examination revealed a Glasgow Coma Scale score of 6. Twelve hours after hospital admission, he developed seizures. His serum carbamazepine concentration, obtained on hospital day 3, was 25 mcg/mL. With gastric lavage, activated charcoal administration, and supportive care, the patient recovered and was discharged 4 days postadmission (Dogan et al, 2010).
e) CASE REPORT (ADULT): A 31-year-old woman, with a history of bipolar disorder, intentionally ingested approximately 10 g of extended-release carbamazepine tablets, and subsequently became unresponsive with hypotension and respiratory failure, necessitating intubation and mechanical ventilation. Despite administration of IV fluids and decontamination with activated charcoal, the patient remained unresponsive, with a carbamazepine level of 26 mg/mL approximately 20 hours post-ingestion. Continuous venovenous hemodiafiltration (CVVHDF) was then started. After 26 hours of CVVHDF, the patient's carbamazepine level decreased to 10 mcg/mL, she regained consciousness and was extubated. Over the next several days, the patient continued to remain stable and was discharged with outpatient psychiatric follow-up (Narayan et al, 2014).

B) SEIZURE

1) WITH POISONING/EXPOSURE

a) Other clinical effects include ataxia, seizures (Drenck & Risbo, 1980; Sullivan et al, 1981; Weaver et al, 1988; Macnab et al, 1993; Bridge et al, 1994; Stremski et al, 1995; Mordel et al, 1998; Spiller & Carlisle, 2002), myoclonus (Dhuna et al, 1991), decreased or increased deep tendon reflexes, dyskinesias (Drenck & Risbo, 1980; Lehrman & Bauman, 1981; Vree et al, 1997), nystagmus, and opisthotonus (Lehrman & Bauman, 1981; Razik & Shahzadi, 1998).

1) Seizures occur particularly in small children following overdose (Prod Info Tegretol(R)-XR, carbamazepine, 2000), but may occur in adults following massive overdose (De Rubeis & Young, 2001).

b) CASE REPORTS: Status epilepticus resistant to conventional therapy was reported in two patients, one with a history of seizure disorder and the other with a history of bipolar disorder, following suicidal ingestions. Amobarbital infusions were unsuccessful in the first patient; diazepam, phenytoin, and phenobarbital were unsuccessful in the second patient (Spiller & Carlisle, 2002).
c) Although mostly reported in patients with underlying seizure disorders (Spiller et al, 1990a), seizures have been reported in patients with no history of epilepsy (Kossoy & Weir, 1985; Deng et al, 1986; Low et al, 1996; Bertram et al, 1998).
d) CASE REPORT: Episodes of grand mal seizures and myoclonic jerks were reported in a 36-year-old man with no history of seizure disorder and no chronic medications following a suicide attempt with CBZ (Low et al, 1996).

C) DYSKINESIA

1) WITH POISONING/EXPOSURE

a) Movement disorders have been reported following overdosage (Bimpong-Buta & Froescher, 1982; Lehrman & Bauman, 1981; Drenck & Risbo, 1980; O'Neal et al, 1984).
b) Choreoathetoid movements were described 14 to 18 hours after massive acute overdose (13.2 g, 20 g, unknown) in 3 patients (Weaver et al, 1988). Chorea occurred 6 hours after ingestion of 10 grams (Drenck & Risbo, 1980) and 45 minutes postingestion after 200 mg/kg (Lehrman & Bauman, 1981).
c) Orofacial dyskinesias have also been described (Joyce & Gunderson, 1980).

D) DYSTONIA

1) WITH POISONING/EXPOSURE

a) Dystonic reactions with opisthotonic posturing have been reported in patients with chronic and acute carbamazepine toxicity (Bradbury et al, 1982; Crosley & Swender, 1979; Jacome, 1979; Soman et al, 1994; Stremski et al, 1995).
b) CASE SERIES: In a series of 3 case reports in children the onset was 2 to 3 weeks after therapy initiation at doses gradually increased to 20 to 25 mg/kg/day (Crosley & Swender, 1979).
c) CASE REPORT: Segmental dystonia, with sudden onset of blepharospasm, retrocollis, anterocollis, and oromandibular dystonia, was reported in a 48-year-old woman who had been stabilized on olanzapine (10 mg/day) and carbamazepine (600 mg/day). She admitted to a suicidal ingestion of 8 g carbamazepine; 2 months later she ingested 16 g carbamazepine with similar symptoms. The dystonia resolved within 1 week both times (Stryjer et al, 2002).

E) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) CASE REPORTS

1) Acute encephalopathy following ingestion of 5.8 g of carbamazepine in a 16-year-old boy was reported (Saloman & Pippenger, 1975). The possibility of overdosage should be considered when symptoms of encephalopathy are present in a patient receiving carbamazepine.
2) A case of encephalomyelopathy has been reported in a 66-year-old taking up to 800 mg per day (Smith, 1991). Peak levels were 2.6 micrograms per mL. The patient was also taking phenytoin.
3) Encephalopathy and brain stem dysfunction were seen in a 6-month-old girl on carbamazepine. Level on admission was 26 mcg/mL, dropping to 10 mcg/mL 36 hours later (Kalaawi et al, 1991).

F) AGGRESSIVE BEHAVIOR

1) WITH POISONING/EXPOSURE

a) Irritability, combativeness, and hallucinations have been reported after acute massive overdose during emergence from coma (Weaver et al, 1988).

G) ATAXIA

1) WITH POISONING/EXPOSURE

a) Progressive ataxia, resulting in difficulty in walking, is common following carbamazepine toxicity (Garcia et al, 2000; Burman & Orr, 2000; de Antonio et al, 2001). Ataxia generally improves as carbamazepine serum concentrations drop.
b) CASE REPORT: Nystagmus, gait ataxia, and asterixis were described in a 66-year-old woman receiving 1200 mg/day (serum level 9.7 mcg/mL) (Chadwick et al, 1976). Asterixis was described in a 45-year-old woman whose blood carbamazepine level was 29 mg/L (Ng et al, 1991).

H) ELECTROENCEPHALOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) Massive overdose may result in reversible encephalopathy with cortical hyperexcitability, a profound burst-suppression EEG pattern (with bursts containing abundant epileptiform activity), and cranial nerve areflexia (De Rubeis & Young, 2001).
b) CASE REPORTS

1) A comatose woman with a plasma carbamazepine level of 27 micrograms/mL showed diffuse theta activity on EEG (Weaver et al, 1988).
2) A 16-year-old girl with a level of 51 micrograms/mL had occipital delta activity which resolved after 48 hours (Howard et al, 1990).
3) Following an overdose on day 1, status epilepticus occurred in a 41-year-old non-epileptic woman. EEG showed generalized seizures lasting 10 to 20 seconds each, with intermittent periods where the EEG was flat and featureless (Cordova & Lee, 2000).
4) A 33-year-old woman was found in deep coma following ingestion of an unknown quantity of carbamazepine. Electrical silence with intermittent bursts of epileptic activity was revealed on EEG. Carbamazepine serum level was reported to be 81 mcg/mL. The patient's neurological status improved over the following 2 weeks as serum carbamazepine levels declined (Bertram et al, 1998).

I) NEUROLEPTIC MALIGNANT SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORTS

1) Neuroleptic malignant syndrome (NMS) was reported in a 57-year-old taking 600 mg/day. This syndrome is characterized by hyperthermia, elevated serum creatine kinase, leukocytosis, rigidity, pallor, diaphoresis, tachycardia, stupor, confusion, mutism, tachypnea, incontinence, and coma (O'Griofa & Voris, 1991).
2) A case of NMS demonstrating rigidity, autonomic instability, and coma after an overdose of trifluoperazine and carbamazepine (amount unknown) was reported (Dalkin & Lee, 1990).

J) OPHTHALMOPLEGIA

1) WITH THERAPEUTIC USE

a) CASE REPORT/DRUG INTERACTION: A 47-year-old woman with bipolar disorder who had been taking carbamazepine (1600 mg daily) for years underwent cardiac surgery. She was restarted on carbamazepine 800 mg on postoperative day 1, along with diltiazem 120 mg/day for sinus tachycardia. By day 2, the patient had developed confusion, agitation, and slurred speech. She also had complete volitional and reflex ophthalmoplegia in all directions; pupils measured 7 mm and constricted normally. Serum carbamazepine level was 26.2 mcg/mL (normal 3 to 12 mcg/mL), and the carbamazepine was stopped. All symptoms cleared by postoperative day 3 (Wijdicks et al, 2004).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Ophthalmoplegia following ingestion of 1.8 to 2 g of carbamazepine over an 8-hour period (producing blood concentrations of 20 mcg/mL (85 mcmol/L)) has been reported in one patient. Eye movements returned to normal with decrease of carbamazepine levels to 2 mcg/mL (8.5 mcmol/L) (Ng et al, 1991).

Gastrointestinal

3.8.2)

A) DRUG-INDUCED ILEUS

1) WITH POISONING/EXPOSURE

a) Decreased gastrointestinal motility may commonly occur following massive overdose (Sullivan et al, 1981; Deshpande et al, 1999; Spiller, 2001; Graudins et al, 2001) and result in cyclic coma. Treatment with repeat charcoal hemoperfusion, until hypomotility is resolved, has been successful (Deshpande et al, 1999).

B) VOMITING

1) WITH POISONING/EXPOSURE

a) Spontaneous emesis is common (Perez & Wiley, 2005; Howard et al, 1990; Stremski et al, 1995).

C) PANCREATITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Chemical pancreatitis (serum amylase 291 units/L, lipase 1379 units/L without accompanying pain or abnormalities on ultrasound) developed in a 5-year-old boy with acute carbamazepine toxicity (Tsao & Wright, 1993).

Hepatic

3.9.2)

A) TOXIC HEPATITIS

1) WITH THERAPEUTIC USE

a) No clinical effects following acute overdose. Hepatitis has been reported during chronic therapy (Pellock, 1987; Pirmohamed et al, 1992; Morales-Diaz et al, 1999). Withdrawal of carbamazepine may be associated with improvement of symptoms. Hepatorenal failure in a child receiving chronic carbamazepine therapy has been reported. Liver and kidney function returned to normal after discontinuing the drug (Haase, 1999).

B) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) Elevations in liver enzymes, mainly GGT and alkaline phosphatase, have been reported after overdose (Seymour, 1993). LDH elevations have also occurred following overdose (Wilschut FA et al, 1997).

C) HYPERAMMONEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Hyperammonemia was reported in 2 children who overdosed. Patient 1 had a venous ammonia concentration of 74 mcg/dL (normal 0 to 70 mcg/dL), and patient 2 had a level of 89 mcg/dL. No other evidence of hepatotoxicity was seen (Cruz & Marcadis, 1991).
b) Other cases have not shown elevated blood ammonia levels (Spiller & Durbin, 1991).

Genitourinary

3.10.2)

A) OLIGURIA

1) WITH POISONING/EXPOSURE

a) Renal failure and oliguria have been reported following overdose (Prod Info Tegretol(R)-XR, carbamazepine, 2000).
b) CASE REPORT: Oliguria developed in a 50-year-old man following the ingestion of carbamazepine 20 g (Leslie et al, 1983). Tubulo-interstitial nephritis has been reported during chronic therapy.

B) RETENTION OF URINE

1) WITH POISONING/EXPOSURE

a) Urinary retention may occur as an anticholinergic effect (Hojer et al, 1993; Prod Info Tegretol(R)-XR, carbamazepine, 2000).

C) RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORTS: Nonoliguric renal failure was reported in a 33-year-old woman who developed rhabdomyolysis after carbamazepine overdose. The patient recovered following 2 weeks of therapy (Bertram et al, 1998). In another case, a 25-year-old woman developed acute renal failure and rhabdomyolysis following a 24-g overdose (Faisy et al, 2000).
b) CASE REPORT: Two days following an overdose of approximately 20 g, prerenal oliguric renal failure was reported in a 56-year-old man. The patient recovered following extensive charcoal hemoperfusion and hemodialysis (Vree et al, 1997).
c) CHRONIC THERAPY in a child has been associated with hepatorenal failure. Liver and kidney function returned to normal within 2 weeks after discontinuing carbamazepine (Haase, 1999).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis may occur following an acute overdose (Smollin et al, 2016; Faisy et al, 2000; Cordova & Lee, 2000).

Hematologic

3.13.2)

A) PANCYTOPENIA

1) WITH THERAPEUTIC USE

a) Neutropenia (75 to 100 cases over 12 years), agranulocytosis (10 cases over 12 years), pancytopenia (8 cases over 12 years), thrombocytopenia (31 cases over 12 years), and aplastic anemia (27 cases over 12 years) have been reported during chronic therapy (Pellock, 1987; Tohen et al, 1995). Two geriatric patients developed concomitant rashes and leukopenia and thrombocytopenia, associated with carbamazepine therapy (Cates & Powers, 1998).

B) LEUKOCYTOSIS

1) WITH POISONING/EXPOSURE

a) Isolated incidences of leukocytosis have been reported following overdose (Prod Info Tegretol(R)-XR, carbamazepine, 2000).
b) CASE REPORT: Leukocytosis was noted in 2 patients who overdosed on carbamazepine (Cruz & Marcadis, 1991).

C) LEUKOPENIA

1) WITH POISONING/EXPOSURE

a) Isolated incidences of reduced leukocyte count have been reported after overdose (Prod Info Tegretol(R)-XR, carbamazepine, 2000).

D) HEMATOLOGY FINDING

1) WITH THERAPEUTIC USE

a) Blackburn et al (1998) reported results of a cohort study investigating frequency of serious blood dyscrasias in patients taking anticonvulsants (Blackburn et al, 1998). The total overall rate for all patients was 3 to 4 per 100,000 prescriptions. The rates did not differ between phenytoin, phenobarbital, carbamazepine, or valproate throughout all age groups.

Dermatologic

3.14.2)

A) BULLOUS ERUPTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Subepidermal bulla formation resembling a barbiturate-induced bullous eruption was reported in a 68-year-old woman following the ingestion of approximately 40 carbamazepine tablets (Godden & McPhie, 1983).

B) PHOTOSENSITIVITY

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 36-year-old woman receiving chronic carbamazepine therapy experienced facial erythema and edema after using a photocopier for 2 hours. Superficial corneal burns were present one month later (Ward, 1987).

C) LICHENOID DERMATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 75-year-old man developed a lichenoid reaction (biopsy specimens confirmed lichen planus) within 2 weeks of initiation of carbamazepine therapy. The rash resolved 7 days after discontinuation of the drug. On rechallenge with carbamazepine, the lichenoid rash reappeared (Thompson & Skaehill, 1994).

D) ERUPTION

1) WITH THERAPEUTIC USE

a) Concomitant rashes and blood dyscrasias have been reported associated with carbamazepine therapy (Cates & Powers, 1998).

E) STEVENS-JOHNSON SYNDROME

1) WITH THERAPEUTIC USE

a) Short-term therapy with carbamazepine has been associated with Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in a case-control study and appears to be a risk factor. Twenty-one cases were reported with either SJS or TEN following a range of therapy of 2 to 4 weeks. The risk is largely confined to the start of carbamazepine therapy (Rzany et al, 1999).
b) In a retrospective study (7-year study period), 22 patients taking anticonvulsants developed SJS or TEN. Eighteen patients (81%) were taking carbamazepine and greater than 50% of these patients were taking carbamazepine for pain (11/18). Patients with a serious underlying systemic disease before the onset of SJS or TEN had a poor prognosis (Devi et al, 2005).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Mild elevations of CPK have been reported, most likely secondary to seizures or prolonged immobility (Seymour, 1993; Faisy et al, 2000).
b) CASE REPORT: Severe rhabdomyolysis with elevated creatine kinase levels was reported in a 33-year-old woman following ingestion of an unknown quantity of carbamazepine. Nonoliguric renal failure resulted from the rhabdomyolysis. The patient recovered after 2 weeks of therapy (Bertram et al, 1998).

Endocrine

3.16.2)

A) DISORDER OF ENDOCRINE SYSTEM

1) WITH THERAPEUTIC USE

a) ANDROGEN: Therapeutic doses of carbamazepine in men appears to decrease the bioactivity of androgens, thus possibly affecting reproduction. In a study of 40 men taking carbamazepine, mean serum levels of dehydroepiandrosterone sulfate were low and serum concentrations of sex hormone-binding globulin were high, as compared to controls not taking carbamazepine. These effects did not appear to be dose-dependent (Rattya et al, 2001).

Immunologic

3.19.2)

A) CELL-MEDIATED IMMUNE REACTION

1) WITH THERAPEUTIC USE

a) Aromatic anticonvulsants, such as carbamazepine, have been reported to cause an unusual idiosyncratic reaction of antiepileptic hypersensitivity syndrome in some patients. Signs/symptoms may include fever, rash, lymphadenopathy, eosinophilia, lymphocytosis, elevated ESR, coagulopathy and hepatotoxicity. If unrecognized and untreated, this syndrome can be fatal (Bessmertny et al, 2001).
b) CASE REPORT: A 13-year-old boy died as a result of eosinophilic myocarditis after starting carbamazepine therapy, 800 mg/day. At the time symptoms were first noted, a serum level of 9.4 mg/L was reported. WBC was reported to be 20,400 per cubic millimeter, with 29% eosinophils. Other symptoms included uncontrollable dysrhythmias, fever, papular-miliary rash, conjunctivitis and elevated CPK (7880 U/L) (Salzman et al, 1997).
c) CASE REPORT: A multisystemic hypersensitivity reaction after 50 days of chronic carbamazepine therapy is described in an 81-year-old man. His reaction was characterized by generalized erythroderma and renal, hepatic and bone marrow failure (dyserythropoietic anemia) (Lombardi et al, 1999). A positive provocative test implicated carbamazepine as the causative factor.

B) DRUG-INDUCED LUPUS ERYTHEMATOSUS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 45-year-old man developed carbamazepine-induced systemic lupus erythematosus syndrome presenting as cardiac tamponade after 8 months of therapy (Verma et al, 2000). Blood serologic studies revealed a positive ANA reaction. Pericardicenteses was performed with immediate relief and carbamazepine was discontinued. The patient fully recovered.

Reproductive

3.20.1)

A) Carbamazepine is classified as FDA pregnancy category D. Craniofacial defects, fingernail hypoplasia, and developmental delays were found in a series of 35 patients whose mothers took only carbamazepine. Human and animal studies indicate that carbamazepine and its epoxide metabolite are found and excreted in breast milk and may affect the nursing child.

3.20.2)

A) CONGENITAL ANOMALY

1) Epidemiological data suggest that an association may exist between the use of carbamazepine in pregnant women and congenital malformations, including spina bifida. A higher prevalence of teratogenic effects has been associated with combination anticonvulsant therapy compared with monotherapy in retrospective case reviews (Prod Info CARBATROL(R) oral extended-release capsules, 2013). Developmental disorders, including developmental delays, and congenital anomalies (eg, craniofacial defects, cardiovascular malformations, hypospadias, anomalies involving various body systems) have also been reported following carbamazepine use during pregnancy (Prod Info Tegretol(R)-XR oral extended-release tablets, 2014; Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014).
2) A case report describes carbamazepine syndrome with right hemihypoplasia of the entire body in an infant exposed to carbamazepine. The mother of the infant became pregnant while taking carbamazepine monotherapy 300 mg for treatment of epilepsy. She also used folic acid 5 mg/day before and during the pregnancy. At 22-weeks gestation, a fetal ultrasonography showed oligohydramnios and left hydronephrosis. A vesicoamniotic shunt was immediately inserted. At week 36, premature rupture of the membranes occurred and the baby was born via vaginal delivery. The infant was admitted to the neonatal intensive care unit due to respiratory insufficiency and multiple anomalies. Physical examination showed facial dysmorphism, bilateral pes equinovarus, oligodactyly and ectrodactyly of the right hand, bilateral hypoplastic nails, and right hemihypoplasia of the entire body was observed. In addition, ambiguous genitalia (clitoromegaly and labial fusion), high type anal atresia without fistula, and skeletal abnormalities including short neck and vertebral scoliosis were observed. At postnatal day 3, the infant underwent surgery for anal atresia and the vesicoamniotic cannula was removed while a vesicostomy was created. A divergent type colostomy was also performed. Blood urea and creatinine levels increased gradually and the patient was given supportive treatment for renal failure. The patient was discharged to a multidisciplinary hospital for urogenital system evaluation and anoplasty on postnatal day 62. The patient died on postnatal day 80 despite his treatment (Akar et al, 2012).
3) A possible risk of birth defects with the folic acid antagonist, carbamazepine, has been found when used during the first trimester of pregnancy (Hernandez-Diaz et al, 2000). Increased risk of neural-tube defects, cardiovascular defects, and urinary tract defects have been reported. Cases of hypoplasia of the nose, anal atresia, meningomyelocele, ambiguous genitalia, congenital heart disease, hypertelorism, cleft lip, hypoplasia of the nails, congenital hip dislocation, spina bifida, and inguinal hernia have also been reported (Iqbal et al, 2001).
4) A negative relationship between serum folate and serum carbamazepine concentrations has been found, suggesting that folate deficiency may play a role in carbamazepine teratogenesis (Lewis et al, 1998).
5) A pattern of teratogenicity which consists of craniofacial defects (11%), fingernail hypoplasia (26%), and developmental delay (20%) in a series of 35 patients whose mothers took only carbamazepine has been reported (Jones et al, 1989).
6) There is a substantially increased risk of teratogenicity in pregnant women using phenytoin, carbamazepine or other prodrugs, and combinations of other anticonvulsants. The teratogenicity of these drugs is largely related to the levels of the reactive epoxide metabolites (Finnell et al, 1992; Van Dyke et al, 1991; Buehler et al, 1990). The epoxide/parent drug ratio is generally increased when phenytoin or carbamazepine is combined with each other, with any other drugs that induce cytochrome P450 enzymes (3A4, 2C9, 2C19), or drugs which inhibit epoxide hydrolase, such as valproic acid, progabide, and lamotrigine. Such combinations increase the risk of major birth defects 3- to 4-fold over monotherapy and about 10-fold over background rates (Spina et al, 1996; Ramsay et al, 1990; Bianchetti et al, 1987).
7) In a large retrospective cohort study (n=1411), an increased risk of major congenital abnormalities was observed in the offspring of women treated with carbamazepine (relative risk (RR) 2.6) or valproate (RR 4.1) monotherapy during the first trimester of pregnancy. Risk was unaffected by the type of seizure disorder, but in the case of valproate and phenobarbital, it was dependent upon the dose used. The risk for phenobarbital was significantly increased when other antiepileptic medications or caffeine were added (RR 2.5) or when all were combined (RR 5.1). Significant associations were observed between neural tube defects and valproate alone (RR 4, p=0.03) and when combined with other antiepileptic medications (RR 5.4, p=0.004), specifically with carbamazepine (RR 8.1, p=0.01). In addition, the risk of hypospadia was higher with valproate alone (RR 4.8, p=0.05) or combined with other antiepileptic drugs (RR 4.8, p=0.03) (Samren et al, 1999).
8) A case of radial microbrain form of microencephaly in a 35-week-old premature infant exposed to carbamazepine in utero was reported. The mother had a history of seizures for which she was receiving carbamazepine 600 mg/day throughout her pregnancy within the therapeutic range (8.4 mcg/mL). At birth, facial dysmorphologies were observed in the infant. An echocardiogram showed normal cardiac structure, but reduced contractility. Cranial ultrasound revealed a grossly undersized but histologically normal brain. Due to an extremely poor prognosis, life support was withdrawn. The absence of trauma, infection, or vascular disease suggests that the disorder was related to impaired neuronal proliferation (Hashimoto et al, 1999).

B) SPINA BIFIDA

1) CASE REPORT: A pregnant 44-year-old woman ingested 24 carbamazepine 200-mg tablets and developed mild clinical toxicity (peak level 28.5 mcg/mL). The last menstrual period, pelvic exam, and sonography indicated she was 3 to 4 weeks postconception at the time of ingestion, which correlated with the period of neural tube closure. Maternal alpha-fetoprotein levels were elevated at 16 weeks gestation and a 20-week sonogram suggested spina bifida. The pregnancy was electively terminated. The sonogram revealed that the fetus had a large open myeloschisis from T 11 to L 5 and a hypoplastic left cerebral hemisphere (Little et al, 1993).

C) LACK OF EFFECT

1) In a population-based study of children exposed in utero to antiepileptic drugs, the carbamazepine monotherapy group (n=86) showed no alterations in intelligence when compared to the control group (n=141). The median maternal doses of carbamazepine during the second half of pregnancy were 600 mg. Mean verbal and nonverbal IQ scores were 96 and 103, respectively, in the carbamazepine group, and 95 and 102, respectively, in the control group. The scores reported for the control group on the standardized cognitive tests Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R) (children less than 6 years) and Wechsler Intelligence Scale for Children-Revised (children older than 6 years) were similar to expected scores observed in the general population (Gaily et al, 2004).

D) ANIMAL STUDIES

1) RATS: Adverse effects in rat reproduction were evident at oral doses 10 to 25 times the maximum human daily dosage, 1200 mg/kg/day. Two of 135 rat offspring had kinked ribs at a dosage of 250 mg/kg/day, and 4 of 119 rat offspring had other anomalies including cleft palate, talipes, and anophthalmos at 650 mg/kg/day. In reproduction studies, the nursing offspring often lacked weight gain and had an unkempt appearance when the maternal dosage level was 200 mg/kg (Prod Info Tegretol(R)-XR oral extended-release tablets, 2014; Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014; Prod Info CARBATROL(R) oral extended-release capsules, 2013).

3.20.3)

A) PREGNANCY CATEGORY

1) Carbamazepine has been classified by the manufacturer as FDA pregnancy category D (Prod Info Tegretol(R)-XR oral extended-release tablets, 2014; Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014; Prod Info CARBATROL(R) oral extended-release capsules, 2013).
2) Weigh the benefits of therapy against the risks when treating women of childbearing potential. Advise the patient of the potential hazards to the fetus if the drug is used during pregnancy or if the patient becomes pregnant while already using the drug. Do not discontinue antiepileptic drugs abruptly in pregnant women who are taking the drug to prevent major seizures, because status epilepticus with attendant hypoxia and threat to life may occur (Prod Info CARBATROL(R) oral extended-release capsules, 2013). Monotherapy may be preferable for pregnant women if therapy is to be continued, as teratogenic effects have been reported at a higher prevalence with combination therapy (Prod Info Tegretol(R)-XR oral extended-release tablets, 2014; Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014).

B) PREGNANCY REGISTRY

1) The manufacturer maintains a North American Antiepileptic Drug (NAAED) Pregnancy Registry to monitor the effects of in utero exposure to carbamazepine. Patients are encouraged to report pregnancies and to obtain more information by calling 1-888-233-2334. Patients may also obtain information on the NAAED on the website: www.aedpregnancyresgistry.org/. Healthcare providers cannot register patients for the NAAED. Registration must be done by the patient (Prod Info Tegretol(R)-XR oral extended-release tablets, 2014; Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014; Prod Info CARBATROL(R) oral extended-release capsules, 2013).

C) COGNITIVE DEVELOPMENT

1) In an interim analysis of the prospective, observational Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, IQ testing at ages 2 and 3 (n=310) and at age 4.5 years (n=209) following prenatal exposure to antiepileptic drugs (AEDs) valproate, carbamazepine, lamotrigine, or phenytoin revealed pediatric cognitive abilities that correlated with maternal IQ for all AEDs but valproate and remained consistent over time. Dose-dependent effects were observed for valproate but not for each of the other AEDs. Using the Bayley Scale of Infant Development (BSID) at age 2 and the Differential Ability Scale (DAS) at ages 3 and 4.5 to assess cognitive development, adjusted mean IQ at age 4.5 in the carbamazepine group was 107 (n=54; confidence interval (CI) 103 to 107; p=0.0032); 106 in the lamotrigine group (n=73; CI 102 to 109; p=0.0056); 106 in the phenytoin group (n=43; CI 102 to 111; p=0.0156), and 96 in the valproate group (n=39; CI 92 to 101; p not applicable). IQ improved from age 3 to 4.5 in the carbamazepine (p=0.008), lamotrigine (p less than 0.0001) and phenytoin groups (p=0.002); no improvement occurred in the valproate group from age 3 to 4.5. The incidence of marked cognitive impairment (IQ of less than 70) at age 4.5 was highest in the valproate group (10%) compared with the other AEDs (0% to 4%; p =0.0064). All 4 AED groups had impaired verbal abilities compared to nonverbal skills (Meador et al, 2012).

D) DRUG INTERACTION

1) Carbamazepine has been reported to decrease the effectiveness of oral contraceptives via its hepatic enzyme-inducing effects. Additionally, unplanned pregnancies may result due to decreased efficacy (lowering plasma concentration) of levonorgestrel implants by carbamazepine (Chang & McAuley, 1998).

E) LACK OF EFFECT

1) No increased risk of neonatal bleeding due to maternal use of hepatic enzyme-inducing antiepileptic drugs, including carbamazepine (463 patients), has been reported. Bleeding was found associated with birth at less than 32 weeks gestation and alcohol use, but not to exposure with carbamazepine (Kaaja et al, 2002).
2) No increased incidence of neonatal blood coagulation disorders was reported in a series of women taking carbamazepine throughout pregnancy. No increased incidence of vitamin K deficiency in neonates was reported (Hey, 1999).

3.20.4)

A) BREAST MILK

1) Carbamazepine and the epoxide metabolite transfer to breast milk. The concentration ratio of breast milk to that in maternal plasma is nearly 50% (0.4 for carbamazepine and 0.5 for the epoxide), and an estimated daily dose given to the newborn are in the range of 2 to 5 mg and 1 to 2 mg, respectively (Prod Info Tegretol(R)-XR oral extended-release tablets, 2014; Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014; Prod Info CARBATROL(R) oral extended-release capsules, 2013).
2) Carbamazepine is excreted in breast milk. A nursing infant is expected to ingest between 2% to 7.2% of the lowest weight-adjusted therapeutic dose (Iqbal et al, 2001a).
3) An infant developed total serum carbamazepine levels of 15% of the total maternal carbamazepine (mother 4.7 mcg/mL and infant 0.7 mcg/mL); free carbamazepine was 20% of maternal values (mother 1.15 mcg/mL and infant 0.22 mcg/mL) (Wisner & Perel, 1998).

3.20.5)

A) DECREASED MALE FERTILITY

1) Impaired male fertility or abnormal spermatogenesis has been reported very rarely in clinical trials of carbamazepine (Prod Info Tegretol(R)-XR oral extended-release tablets, 2014; Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014).

Carcinogenicity

3.21.2)

A) At the time of this review, the manufacturer does not report any human carcinogenic potential.

3.21.4)

A) HEPATOCELLULAR TUMORS

1) A dose-related increase in hepatocellular tumors was reported in female Sprague-Dawley rats who received carbamazepine in the diet at doses of 25, 75, and 250 mg/kg/day (Prod Info TEGRETOL(R), TEGRETOL(R)-XR extended-release tablets, oral chewable tablets, suspension, tablets, 2009).

B) TESTICULAR CELL TUMOR

1) A dose-related increase in benign testicular interstitial cell tumors was reported in male Sprague-Dawley rats who received carbamazepine in the diet at doses of 25, 75, and 250 mg/kg/day (Prod Info TEGRETOL(R), TEGRETOL(R)-XR extended-release tablets, oral chewable tablets, suspension, tablets, 2009).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor mental status, pulse oximetry and initiate continuous cardiac monitoring. Obtain an initial carbamazepine serum concentration every 4 hours until the concentration has peaked and is clearly declining.
B) An ECG should be obtained upon initial evaluation and repeated every hour initially following a significant overdose.
C) A basic metabolic panel should be obtained to evaluate serum sodium, potassium, and creatinine. Blood dyscrasias can be monitored with a CBC.
D) An ABG should be obtained in patients with significant respiratory depression.
E) Creatinine kinase should be measured in patients with prolonged coma or seizures.
F) Carbamazepine will cause a false positive for tricyclic antidepressant on many urine drug screens.

4.1.2)

A) TOXICITY

1) Determination of blood carbamazepine levels should be available from toxicology laboratories. False-positive tricyclic antidepressant drug screen results have been reported following carbamazepine toxicity. A GC-MS technique may be most reliable for determination of carbamazepine (Matos et al, 2000). Immunoassays are most commonly used.

a) The therapeutic levels of carbamazepine vary between 4 to 12 mg/L (Cruz & Marcadis, 1991). Ataxia and nystagmus may occur at levels greater than 12 mcg/mL (51 mcmol/L).

B) BLOOD/SERUM CHEMISTRY

1) Liver function tests and serum electrolytes may be valuable.

C) ACID/BASE

1) Monitor arterial blood gasses or pulse oximetry in patients with significant CNS or respiratory depression.

D) HEMATOLOGIC

1) Since carbamazepine in therapeutic quantities may result in blood dyscrasias a CBC should be obtained.

E) LABORATORY INTERFERENCE

1) A tricyclic antidepressant (TCA) serum screen assay may be reported as positive following a carbamazepine overdose. A cross-reactivity of carbamazepine with a TCA screen has been reported (Fleischman & Chiang, 2001).

4.1.4)

A) OTHER

1) MONITORING

a) ECG

1) Follow electrocardiogram and initiate continuous monitoring of electrocardiogram and blood pressure in patients with significant symptoms or rapidly rising levels.

b) EEG

1) A continuous EEG may be beneficial to manage seizures that occur as a complication of massive carbamazepine overdose and to provide assistance with prognosis. Massive overdoses have been shown to produce reversible encephalopathy which includes cortical hyperexcitability, a profound burst-suppression EEG pattern, and cranial nerve areflexia (De Rubeis & Young, 2001).

2) HAIR ANALYSIS

a) Hair sampling (carbamazepine concentrations were measured in 1-cm hair segments) was found to be useful in differentiating chronic vs. acute carbamazepine toxicity in a 12-year-old child on chronic carbamazepine therapy who was found comatose. It was determined that the child's hair carbamazepine levels (1 cm hair samples were analyzed) began to increase and eventually doubled over time. The authors concluded that sectional hair analysis along with laboratory findings (ie, serum concentration), led to the diagnosis of chronic carbamazepine toxicity in this patient (Mantzouranis et al, 2004).

Radiographic Studies

A)

1) Patients with rising serum levels have been reported to have a coagulum of undigested tablets, which may be visualized on abdominal x-ray with contrast media (Coutselinis & Poulus, 1980).

Methods

A)

1) An EMIT(R) homogeneous enzyme immunoassay is available for quantitation of carbamazepine in serum or plasma. The assay's range of quantitation is 2 to 20 mcg/mL (8.5 to 85 mcmol/L) carbamazepine.

a) Clinical studies show excellent correlation between this method and GLC. The presence of the active metabolite can produce a cross-reactivity and falsely elevated CBZ level. A CBZE level of 10 mg/L resulted in an apparent CBZ level of 2.3 mg/L (Deng et al, 1986).

2) Determination of free CBZ in blood has been recommended in cases of overdose because of the variability in binding from patient to patient (10% to 47.8%) (Lawless & De Monaco, 1982).

a) However, free CBZ determinations are felt to be not clinically useful in overdose but rather in routine therapeutic monitoring (Sullivan, 1982).

B)

1) HPLC method simultaneously quantitates CBZ (detection limit, 80 mcg/L) and the active epoxide metabolite.
2) Minkova & Getova (2001) described a gas-chromatography with mass spectrometry method for the simultaneous determination and quantitation of both carbamazepine and its epoxide metabolite in human serum. Limits of detection were 10 mcg/L and 40 mcg/L, respectively, for carbamazepine and carbamazepine epoxide. Both drug and metabolite had a limit of quantitation of 0.1 mg/L. 82.5% recovery for carbamazepine epoxide and 92.5% recovery for carbamazepine were reported (Minkova & Getova, 2001).
3) Simultaneous determination of lamotrigine and carbamazepine in plasma via high-resolution gas chromatography (HRGC) or high-performance liquid chromatography (HPLC) is described. More sensitivity was noted for the HPLC method for both drugs. The lowest limits of quantitation for carbamazepine were 0.1 mcg/mL (HPLC) and 0.25 mcg/mL (HRGC) (Queiroz et al, 2001).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with severe toxicity or those that are not able to ambulate safely should be admitted until symptoms resolve.

6.3.1.2) HOME CRITERIA/ORAL

A) All suicide attempts should be referred to a health care facility. Asymptomatic patients with inadvertent ingestion of therapeutic doses may be observed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) A toxicologist should be consulted for patients with severe toxicity.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate or large ingestions should be observed for at least 6 to 8 hours (OR 12 to 24 hours if a sustained release formulation is ingested), until serial carbamazepine concentrations have clearly peaked and are declining due to erratic absorption of the drug. Patients who develop significant symptoms should be admitted.

Monitoring

A)

B)

C)

D)

E)

F)

Oral Exposure

6.5.1)

A) NOT RECOMMENDED

1) Because of the risk of CNS depression and subsequent aspiration, prehospital decontamination should generally be avoided.

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) 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.

C) MULTIPLE DOSE ACTIVATED CHARCOAL

1) Multiple dose charcoal was reported to enhance the elimination of carbamazepine in human volunteers and overdose cases (Howard et al, 1990; Neuvonen & Elonen, 1980; Stremski et al, 1995; Boldy et al, 1987) (Crome et al, 1977). The patient's airway should be protected prior to use of multiple dose AC (Spiller, 2001).

a) STUDY: In a randomized trial of 12 patients with carbamazepine poisoning, patients treated with multiple dose activated charcoal had a shorter duration of coma (20.33 +/- 3.05 hrs vs 29.33 +/- 4.11 hrs), mechanical ventilation (24.1 +/- 4.2 hrs vs 36.4 +/- 3.6 hrs) and hospitalization (30.3 +/- 3.4 hrs vs 39.7 +/- 7.3 hrs) compared with patients treated with a single dose of charcoal. Half life of carbamazepine was shorter in patients treated with activated charcoal (12.56 +/- 3.5 hrs vs 27.88 +/- 7.36 hrs) (Brahmi et al, 2006). Glasgow coma score, APACHE II and SAPS II scores (severity of illness), initial and peak carbamazepine concentrations were similar between the two groups.
b) STUDY: There was no advantage to giving more than 3 doses of activated charcoal in a study of 5 children with acute or acute-on-chronic carbamazepine overdose.

1) Larger total doses of charcoal (60 to 90 grams) did result in a shorter carbamazepine half-life (7.21 hours) compared to a lower total dose (30 to 50 grams; half-life 10.17 hours).
2) The time to neurological recovery was not affected by multiple-dose charcoal administration despite shortening of the plasma half-life (Wason et al, 1992).

2) Use of multiple dose activated charcoal should be considered if a patient has ingested a potentially life threatening amount of carbamazepine (Vale et al, 1999).
3) CAUTION should be observed when giving multiple dose AC since carbamazepine inhibits gastrointestinal motility and may produce ileus (Soderstrom et al, 2006; Spiller, 2001).

a) CASE REPORT: An adult received multiple dose activated charcoal following the ingestion of 40 grams of a controlled-release formulation and developed an ileus and bowel obstruction from charcoal concretions requiring surgical intervention with an ileostomy (Soderstrom et al, 2006).

4) MULTIPLE DOSE ACTIVATED CHARCOAL

a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
e) Vomiting is a common adverse effect; antiemetics may be necessary.
f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).

6.5.3)

A) MONITORING OF PATIENT

1) Monitor mental status, pulse oximetry, and initiate continuous cardiac monitoring. Obtain an initial carbamazepine serum concentration every 4 hours until the concentration has peaked and is clearly declining.
2) An ECG should be obtained upon initial evaluation and repeated every hour initially following a significant overdose.
3) A basic metabolic panel should be obtained to evaluate serum sodium, potassium, and creatinine. Blood dyscrasias can be monitored with a CBC.
4) ABGs should be obtained in patients with significant respiratory depression.
5) Creatinine kinase should be measured in patients with prolonged coma or seizures.
6) Carbamazepine will cause a false positive for tricyclic antidepressant on many urine drug screens.

B) 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).

C) 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, 2010; 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).

D) HYPOTHERMIA

1) Hypothermia should be managed by gradual rewarming.

E) BODY TEMPERATURE ABOVE REFERENCE RANGE

1) Hyperthermia should be managed with use of cooling blankets. Control seizure activity and agitation.

F) DRUG-INDUCED DYSTONIA

1) In overdose chorea or ballismo-athetosis have been more common, although dystonia and oculogyric crisis have been rarely described after chronic therapy.
2) CHOREA - Is generally self-limited. Observation and airway protection may be all that is required. Physostigmine has been used in the three reported cases, but is not routinely recommended (Lehrman & Bauman, 1981; O'Neal et al, 1984).
3) ADULT

a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).

4) CHILDREN

a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).

G) FLUMAZENIL

1) Flumazenil 50 milligrams intravenously was reported to reverse coma in a 35-year-old woman with a negative plasma toxicology screen for benzodiazepines and a carbamazepine level of 27.8 milligrams/liter (Zuber et al, 1988).
2) Flumazenil should be used cautiously in patients with a history of seizure disorder.

H) 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).

I) SEROTONIN SYNDROME

1) SUMMARY

a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).

2) HYPERTHERMIA

a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
c) Non-depolarizing paralytics may be used in severe cases.

3) CYPROHEPTADINE

a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).

4) HYPERTENSION

a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.

5) HYPOTENSION

a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
c) NOREPINEPHRINE

1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
2) INITIAL DOSE

a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.

3) MAINTENANCE DOSE

a) 0.5 to 1 mL (2 to 4 mcg)/minute.

6) SEIZURES

a) DIAZEPAM

1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.

b) LORAZEPAM

1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2010; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).

c) RECURRING SEIZURES

1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.

d) PHENOBARBITAL

1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.

7) CHLORPROMAZINE

a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.

8) NOT RECOMMENDED

a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

J) NALOXONE

1) CHILDREN

a) Intravenous naloxone (0.4 mg bolus) was administered to a 9-year-old girl in deep coma and with marked respiratory depression following a carbamazepine overdose (no known concomitant drugs). Immediate improvement in blood pressure and respiratory effort was reported as well as a positive change in mental status. A second bolus was repeated 30 minutes later with further improvement (Razik & Shahzadi, 1998). Naloxone is not routinely recommended in carbamazepine overdoses. Further studies are necessary to establish the effectiveness of naloxone.

K) CARDIOPULMONARY BYPASS OPERATION

1) CASE REPORT: A 26-year-old man developed severe cardiogenic shock after overdose with 32 grams slow release carbamazepine and 600 units of insulin. Despite volume expansion, epinephrine and norepinephrine infusions, he had refractory hypotension, oliguria, pulmonary edema, and an ejection fraction of 20%. He was treated with extracorporeal life support for 6 days and survived with recovery of neurologic and cardiac function (Megarbane et al, 2006).

Enhanced Elimination

A)

1) Multiple dose activated charcoal increases clearance of carbamazepine and should be considered in patients with severe overdose. Because of a high degree of protein binding, peritoneal dialysis and hemodialysis would not be expected to be of great clinical benefit (Lee et al, 1980; Clancy, 1987; Durelli et al, 1989). Case reports suggest that high flux or high efficiency hemodialysis may enhance carbamazepine removal after overdose (Koh & Tan, 2006). Hemoperfusion has been used with success; there is limited experience with plasmapheresis.
2) According to the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup, who conducted a systematic case review of carbamazepine intoxications, involving case reports, case series, observational studies, pharmacokinetic studies, in vitro studies, and a descriptive cohort study, extracorporeal treatments (ECTR) are suggested in cases of severe carbamazepine poisoning, with intermittent hemodialysis as the preferred therapy, and intermittent hemoperfusion or continuous renal replacement therapy as alternative therapies if hemodialysis is unavailable (Ghannoum et al, 2014)

a) ECTR is recommended if multiple seizures refractory to therapy occur, or if life-threatening dysrhythmias occur (Ghannoum et al, 2014).
b) ECTR is suggested if prolonged coma or respiratory depression requiring mechanical ventilation are either present or expected, or if significant toxicity persists, particularly when carbamazepine concentrations either remain elevated or are increasing despite the use of multiple dose activated charcoal and supportive care (Ghannoum et al, 2014).

B)

1) Multiple dose charcoal was reported to enhance the elimination of carbamazepine in human volunteers and overdose cases (Sikma et al, 2012; Howard et al, 1990; Neuvonen & Elonen, 1980; Stremski et al, 1995; Boldy et al, 1987) (Crome et al, 1977). The patient's airway should be protected prior to use of multiple dose AC (Spiller, 2001).

a) STUDY: In a randomized trial of 12 patients with carbamazepine poisoning, patients treated with multiple dose activated charcoal had a shorter duration of coma (20.33 +/- 3.05 hrs vs 29.33 +/- 4.11 hrs), mechanical ventilation (24.1 +/- 4.2 hrs vs 36.4 +/- 3.6 hrs) and hospitalization (30.3 +/- 3.4 hrs vs 39.7 +/- 7.3 hrs) compared with patients treated with a single dose of charcoal. Half life of carbamazepine was shorter in patients treated with activated charcoal (12.56 +/- 3.5 hrs vs 27.88 +/- 7.36 hrs) (Brahmi et al, 2006). Glasgow coma score, APACHE II and SAPS II scores (severity of illness), initial and peak carbamazepine concentrations were similar between the two groups.
b) STUDY: There was no advantage to giving more than 3 doses of activated charcoal in a study of 5 children with acute or acute-on-chronic carbamazepine overdose.

1) Larger total doses of charcoal (60 to 90 grams) did result in a shorter carbamazepine half-life (7.21 hours) compared to a lower total dose (30 to 50 grams; half-life 10.17 hours).
2) The time to neurological recovery was not affected by multiple-dose charcoal administration despite shortening of the plasma half-life (Wason et al, 1992).

2) Use of multiple dose activated charcoal should be considered if a patient has ingested a potentially life threatening amount of carbamazepine (Vale et al, 1999).
3) CAUTION should be observed when giving multiple dose AC since carbamazepine inhibits gastrointestinal motility and may produce ileus (Soderstrom et al, 2006; Spiller, 2001).

a) CASE REPORT: An adult received multiple dose activated charcoal following the ingestion of 40 grams of a controlled-release formulation and developed an ileus and bowel obstruction from charcoal concretions requiring surgical intervention with an ileostomy (Soderstrom et al, 2006).

4) MULTIPLE DOSE ACTIVATED CHARCOAL

a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
e) Vomiting is a common adverse effect; antiemetics may be necessary.
f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).

C)

1) According to the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup, who conducted a systematic case review of carbamazepine intoxications, involving case reports, case series, observational studies, pharmacokinetic studies, in vitro studies, and a descriptive cohort study, intermittent hemodialysis is considered the preferred extracorporeal treatment (ECTR) in cases of severe carbamazepine poisoning. Multiple dose activated charcoal should be continued during ECTR (Ghannoum et al, 2014).

a) Alternative therapies that may be of use when hemodialysis is not available include intermittent hemoperfusion or continuous renal replacement therapy (Ghannoum et al, 2014).

2) CASE REPORT: A 58-year-old man developed progressive stupor, requiring intubation, after ingesting greater than 14 g of sustained-release carbamazepine, 60 mg of lorazepam, and ethanol. Initial carbamazepine (CBZ) concentration was 25 mcg/mL (therapeutic range, 2.8 to 11.8 mcg/mL). Despite decontamination with activated charcoal (total dose, 200 g), CBZ levels increased to 47.6 mcg/mL and his neurological symptoms worsened. Several different extracorporeal treatments were then initiated. Because of varying CBZ levels and worsening of neurological symptoms, the patient underwent 3 sessions of intermittent hemodialysis (IHD) (4 hours each), 2 sessions of continuous veno-venous hemofiltration (CVVH) (19 hours and 16 hours) and a session of intermittent hemodialysis with charcoal hemoperfusion (IHD-HP) (6 hours). Following the last session of IHD-HP for recurrent neurologic symptoms, the patient's CBZ level was 10.1 mcg/mL and he was extubated within 24 hours. Approximately 1.73 g of carbamazepine was removed over a 43-hour period. Carbamazepine clearances during IHD were higher (99.7 mL/min and 112.7 mL/min) compared to CVVH (18.4 and 24.8 mL/min). The extracorporeal treatments resulting in the shortest to longest carbamazepine half-lives were IHD-HP (5.1 hours), followed by IHD (7.6, 8.8, and 10 hours) and CVVH (73 and 27 hours). He was discharged without sequelae after day 16 (Payette et al, 2015).

D)

1) Reports on the use of hemodialysis alone for the treatment of an acute overdose of CBZ are limited. Use of high-flux dialyzers may be effective. Following a massive overdose, carbamazepine and its active epoxide metabolite are progressively less protein-bound, with increasing serum concentrations. Indications for high-efficiency hemodialysis may include unstable cardiac status or status epilepticus, complicated by bowel hypomotility that has not responded to conventional therapy (Spiller, 2001). Most patients with carbamazepine overdose do well with supportive care alone.
2) CASE REPORT: After an unknown intentional ingestion of carbamazepine, a 32-year-old woman developed neurological and respiratory insufficiency, which did not respond to conservative measures (i.e., gastric lavage and activated charcoal). Serum carbamazepine was 25.67 mcg/mL on admission and remained persistently high 58 hours later. Within 2 hours of starting hemodialysis, the patient's neurological status improved, and the carbamazepine level decreased to 12.26 mcg/mL. Hemodialysis was performed for 4 hours. The patient was successfully extubated 40 hours after admission, and was discharged to home on day 5 (Chetty et al, 2003).
3) Following single doses of 500 milligrams, approximately 50 milligrams of drug was removed over a 4 hour period with blood flow rates of 250 milliliters/minute and dialysate flow rates of approximately 610 milliliters/minute (Lee et al, 1980).
4) RETROSPECTIVE ANALYSIS: Records of 49 patients with carbamazepine intoxication were analyzed retrospectively. The patients were divided into 2 groups: those who received hemodialysis (group 1; n=13) and those who did not receive hemodialysis, but instead received multiple-dose activated charcoal and supportive therapy (group 2; n=36). Both groups received activated charcoal and gastric lavage at time of presentation. Initially, there was a statistically significant difference in mean carbamazepine concentrations between the 2 groups, with concentrations of 37.37 +/-10.39 mcg/mL and 20.82 +/-10.29 mcg/mL in groups 1 and 2, respectively. In terms of clinical findings, only group 1 patients developed seizures, respiratory depression, and coma. Following a single session of low flow-high activity standard hemodialysis, the mean carbamazepine concentration in the group 1 patients was 15.67 +/-6.33 mcg/mL (a mean decrease of 58.07%) (Ozhasenekler et al, 2012).
5) HIGH-EFFICIENCY HEMODIALYSIS (HEHD)

a) HEHD was reported to be successful in lowering serum CBZ levels, with no complications, in an 18-month-old child. A Baxter 1550 machine at a blood flow rate of 150 mL/min using a dialysate rate of 700 mL/min was used for the HEHD. Carbamazepine level was 26 micrograms/milliliter at initiation of dialysis; 30 minutes into dialysis pre and post dialysis membrane plasma carbamazepine levels were 18 and 10 micrograms/milliliter respectively. Normalization of CBZ level resulted in less than 5 hours.

1) Because CBZ is 75% protein-bound, standard hemodialysis or peritoneal dialysis may be less effective for drug removal. However, HEHD procedure involves a highly permeable membrane and an increase in dialysate flow that may provide increased clearance (Schuerer et al, 2000).

b) HFHD, or high-flux hemodialysis, has been reported to be an effective alternative to hemoperfusion for removal of carbamazepine following an overdose. Following an approximate 120 gram overdose in a 31-year-old woman, high-flux hemodialysis, using the Genius batch dialysis system, was started. Initial carbamazepine serum level was reported to be 43 mg/L, with a total body burden of 4.5 grams estimated with a volume of distribution of 1.4 L/kg. The serum level decreased to 33.8 mg/L after 3.5 hours of dialysis. The total amount of carbamazepine recovered in 75 L of dialysate was 520 mg.

1) After HFHD, the patient was started on hemoperfusion, with serum levels decreasing from 30.8 to 20.9 mg after 2 hours of treatment. Continuous charcoal oral dosing (40 g every 4 hr) was then started, with serum levels finally decreasing to 5.2 mg/L approximately 90 hours after the carbamazepine ingestion (Kielstein et al, 2002).

c) Tapolyai et al (2002) reported a case of overdose with an unknown amount of carbamazepine with lithium (Tapolyai et al, 2002). Following 3 hours of high-flux hemodialysis, the serum carbamazepine level was reduced by 27.7%. It was reduced a further 25.3% by a subsequent 3-hour charcoal hemoperfusion session. Dialysis clearance of carbamazepine was not determined.
d) A 41-year-old man, who was taking carbamazepine 400 mg 5 times per day, became comatose 2 days after beginning IV amiodarone therapy, 300 mg/day, for treatment of recurring ventricular fibrillation. A total carbamazepine plasma concentration was 27.4 mg/L, of which approximately 40% was unbound (10.9 mg/L). Multiple dose activated charcoal and high-flux hemodialysis were initiated approximately 14 hours post-admission and continued together for approximately 6 hours. A repeat carbamazepine plasma concentration revealed a decrease to 13 mg/L (4.1 mg/L unbound; 32%). The patient made a complete recovery (Sikma et al, 2012).

6) LOW-FLUX HEMODIALYSIS

a) Standard low-flux hemodialysis was used in two patients following carbamazepine poisoning. The first patient was a 14-year-old boy who ingested 20 300-mg tablets of carbamazepine (133 mg/kg) and subsequently became unresponsive. His initial blood carbamazepine level was 22.5 mcg/mL. After a single 3-hour standard low-flux hemodialysis session, the patient became alert with a blood carbamazepine level of 15.5 mcg/mL that gradually decreased to 11 mcg/mL 6 hours after the procedure. The second patient was a 12-year-old girl who became comatose and developed generalized seizures after ingesting 14 tablets of carbamazepine (140 mg/kg). Initially, her blood carbamazepine level was 20 mcg/mL. Thirty minutes after a low-flux hemodialysis session, her blood carbamazepine level was 15.2 mcg/mL that continued to decrease to 8.14 mcg/mL 12 hours after the procedure (Bek et al, 2007).

7) CONTINUOUS VENO-VENOUS HEMODIALYSIS

a) CASE REPORT (CHILD): Albumin-enhanced continuous veno-venous hemodialysis (CVVHD) was used to treat a 10-year-old girl (30 kg) with a newly diagnosed seizure disorder, who was admitted about 4 hours after an intentional ingestion of 1400 mg of extended-release carbamazepine. The patient was comatose (Glasgow coma score = 3) and required intubation, and had an initial carbamazepine level of 44 mcg/mL (therapeutic: 4 to 12 mcg/mL). Despite repeated doses of activated charcoal, the carbamazepine level remained at 43 to 44 mcg/mL over the first 12 hours of hospitalization. Within 16 hours of ingestion, CVVHD was begun and the composition of the dialysis fluid was adjusted to 4.5 g/dL of albumin using a 25% albumin solution. It was administered by using a PRIMSA CRRT M60 circuit with an in-line blood warmer set at 35 to 36 degrees Celsius. Anticoagulation of the extracorporeal circuit was attained by using citrate.
b) At the start of the procedure, the child developed a brief episode of hypotension (lowest reading: 60/40 mmHg). Ionized calcium level was 1.04. The patient responded to an increase in calcium chloride administration and a normal saline bolus (100 mL). Four hours after the start of therapy, the CVVHD circuit clotted, but was restarted using the same protocol. After a total of 12 hours of therapy, the patient's carbamazepine level was 10.4 mcg/mL, and therapy was stopped at 17 hours with a serum level of 6.6 mcg/mL; no drug rebound occurred. The patient was successfully extubated, and continued to progress well, and was discharged within 90 hours of ingestion.

1) Albumin enhanced CVVHD may be more effective at enhancing carbamazepine due to its high protein binding. While increasing clearance may shorten the need for mechanical ventilation and ICU stay, it has not been shown to affect outcome. The risks of CVVHD in small children may be greater due to their smaller blood volumes. The effect of albumin-enhanced CVVHD on calcium and citrate fluxes is not well understood. (Askenazi et al, 2004). Therapy to enhance elimination should be considered in patients with hemodynamic instability, recurrent seizures, and those not responding to conventional supportive care.

E)

1) CASE REPORT: A 17-year-old girl presented to the hospital comatose 9 hours after intentionally ingesting 40 400-mg carbamazepine tablets. Her serum carbamazepine level was 54.99 mcg/mL. Continuous venovenous hemodiafiltration (CVVDHF) was initiated at a blood flow rate of 75 to 175 mL/hour with an effluent filtration rate of 2000 to 3500 mL/hour, and continued for 24 hours. Repeat serum carbamazepine levels, obtained immediately after CVVDHF had ended and 20 hours post procedure, were 9.81 mcg/mL and 6.8 mcg/mL, respectively. CVVDHF clearance was not determined (Goktas et al, 2010).
2) CASE REPORT: A 31-year-old woman, with a history of bipolar disorder, intentionally ingested approximately 10 g of extended-release carbamazepine tablets, and subsequently became unresponsive with hypotension and respiratory failure, necessitating intubation and mechanical ventilation. Despite administration of IV fluids and decontamination with activated charcoal, the patient remained unresponsive, with a carbamazepine level of 26 mg/mL approximately 20 hours postingestion. Continuous venovenous hemodiafiltration (CVVHDF) was then started at a blood flow rate of 150 mL/min and a dialysate flow rate of 2 L/min, using a 5% albumin-enhanced dialysate. After 26 hours of CVVHDF, the patient's carbamazepine level decreased to 10 mcg/mL, she regained consciousness and was extubated. Over the next several days, the patient continued to remain stable and was discharged with outpatient psychiatric follow-up (Narayan et al, 2014).
3) MIXED INGESTION: A 16-year-old girl intentionally ingested an estimated 16.4 g of carbamazepine (CBZ) (extended release tablets) and 14.5 g of valproic acid (extended release tablets) approximately 3 hours prior to admission. She was found unconscious by her parents. Five hours after ingestion, her CBZ level was 43.1 mcg/mL and her valproic acid level was 111.5 mcg/mL (peak, 283 mcg/mL). Activated charcoal was given every 6 hours for the first 24 hours along with enteral polyethylene glycol (Macrogol) to accelerate bowel elimination. However, 15 hours after ingestion, no neurologic improvement was observed and she was started on continuous charcoal hemoperfusion for 4 hours with significant laboratory improvement in drug levels, but a decrease in her platelet count (167,000/mcL to 45,000/mcL) occurred. Continuous venovenous hemodiafiltration (CVVHDF) was then performed for 48 hours. At the end of the treatment period, CBZ level was 17.8 mcg/l and valproic acid was 119 mcg/L and both were continuing to decrease. Ninety hours after ingestion, the patient became more alert and was successfully extubated at 120 hours. She continued to do well with no neurologic deficits and was discharged to home on day 8 with ongoing mental health support (Moinho et al, 2014).

F)

1) CASE REPORT: A 58-year-old man developed progressive stupor, requiring intubation, after ingesting greater than 14 g of sustained-release carbamazepine, 60 mg of lorazepam, and ethanol. Initial carbamazepine (CBZ) concentration was 25 mcg/mL (therapeutic range, 2.8 to 11.8 mcg/mL). Despite decontamination with activated charcoal (total dose, 200 g), CBZ levels increased to 47.6 mcg/mL and his neurological symptoms worsened. Several different extracorporeal treatments were then initiated. Because of varying CBZ levels and worsening of neurological symptoms, the patient underwent 3 sessions of intermittent hemodialysis (IHD) (4 hours each), 2 sessions of continuous veno-venous hemofiltration (CVVH) (19 hours and 16 hours) and a session of intermittent hemodialysis with charcoal hemoperfusion (IHD-HP) (6 hours). Following the last session of IHD-HP for recurrent neurologic symptoms, the patient's CBZ level was 10.1 mcg/mL and he was extubated within 24 hours. Approximately 1.73 g of carbamazepine was removed over a 43-hour period. Carbamazepine clearances during IHD were higher (99.7 mL/min and 112.7 mL/min) compared to CVVH (18.4 and 24.8 mL/min). The extracorporeal treatments resulting in the shortest to longest carbamazepine half-lives were IHD-HP (5.1 hours), followed by IHD (7.6, 8.8, and 10 hours) and CVVH (73 and 27 hours). He was discharged without sequelae after day 16 (Payette et al, 2015).
2) CASE REPORT: A 41-year-old woman was found unresponsive by her husband, in the presence of multiple empty medication bottles, including valproic acid and carbamazepine. At the arrival of emergency personnel, the patient was in asystole, but had a return of spontaneous circulation approximately 20 minutes after initiation of resuscitative efforts. At arrival to the emergency department, the patient was tachycardic (97 beats/min) and hypotensive (78/44 mmHg), with a Glasgow Coma Scale score of 3, fixed pupils, and an absence of gag, cough, or corneal reflexes. An ECG revealed incomplete right bundle branch block and a prolonged QTc interval (519 msec). Laboratory data demonstrated metabolic acidosis, elevated serum creatinine, elevated liver enzymes, mild coagulopathy, and serum valproic acid and carbamazepine concentrations of 57.9 mcg/mL (normal 50 to 125 mcg/mL) and 57.8 mcg/mL (normal 4 to 12 mcg/mL), respectively. Supportive treatment and multiple dose activated charcoal was started; however, due to her continued hemodynamic instability and a progressive increase in her carbamazepine levels, continuous venovenous hemofiltration (CVVH) was initiated approximately 15 hours post-presentation. Gradually, the patient's blood pressure stabilized and she was started on conventional hemodialysis with continued intermittent sessions of CVVH. However, an anoxic brain injury had occurred, and the patient died on hospital day 10 (Smollin et al, 2016).

a) Serum samples from the patient were obtained during the first 30 hours of CVVH, with serum and effluent levels of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (metabolite [CBZE]) measured via immunoassay. Over the course of 30 hours a total of 1293 mg CBZ and 1261 mg CBZE were removed, with mean clearances of 18.1 mL/min (range 12.7 to 28.7 mL/min) and 25.2 mL/min (range 17.7 to 42.6 mL/min) for CBZ and CBZE, respectively (Smollin et al, 2016).

G)

1) Hemoperfusion has been used to treat acute, life-threatening CBZ overdose (Li et al, 2011; Deshpande et al, 1999; Low et al, 1996; Kuhlmann et al, 1992; Leslie et al, 1983; Gary et al, 1981; Chan et al, 1981) . This technique is especially useful when carbamazepine-induced gastrointestinal hypomotility prevents elimination via the gut (Deshpande et al, 1999). Continued absorption of carbamazepine may cause increasing levels and worsening toxic effects after hemoperfusion is discontinued, particularly following ingestion of a controlled-release preparation (Vree et al, 1997). Blood flow rates of 240 milliliters/minute for 4 hours and 200 milliliters/minute for 2 hours removed approximately 2.4 grams and 1.4 grams of CBZ, respectively.
2) CASE REPORTS

a) MIXED INGESTION: A 16-year-old girl intentionally ingested an estimated 16.4 g of carbamazepine (CBZ) (extended release tablets) and 14.5 g of valproic acid (extended release tablets) approximately 3 hours prior to admission. She was found unconscious by her parents. Five hours after ingestion, her CBZ level was 43.1 mcg/mL and her valproic acid level was 111.5 mcg/mL (peak, 283 mcg/mL). Activated charcoal was given every 6 hours for the first 24 hours along with enteral polyethylene glycol (Macrogol) to accelerate bowel elimination. However, 15 hours after ingestion, no neurologic improvement was observed and she was started on continuous charcoal hemoperfusion for 4 hours with significant laboratory improvement in drug levels, but a decrease in her platelet count (167,000/mcL to 45,000/mcL) occurred. Continuous venovenous hemodiafiltration (CVVHDF) was then performed for 48 hours. At the end of the treatment period, CBZ level was 17.8 mcg/l and valproic acid was 119 mcg/L and both were continuing to decrease. Ninety hours after ingestion, the patient became more alert and was successfully extubated at 120 hours. She continued to do well with no neurologic deficits and was discharged to home on day 8 with ongoing mental health support (Moinho et al, 2014).
b) A 50-year-old man who ingested 20 grams of carbamazepine was hemoperfused for five hours. The plasma carbamazepine concentration during hemoperfusion fell from 31 to 15 milligrams/liter (131 to 63 micromoles/liter) and the initial clearance across the column was 174 milliliters/minute which fell to 80 milliliters/minute. The estimated total amount of drug removed was less than one gram (Leslie et al, 1983).
c) Hemoperfusion was used to treat a severe case of CBZ ingestion (80 grams). Clearance rate was 80 to 90 milliliters/minute, but effect of hemoperfusion was limited probably because of ongoing absorption of CBZ from the gut. Authors recommended long hemoperfusion periods due to the pharmacokinetic pattern of carbamazepine (Nilsson et al, 1984).
d) Hemoperfusion (HP) was used to treat an acute CBZ overdose with serum level of about 55 micrograms/milliliter at 20 hours postingestion. The patient was not on chronic CBZ prior to the overdose. Half-life of CBZ prior to HP was estimated to be about 30 hours, and decreased to 6 hours during HP. Intrinsic and HP clearances were calculated as 2 mL/hr/kg and 10 mL/hr/kg, respectively. Approximately 1.4 grams of CBZ were removed in a 4 hr treatment session, or about 25% of the total body burden. No rebound pattern was observed in this patient (Low et al, 1996).
e) Two hemoperfusion sessions were performed over the first 48 hours in a 32-year-old woman following an intentional overdose, with carbamazepine serum level of 369 mcmol/L (871 mcg/mL) on admission. Serum level was reduced to 150 mcmol/L (354 mcg/mL) following hemoperfusion. The patient died due to respiratory and circulatory failure 72 hours after admission (De Rubeis & Young, 2001).
f) Following the ingestion of 60 grams of controlled-release carbamazepine, a 31-year-old woman was started on whole-bowel irrigation, which was stopped due to development of an ileus. By day four, serum carbamazepine levels had peaked at 196 micromoles/liter. After initiation of charcoal hemoperfusion, drug levels fell from 176 to 106 micromoles/liter after 1 hour of hemoperfusion and continued to fall over the next 48 hours (Graudins et al, 2001).
g) Hemoperfusion was used following the ingestion of 40 grams of controlled-release carbamazepine in an adult after the development of an ileus following multiple dose activated charcoal and persistent CNS depression. The patient was also weaned successfully from inotropes after hemoperfusion was completed (Soderstrom et al, 2006).
h) A 3-hour charcoal hemoperfusion procedure was performed on a 13-year-old girl who ingested 12 400-mg carbamazepine tablets (145 mg/kg). On admission, her blood carbamazepine level was 34 mcg/mL and 30 minutes after hemoperfusion, her blood carbamazepine level was 29.7 mcg/mL, gradually decreasing to 7.7 mcg/mL 24 hours after the procedure (Bek et al, 2007).

3) Indications for hemoperfusion might include a deteriorating clinical state or failure to respond to supportive medical care (Soderstrom et al, 2006)
4) Adverse effects of hemoperfusion may include thrombocytopenia, coagulopathy, hypothermia, and hypocalcemia (Schuerer et al, 2000).

H)

1) CASE REPORT: Combined charcoal hemoperfusion and hemodialysis was performed for 4 hours in a 45-year-old woman beginning 32 hours after ingestion of 4 to 36 grams of carbamazepine.

a) Her clinical condition had deteriorated, necessitating vasopressors and mechanical ventilation. Improvement was noted during the procedure, enabling discontinuation of pressors and ventilation after 2 hours.
b) The serum carbamazepine level was 30 mcg/mL at the beginning and 14.6 mcg/mL at the end of the procedure. A small rebound to a serum level of 15.4 mcg/mL occurred (Bock et al, 1989).

2) CASE REPORT: High efficiency hemodialysis combined with charcoal hemoperfusion (HD/CHP) was performed over a 4-hour period on a 22-year-old woman who intentionally ingested an unknown amount of 200 mg extended-release carbamazepine. Her plasma carbamazepine concentration, obtained approximately 10 hours postingestion, was 54 mg/L. After completing HD/CHP treatment, her plasma carbamazepine concentration decreased to 12 mg/L, rebounded to 42 mg/L two hours later, then decreased to 18.7 mg/L 12 hours after cessation of HD/CHP treatment. The patient recovered without neurological sequelae. Extraction ratio for the hemodialysis was 0.45 to 0.54, the extraction ratio for hemoperfusion was 0.44 to 0.71 (Pilapil & Petersen, 2008).
3) CASE REPORT: A 58-year-old man developed progressive stupor, requiring intubation, after ingesting greater than 14 g of sustained-release carbamazepine, 60 mg of lorazepam, and ethanol. Initial carbamazepine (CBZ) concentration was 25 mcg/mL (therapeutic range, 2.8 to 11.8 mcg/mL). Despite decontamination with activated charcoal (total dose, 200 g), CBZ levels increased to 47.6 mcg/mL and his neurological symptoms worsened. Several different extracorporeal treatments were then initiated. Because of varying CBZ levels and worsening of neurological symptoms, the patient underwent 3 sessions of intermittent hemodialysis (IHD) (4 hours each), 2 sessions of continuous veno-venous hemofiltration (CVVH) (19 hours and 16 hours) and a session of intermittent hemodialysis with charcoal hemoperfusion (IHD-HP) (6 hours). Following the last session of IHD-HP for recurrent neurologic symptoms, the patient's CBZ level was 10.1 mcg/mL and he was extubated within 24 hours. Approximately 1.73 g of carbamazepine was removed over a 43-hour period. Carbamazepine clearances during IHD were higher (99.7 mL/min and 112.7 mL/min) compared to CVVH (18.4 and 24.8 mL/min). The extracorporeal treatments resulting in the shortest to longest carbamazepine half-lives were IHD-HP (5.1 hours), followed by IHD (7.6, 8.8, and 10 hours) and CVVH (73 and 27 hours). He was discharged without sequelae after day 16 (Payette et al, 2015).

I)

1) CASE REPORTS

a) Plasmapheresis was employed in the treatment of a 21-year-old man with severe carbamazepine intoxication (peak level 58 mcg/mL). Carbamazepine clearance increased from 2.04 liters/hour with multiple dose charcoal to 3.42 liters/hour during plasmapheresis; however, significant rebound (40 percent) in blood concentrations were observed and only 6 percent of the estimated body burden was removed with three treatments (Kale et al, 1993). This does not appear to be effective therapy for carbamazepine overdose.
b) Following an overdose of at least 4.6 grams of carbamazepine (plasma level of 190 mcmol/L), plasmapheresis, started 20 hours after admission, was successful in lowering plasma levels in a 15-year-old girl. Immediately after the procedure, carbamazepine level was 101 mcmol/L, with levels falling to 72, 33 and 20 mcmol/L at the 36th, 60th, and 84th hours, respectively. Her neurological status improved gradually, and she was discharged on the 4th day (Duzova et al, 2001).
c) Two plasma exchange sessions were performed on a 3-year-old child with severe carbamazepine intoxication following ingestion of 20 400-mg carbamazepine tablets (serum carbamazepine level 37 mcg/mL; therapeutic range, 8 to 12 mcg/mL). Following the first session, performed 12 hours post-admission, the patient's carbamazepine level decreased to 25 mcg/mL, with slight clinical improvement. Following the second session, performed 36 hours post-admission, the carbamazepine level decreased to less than 10 mcg/mL, with greater improvement clinically. After gradually regaining his physical and mental activity, the patient was discharged on hospital day 6 (Kozanoglu et al, 2014).

Abstracts

Case Reports

A)

1) Severe myocardial depression with bradycardia, conduction defects and hypotension has been reported in a fifty-year-old man following the ingestion of twenty grams of carbamazepine (Leslie et al, 1983).
2) A 16-year-old girl with a carbamazepine level of 51 micrograms/mL presented with vomiting, stupor, and occipital delta activity from which she recovered following a 24-hour course of activated charcoal (Howard et al, 1990). She presented with vomiting and response only to deep pain after a suicidal attempt.

a) With a plasma carbamazepine level of 51 micrograms/mL, cardiovascular, respiration, and neurologic findings were normal except for stupor, dilated but responsive pupils, absent deep tendon reflexes, positive Babinski, and occipital delta activity on EEG.
b) After 24 hours of activated charcoal, she became alert and oriented and the carbamazepine level fell to 4 micrograms/mL. 48 hours later, her EEG was normal except for minor residual changes.

3) Saloman & Pippenger (1975) describe a case of encephalopathy resulting from massive overdose of carbamazepine (5.8 g), as a single dose in a 16-year-old boy (Saloman & Pippenger, 1975). Following ingestion of twenty-nine 200 mg tablets, the patient was admitted to the hospital because of apparent failure to recover from a presumed psychomotor seizure. He was in a profound stupor and did not respond to speech.

a) Minimal painful stimuli elicited semi-purposeful movements of the extremities and the patient exhibited planar disconjugate gaze and absent response to Doll's head maneuver. On the second hospital day, the patient emerged from stupor and by the fourth hospital day he was fully alert and oriented. Plasma carbamazepine levels at this time were measurable.

B)

1) INFANT

a) A 23-month-old boy ingested 2 grams (148 mg/kg) of carbamazepine and was lethargic and ataxic within 3 hours and became comatose 9 hours postingestion. Multiple-dose charcoal and cathartic therapy was given. At 26 hours postingestion tonic-clonic seizures began which resolved with intravenous diazepam therapy. All symptoms resolved within a few days, with no sequelae (Deng et al, 1986).

1) The peak carbamazepine level of 42 milligrams/liter occurred 16 hours postingestion (by EMIT); however, the peak combined CBZ and metabolite level occurred 26 hours postingestion.

2) OTHER

a) Ophthalmoplegia following ingestion of 1.8 to 2 g of carbamazepine over an 8 hour period (producing blood concentrations of 20 mcg/mL (85 mcmol/L)) has been reported in one patient (Mullally, 1982). Eye movements return to normal with decrease of carbamazepine levels to 2 mcg/mL (8.5 mcmol/L).
b) OROFACIAL DYSKINESIAS with grimacing, involuntary tongue protrusion and repetitive movements of the tongue from side to side were seen in a patient who ingested 24 g of carbamazepine. Within 24 hours of the ingestion the orofacial dyskinesias had improved, and all symptoms resolved after the first week (Joyce & Gunderson, 1980).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) EPILEPSY

1) EXTENDED-RELEASE TABLETS AND CAPSULES: Initially, 200 mg orally twice daily; may increase dosage by 200 mg/day, in two divided doses, at weekly intervals, up to a MAXIMUM dose of 1600 mg/day. Extended-release tablets and capsules should be swallowed whole and should NOT be crushed or chewed (Prod Info Tegretol(R)-XR oral extended-release tablets, 2014; Prod Info CARBATROL(R) oral extended-release capsules, 2013).
2) CHEWABLE TABLETS: Initially, 200 mg orally twice daily; may increase dosage by 200 mg/day, in 3 or 4 divided doses, at weekly intervals, up to a MAXIMUM dose of 1600 mg/day (Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014).
3) ORAL SUSPENSION: 1 teaspoon (100 mg) four times daily; may increase dosage by 200 mg/day, in three or four divided doses, at weekly intervals, up to a MAXIMUM dose of 1600 mg/day (Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014).

B) TRIGEMINAL NEURALGIA

1) EXTENDED-RELEASE TABLETS AND CAPSULES: Initially, 100 mg twice daily; may increase dosage by 200 mg/day, in 2 divided doses, up to a MAXIMUM dose of 1200 mg daily. Extended-release tablets and capsules should be swallowed whole and should NOT be crushed or chewed (Prod Info Tegretol(R)-XR oral extended-release tablets, 2014; Prod Info CARBATROL(R) oral extended-release capsules, 2013)
2) CHEWABLE TABLETS: Initially, 100 mg twice daily; may increase dosage by 200 mg/day, in 2 divided doses, up to a MAXIMUM dose of 1200 mg daily (Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014).
3) ORAL SUSPENSION: 1/2 teaspoon (50 mg) 4 times daily; may increase dosage up to 200 mg daily in increments of 50 mg 4 times daily, up to a MAXIMUM dose of 1200 mg daily (Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014).

7.2.2)

A) EPILEPSY

1) LESS THAN 6 YEARS OF AGE

a) CHEWABLE TABLETS: Initially, 10 to 20 mg/kg/day, in 2 or 3 divided doses; may increase dosage at weekly intervals, given 3 or 4 times daily, up to a MAXIMUM dose of 35 mg/kg/day (Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014)
b) ORAL SUSPENSION: Initially, 10 to 20 mg/kg/day, in 4 divided doses; may increase dosage at weekly intervals, given 3 or 4 times daily, up to a MAXIMUM dose of 35 mg/kg/day (Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014)

2) 6 TO 12 YEARS

a) EXTENDED-RELEASE TABLETS: Initially, 100 mg twice daily; may increase dosage up to 100 mg/day, in 2 divided doses, at weekly intervals, up to a MAXIMUM dose of 1000 mg daily. Extended-release tablets should be swallowed whole and should NOT be crushed or chewed (Prod Info Tegretol(R)-XR oral extended-release tablets, 2014).
b) CHEWABLE TABLETS: Initially, 100 mg twice daily; may increase dosage up to 100 mg/day, in 3 or 4 divided doses, at weekly intervals, up to a MAXIMUM dose of 1000 mg daily (Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014).
c) ORAL SUSPENSION: 1/2 teaspoon (50 mg) 4 times daily; may increase dosage up to 1 teaspoon (100 mg) daily, in 3 or 4 divided doses, at weekly intervals, up to a MAXIMUM dose of 1000 mg/day (Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014).

3) GREATER THAN 12 YEARS OF AGE

a) EXTENDED-RELEASE TABLETS AND CAPSULES: Initially, 200 mg orally twice daily; may increase dosage by 200 mg/day, in two divided doses, at weekly intervals, up to a MAXIMUM dose of 1000 mg (12 to 15 years of age), and 1200 mg (greater than 15 years of age). Extended-release tablets and capsules should be swallowed whole and should NOT be crushed or chewed (Prod Info Tegretol(R)-XR oral extended-release tablets, 2014; Prod Info CARBATROL(R) oral extended-release capsules, 2013).
b) CHEWABLE TABLETS: Initially, 200 mg orally twice daily; may increase dosage by 200 mg/day, in 3 or 4 divided doses, at weekly intervals, up to a MAXIMUM dose of 1000 mg/day (12 to 15 years of age) and 1200 mg/day (greater than 15 years of age) (Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014).
c) ORAL SUSPENSION: 1 teaspoon (100 mg) four times daily; may increase dosage by 200 mg/day, in three or four divided doses, at weekly intervals, up to a MAXIMUM dose of 1000 mg (12 to 15 years of age) and 1200 mg (greater than 15 years of age) (Prod Info Tegretol(R) oral chewable tablets, oral tablets, oral suspension, 2014).

Minimum Lethal Exposure

A)

1) Seizures, coma, and severe respiratory depression following large ingestions independently predict a poor prognosis. Ingestion of greater than 24 g is also a predictor of a poor prognosis in adults (De Rubeis & Young, 2001).

B)

1) The lowest known lethal dose reported was 3.2 g in a 24-year-old woman (death due to cardiac arrest) and in a 24-year-old man (death due to pneumonia and hypoxic encephalopathy) (Prod Info Tegretol(R)-XR, carbamazepine, 2000).
2) A fatality was reported in a 26-year-old man who ingested 60 g (Denning et al, 1985).
3) A 34-year-old man, with history of seizure disorder, died 4 days after admission from complications of a carbamazepine (amount unknown) overdose. His carbamazepine serum concentration was 54 mg/L on admission (Fisher & Cysyk, 1988).
4) A 32-year-old woman died approximately 72 hours after hospital admission due to a massive carbamazepine overdose (exact amount unknown). Serum CBZ level on admission was 871 mcg/mL (369 micromols/L) (De Rubeis & Young, 2001).

C)

1) The lowest known lethal dose reported in a child is 1.6 g, ingested by a 3-year-old girl who died of aspiration pneumonia (Prod Info Tegretol(R)-XR, carbamazepine, 2000).

Maximum Tolerated Exposure

A)

1) Serious toxicity with survival has been reported after ingestions of up to 40 g in adults (Soderstrom et al, 2006; Weaver et al, 1988; Leslie et al, 1983; Hajnsek & Sartorius, 1964; Vree et al, 1997; Joyce & Gunderson, 1980). A 13 year-old survived an ingestion of 34 g (640 mg/kg) (Patsalos et al, 1987).

a) Severe cardiac complications generally occur only when very high doses (greater than 60 g) are ingested (Prod Info Tegretol(R)-XR, carbamazepine, 2000).
b) Survival in adults has been reported after ingestion of 150 mg/kg (Smoot & Wood, 1977), 200 mg/kg (Lehrman & Bauman, 1981), and 640 mg/kg (Patsalos et al, 1987).

2) ADULT

a) CASE REPORT: An adult intentionally ingested 40 g of controlled-release carbamazepine and developed CNS depression. Serum carbamazepine level peaked at 41 mg/L (175 mmol/L) at 36 hours. Levels remained above 30 mg/L over the first week during which time the patient remained unresponsive. Following hemoperfusion, the patient regained consciousness and was successfully extubated 12 days after exposure (Soderstrom et al, 2006).
b) CASE REPORT: A 31-year-old woman, with a history of bipolar disorder, intentionally ingested approximately 10 g of extended-release carbamazepine tablets, and subsequently became unresponsive with hypotension and respiratory failure, necessitating intubation and mechanical ventilation. Despite administration of IV fluids and decontamination with activated charcoal, the patient remained unresponsive, with a carbamazepine level of 26 mg/mL approximately 20 hours post-ingestion. Continuous venovenous hemodiafiltration (CVVHDF) was then started. After 26 hours of CVVHDF, the patient's carbamazepine level decreased to 10 mcg/mL, she regained consciousness and was extubated. Over the next several days, the patient continued to remain stable and was discharged with outpatient psychiatric follow-up (Narayan et al, 2014).

3) ADOLESCENTS

a) Acute encephalopathy following ingestion of 5.8 g of carbamazepine in a 16-year-old boy was reported by (Saloman & Pippenger, 1975). The plasma level was 10.1 micrograms/milliliter 36 hours postingestion.
b) Survival was reported in a 14-year-old who ingested 5 g and an 18-year-old who ingested 4 to 4.8 g (Livingston et al, 1974).

B)

1) Ingestion of 10 g of carbamazepine by a 6-year-old boy resulted in coma and respiratory depression (Prod Info Tegretol(R), 1968). Full recovery was noted within 24 hours.
2) Ingestion of 2 g (148 mg/kg) by a 23-month-old boy resulted in coma and seizures (Deng et al, 1986).
3) Ingestion of 400 mg of carbamazepine by a 22-month-old boy resulted in drowsiness, which resolved after gastric lavage was performed (Prod Info Tegretol(R), 1968).
4) CASE REPORT: A 7-year-old boy, with a 2-year history of epilepsy treated with carbamazepine, presented to the emergency department comatose 6 hours after ingesting 10 200-mg (100 mg/kg) carbamazepine tablets. A neurologic examination revealed a Glasgow Coma Scale score of 6. Twelve hours after hospital admission, he developed seizures. His serum carbamazepine concentration, obtained on hospital day 3, was 25 mcg/mL. With gastric lavage, activated charcoal administration, and supportive care, the patient recovered and was discharged 4 days post-admission (Dogan et al, 2010).
5) CASE REPORT: A 3-year-old child ingested 20 400-mg carbamazepine tablets and subsequently became comatose (Glasgow Coma Scale score of 4), tachycardic (134 bpm), and hypotensive (80/40 mmHg) about 6 hours after exposure. His serum carbamazepine level was 37 mcg/mL (therapeutic range, 8 to 12 mcg/mL). Despite decontamination with activated charcoal and gastric lavage, and administration of hemodialysis, the serum carbamazepine level was persistently high, and two plasma exchange sessions were then initiated. Following the first session, 12 hours post-admission, the carbamazepine level decreased to 25 mcg/mL, with slight clinical improvement. After the second session, 36 hours post-admission, the carbamazepine level decreased to less than 10 mcg/mL with greater clinical improvement. After gradually regaining his physical and mental activity, he was discharged on hospital day 6 (Kozanoglu et al, 2014).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) ACUTE

a) GENERAL

1) Ataxia and nystagmus may occur with levels greater than 12 micrograms/milliliter (50 micromoles/liter). Other toxic manifestations occur at higher levels.
2) Peak serum levels below 30 mcg/mL (127 micromol/L) are generally associated with relatively mild toxicity including somnolence, ataxia, nystagmus, movement disorders, hallucinations, and vomiting (Tibballs, 1993)(Macnab et al, 1993). Peak levels of 40 mcg/mL (170 micromol/L) or more are associated with coma, seizures, dysrhythmias, respiratory depression and hypotension (Soderstrom et al, 2006; Macnab et al, 1993; Tibballs, 1992). Children may develop severe toxicity at lower levels (Spiller & Krenzelok, 1993).
3) Spiller et al (1990) found poor correlation between rising peak measured serum levels of carbamazepine and the presence of coma, seizure activity, or respiratory depression requiring mechanical ventilation (Spiller et al, 1990).
4) Bridge et al (1991) found that serum levels were predictive of major toxicity symptoms (apnea, seizures, coma) in a 30 patient retrospective study (Bridge et al, 1991).
5) CASE SERIES: In a study of 250 carbamazepine poisonings, Montgomery et al (1995) identified serum levels of 81 to 155 mcmol/L (19.4 to 37 mcg/mL) as being a risk factor for severe toxicity in 98% of these patients and warranting more aggressive monitoring (Montgomery et al, 1995).
6) POSTMORTEM: Carbamazepine does not appear to undergo significant postmortem redistribution. Antemortem and postmortem serum carbamazepine concentrations (drawn from a peripheral vein) following a massive overdose (amount unknown) are reported as 47.7 mcg/mL 9 hr postingestion (2 hr antemortem) and 53 mcg/mL at 9 hr postmortem. Continued drug absorption in the last 2 hours prior to death may have occurred (Spiller & Carlisle, 2001).

b) ADULT

1) Following the ingestion of 20 grams of carbamazepine, the plasma carbamazepine concentration (enzyme multiplied immunoassay technique) was 62 milligrams/liter (261 micromoles/liter) (Leslie et al, 1983). Vree et al (1997) reported a peak plasma level of 49.2 mg/L following ingestion of 20 grams in an adult (Vree et al, 1997).
2) Bertram et al (1998) reported a carbamazepine serum level of 81 mcg/mL in a 33-year-old woman following a suicidal ingestion. The patient eventually recovered despite an EEG reading of electrical silence with intermittent bursts of epileptic activity (Bertram et al, 1998).
3) A serum carbamazepine level of 70 mcg/mL 5 hours following a fatal ingestion was reported in a 27-year-old man (Mordel et al, 1998).
4) Low et al (1996) reported carbamazepine serum concentrations of 54 mcg/mL 10 hours following an acute ingestion of an unknown quantity in a 36-year-old man. Severe altered mental status, respiratory failure and grand mal seizures were reported. The patient had not been on carbamazepine therapy prior to the suicide attempt (Low et al, 1996).
5) A level of 71.5 mcg/mL was seen in a patient with absent bowel sounds, flushed skin, complete ophthalmoplegia, combative behavior, and unresponsiveness (Spiller & Durbin, 1991).

c) ADOLESCENTS

1) Acute ingestion of 5.8 grams (116 mg/kg) carbamazepine (CBZ) in a 16-year-old boy resulted in acute encephalopathy and a serum CBZ level of 10.1 mcg/mL (42.8 micromoles/liter) at 36 hours after ingestion (Saloman & Pippenger, 1975).

a) Peak CBZ levels of greater than 30 micrograms/milliliter (127 micromoles/liter) may have occurred in this patient. The patient was alert and oriented by the fourth hospital day following supportive therapy.

2) CHRONIC TOXICITY: 12-year-old girl, with an epileptic disorder that was maintained on carbamazepine, was found comatose. A carbamazepine serum level of 65.3 mcg/mL (276.2 mcmol/L) was noted at the time of admission. Despite an elevated serum level and comatose state, mechanical ventilation was not required. The patient recovered following supportive care. Hair and serum analyses determined that chronic toxicity occurred due to a decrease in drug clearance of an unknown etiology (Mantzouranis et al, 2004).

d) PEDIATRIC

1) Acute carbamazepine exposure (9.6 micrograms/milliliter at 5.5 hours postingestion) in a 2-year-old child resulted coma and respiratory depression (Spiller et al, 1990a).
2) A 9-year-old girl was reported to have a serum carbamazepine level of 37 milligrams/liter approximately 45 minutes after the ingestion of 2 bottles of carbamazepine syrup. The patient recovered following therapy with naloxone (Razik & Shahzadi, 1998).
3) After the ingestion of unknown quantities of carbamazepine suspension (100 mg/5 mL, maximum possible dose of 7 g; 350 mL), two toddlers (a 3.5-year-old girl and a 2.5-year-old boy) developed coma and tachycardia; the girl also developed transient prolongation of the QTc and respiratory depression requiring endotracheal intubation. Initial carbamazepine levels were 36.6 mg/L and 22.7 mg/L (therapeutic range 4-12 mg/L), respectively. Following supportive care, both patients recovered within 24 hours (Perez & Wiley, 2005).

Toxicity Information

7.7.1)

A) ANIMAL DATA

1) LD50- (ORAL)MOUSE:

a) 529 mg/kg (RTECS , 2001)

2) LD50- (SUBCUTANEOUS)MOUSE:

a) >1 gm/kg (RTECS , 2001)

3) LD50- (ORAL)RAT:

a) 1957 mg/kg (RTECS , 2001)

4) LD50- (SUBCUTANEOUS)RAT:

a) >1500 mg/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

A)

Physicochemical

Physical Characteristics

A)

Molecular Weight

A)

Animal Toxicology

References

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FeedBack

CARBAMAZEPINE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

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Neurologic

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Genitourinary

Acid-Base

Hematologic

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Endocrine

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Monitoring Parameters Levels

Radiographic Studies

Methods

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Patient Disposition

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Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicity Information

Pharmacologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography