Substances Included Synonyms

Therapeutic Toxic Class

A)

B)

Specific Substances

A)

1) Carisoprodol (synonym)
2) Chlorphenesin carbamate
3) Chlormezanone
4) Chlorzoxazone
5) Mephenesin
6) Methocarbamol (synonym)
7) Zoxazolamine
8) Tolperisone

1) Centrally Acting Skeletal Muscle Relaxants
2) Centrally Acting Muscle Relaxants

1.2.1) MOLECULAR FORMULA
1) CARISOPRODOL: C12H24N2O4
2) CHLORZOXAZONE: C7H4ClNO2

Available Forms Sources

A)

1) CENTRALLY ACTING MUSCLE RELAXANTS

DRUGS	DOSAGE FORMS	SINGLE DOSE
Carisoprodol (Rela, Soma)	350 mg tablet	350 mg
Chlorphenesin carbamate (Maolate)	400 mg tablet	800 mg
Chlorzoxazone (Paraflex)	250 mg tablet	250-750 mg
Mephenesin	500 mg tablet	1-2 g
Methocarbamol, USP (Robaxin, others)	500,750 mg tablet; 100 mg/mL injection	1-2 g oral; 1-3 g IV

2) CHLORMEZANONE: As of November, 1996, Sanofi Winthrop manufacturers worldwide have voluntarily instituted a recall of all products which contain chlormezanone (Trancopal(R), Trancopal(R) compositum, Muskel Trancopal(R), Muskel Trancopal(R) compositum, Muskel Trancopal(R) cum codeino), due to toxic epidermal necrolytic reactions (Prod Info Trancopal(R), chlormezanone, 1996).
3) TOLPERISONE: A centrally acting muscle relaxant with an additional vasodilating effect was first described in the early 1960s and generally used as a racemic mixture. It reportedly has fewer sedative side effects than other muscle relaxants. It has been used in Europe and Asia but is NOT available in the US. There have been 3 reports of fatal poisoning associated with intentional tolperisone exposure. Although intoxication is rare, postmortem findings were consistent with a tolperidone-alone exposure (Sporkert et al, 2012). Tolipersone has also been suggested for the treatment of peripheral vascular disease (Martos et al, 2015).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: These medications are used for pain syndromes and muscle spasms. Common medications in this class include carisoprodol and methocarbamol. Other medications in this class include chlorzoxazone, chlorphenesin carbamate, mephenesin, tolperisone (available in Europe and Asia) and zoxazolamine. Tolperisone is a central acting muscle relaxant along with vasodilating effects. These drugs cause their therapeutic effects through CNS depression. They have been used for recreational abuse.
B) PHARMACOLOGY: The mechanism of action of many of these drugs is unknown. Overall, they cause generalized CNS depression, which may alter the perception of pain. The specific mechanisms of carisoprodol and methocarbamol include blockade of interneuronal activity and depression of the polysynaptic neuronal transmission in the spinal cord and reticular formation of the brain.
C) TOXICOLOGY: Their toxicity is an extension of their pharmacology, generally causing CNS depression.
D) EPIDEMIOLOGY: There are thousands of exposures to these drugs in the United States every year. Deaths are very uncommon.
E) WITH THERAPEUTIC USE

1) At therapeutic dosing, one might expect drowsiness, dizziness, and headache. Carisoprodol, in postmarketing reporting and in case reports, has been associated with seizures and idiosyncratic reactions, including severe weakness, transient quadriplegia, euphoria, and temporary vision loss. Hepatotoxicity has rarely been reported following therapeutic doses of chlorzoxazone.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Mild to moderate overdose may cause mental status depression, nystagmus, mydriasis, blurred vision, tachycardia, mild hypotension, nausea, vomiting, dry mouth, lethargy, euphoria, confusion, incoordination, hallucinations, ataxia, and muscle weakness. Anticholinergic symptoms are common with some of these medications, including carisoprodol. Serotonin syndrome has been reported with carisoprodol.
2) SEVERE TOXICITY: Severe overdose may rarely cause coma, shock, respiratory depression, and seizures. Death is extremely rare.

0.2.20)

A) Carisoprodol/aspirin and carisoprodol/aspirin/codeine are classified as FDA pregnancy category D. Carisoprodol, chlorzoxazone, and methocarbamol are classified as FDA pregnancy category C. There have been reports of fetal and congenital anomalies and defects following in utero exposure to methocarbamol. In animal studies, fetal weight gain and postnatal weight gain and survival were decreased following carisoprodol exposure. Carisoprodol achieves measurable concentrations in breast milk of 2 to 4 times those observed in plasma. In a case report of a nursing mother who was taking carisoprodol, there was no evidence of harm to the nursing infant. In animal studies, methocarbamol has been shown to be excreted in dog milk. In mice studies, there was evidence of longer estrous cycles in female mice and reduced testes weight and sperm motility in male mice.

Laboratory Monitoring

A)

B)

C)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) For mild to moderate exposures, good symptomatic and supportive care is the only necessary treatment. While decontamination may decrease the absorption of these drugs, it may not be necessary as most patients require little more than supportive care.

B) MANAGEMENT OF SEVERE TOXICITY

1) For severe toxicity, administer intravenous fluids and vasopressors for hypotension, and endotracheal intubation and mechanical ventilation for severe CNS and respiratory depression. For seizures, administer benzodiazepines initially and add propofol or phenobarbital if seizures persist.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital decontamination is not recommended because of the risk of CNS and respiratory depression and subsequent aspiration.
2) HOSPITAL: Activated charcoal should be considered in patients with large overdoses who present early and are not demonstrating CNS depression and can protect the airway. Gastric lavage is not recommended as these ingestions are rarely life-threatening.

D) AIRWAY MANAGEMENT

1) Airway management may be an issue after large ingestions, and these patients may require intubation for respiratory depression/airway protection.

E) ANTIDOTE

1) None

F) ENHANCED ELIMINATION

1) For ingestions, there is no role for dialysis, hemoperfusion, urinary alkalinization, or multiple dose activated charcoal.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Patients with mild symptoms after small unintentional ingestions may be watched at home as long as someone else is available to obtain help should the patient deteriorate.
2) OBSERVATION CRITERIA: All patients with intentional overdoses, who are having increasing symptoms or are not safe for home management, should be sent in to a health care facility for observation until symptoms improve.
3) ADMISSION CRITERIA: Patients who are symptomatic after a period of observation should be admitted to the hospital. Depending on the severity of the symptoms, the patient may require an ICU admission. Criteria for discharge should be clear improvement of symptoms (eg, patient is alert and able to ambulate safely).
4) CONSULT CRITERIA: A medical toxicologist or poison center should be consulted for patients with severe toxicity or unclear diagnosis.

H) PITFALLS

1) Patients may have prolonged deep coma but still recover. Patients may be symptomatic for a prolonged length of time due to the active metabolites (eg, carisoprodol to meprobamate) and long half-lives (eg, meprobamate) of these drugs.

I) PHARMACOKINETICS

1) Onset, duration of action, absorption, distribution, protein binding, and half-life varies depending on the individual drug. These drugs all undergo hepatic metabolism via both phase I and phase II metabolism pathways and then have excretion through the urine largely as metabolites. Onset of action is usually within 30 minutes with protein binding varying widely. The volume of distribution of these drugs is generally large. Half-lives are as follows: carisoprodol 2 hours; methocarbamol 0.9 to 2 hours; chlorphenesin 3 to 4 hours.

J) PREDISPOSING CONDITIONS

1) These drugs should be used with caution in those with hepatic and renal impairment secondary to their metabolism via these organ systems. Carisoprodol is metabolized primarily via CYP2C19 and should be used with caution in patients with reduced functional alleles of CYP2C19. Poor metabolizers may have a fourfold increase in exposure to carisoprodol and a 50% reduced exposure to the metabolite, meprobamate, compared to normal mechanisms. Depending on the specific agent, patients taking other drugs that inhibit a particular P450 enzyme may be at increased risk of toxicity.

K) DIFFERENTIAL DIAGNOSIS

1) Differential diagnosis includes other causes of depressed mental status (eg, trauma, infection) as well as other sedating medications (eg, benzodiazepines, opioids, etc.).

Range Of Toxicity

A)

B)

Clinical Effects

Vital Signs

3.3.3)

A) WITH POISONING/EXPOSURE

1) CARISOPRODOL: Fever has been reported following overdose (Bramness et al, 2005; Siddiqi & Jennings, 2004).

3.3.4)

A) WITH POISONING/EXPOSURE

1) CARISOPRODOL: Both mild hypertension and mild hypotension have been reported in conjunction with serotonin syndrome after carisoprodol overdose (Bramness et al, 2005).

3.3.5)

A) WITH POISONING/EXPOSURE

1) Mild tachycardia has been reported in overdose with carisoprodol and chlormezanone (Bramness et al, 2005; Goldberg, 1969; Netter et al, 1984).
2) CARISOPRODOL: Sinus tachycardia (130 beats/minute) with a prolonged QT interval has been reported following an overdose (Siddiqi & Jennings, 2004).

Heent

3.4.3)

A) NYSTAGMUS: Horizontal nystagmus and blurred vision have been reported with carisoprodol overdose (Goldberg, 1969).
B) MYDRIASIS was reported after ingestion of 11 g of chlormezanone in a 32-year-old man (Kirkham & Edelman, 1986).

Cardiovascular

3.5.2)

A) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Mild tachycardia has been reported in overdose with carisoprodol and chlormezanone(Bramness et al, 2005; Goldberg, 1969; Netter et al, 1984).
b) CARISOPRODOL: After ingesting 60 carisoprodol tablets (21 g) and an unknown quantity of chlordiazepoxide and temazepam, a 40-year-old man developed coma (with absent tendon and plantar reflexes), sinus tachycardia (130 beats per minute) with a prolonged QT interval, mild respiratory acidosis (pH 7.31; pCO2 50.1 mmHg [partially compensated with artificial ventilation]), fever (100.5 degrees F), hypertension (220/118 mmHg; previous history of hypertension), and dry and warm skin. Following supportive care, he recovered completely without further sequelae (Siddiqi & Jennings, 2004).

B) HYPOTENSIVE EPISODE

1) Mild hypotension has been reported with chlormezanone and carisoprodol (Bramness et al, 2005; Armstrong et al, 1983). Shock has been rarely reported following overdose of carisoprodol (Prod Info carisoprodol oral tablets, 2006).

C) ELECTROCARDIOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) CARISOPRODOL: After ingesting 60 carisoprodol tablets (21 grams) and an unknown quantity of chlordiazepoxide and temazepam, a 40-year-old man developed coma (with absent tendon and plantar reflexes), sinus tachycardia (130 beats per minute) with a prolonged QT interval, mild respiratory acidosis (pH 7.31; pCO2 50.1 mmHg [partially compensated with artificial ventilation]), fever (100.5 degrees F), hypertension (220/118 mmHg; previous history of hypertension), and dry and warm skin. Following supportive care, he recovered completely without further sequelae (Siddiqi & Jennings, 2004).

Respiratory

3.6.2)

A) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) Respiratory depression may occur in patients with significant CNS depression following overdose (Adams et al, 1975; Paillassou-Vakanas et al, 1987; Green & Caravati, 2001).
b) CARISOPRODOL: A 2-year-old ingested 700 mg of carisoprodol and became increasingly drowsy over 60 minutes with symptoms progressing to lethargy and hypoxia. The patient's level of consciousness declined significantly requiring intubation and ventilation. Following activated charcoal and supportive care the patient recovered fully within 12 hours (Green & Caravati, 2001).
c) TOLPERISONE/TODDLER: A 19-month-old toddler ingested up to 1500 mg (150 mg/kg) of tolperisone and developed a rapid decrease in level of consciousness. Within one hour of ingestion, the patient was admitted to the ED in a coma (Glasgow Coma Scale score of 3). Respiratory acidosis (pH 6.90) was present requiring immediate intubation and mechanical ventilation. The patient improved rapidly and was extubated a few hours later and made a complete recovery (Martos et al, 2015).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) SUMMARY

a) The principal toxic effect of intoxication with skeletal muscle relaxants is central nervous depression with coma. Lethargy, drowsiness and fatigue are common side effects at therapeutic doses and may also occur in overdose (Martos et al, 2015; Siddiqi & Jennings, 2004; Stien et al, 1987; Chesrow et al, 1966; Miller, 1976; Ghosh, 1982; Hoogstraten et al, 1988; Bass et al, 1988; Preston et al, 1989).
b) More severe CNS depression including confusion, amnesia and coma is less common (Netter et al, 1984; Liederman & Boldus, 1967; Adams et al, 1975; Armstrong et al, 1983; Roberge et al, 2000; Green & Caravati, 2001).

2) CASE REPORTS

a) CARISOPRODOL: A 2-year-old ingested 700 mg of carisoprodol and became increasingly drowsy over 60 minutes with symptoms progressing to lethargy and hypoxia. The patient's level of consciousness declined significantly requiring respiratory ventilation. Following activated charcoal and supportive care the patient recovered fully within 12 hours (Green & Caravati, 2001).
b) CARISOPRODOL: A 52-year-old woman was taking her carisoprodol tablets in an erratic manner (an estimated 35 extra 350-mg tablets were taken over a 13 day period) and developed stupor (aroused with stimulation) along with confusion and garbled speech. The patient received naloxone with no noticeable improvement; clinical symptoms improved within minutes of flumazenil (0.2 mg IV) administration. A second dose reversed all symptoms of intoxication (Roberge et al, 2000).
c) TOLPERISONE/TODDLER: A 21-month-old toddler ingested 2700 mg (225 mg/kg) of tolperisone and within 35 minutes developed generalized tonic-clonic seizures, apnea and cardiac arrest. Following prolonged resuscitation efforts, the patient had severe acidosis (pH: 6.98), hypokalemia (2.4 mmol/L) and evidence of cerebral hypoxia with spasticity. Fourteen hours after exposure, the plasma tolperisone concentration was 720 mcg/L (therapeutic range: 64 to 785 mcg/L, Tmax 0.9 hours). Persistent neurological sequelae (ie, developmental impairments and muscle spasticity) was still present 9 months after exposure despite rehabilitation (Martos et al, 2015).
d) TOLPERISONE/TODDLER: A 19-month-old toddler ingested up to 1500 mg (150 mg/kg) of tolperisone and developed a rapid decrease in level of consciousness. Within one hour of ingestion, the patient was admitted to the ED in a coma (Glasgow Coma Scale score of 3). Respiratory acidosis (pH 6.90) was present requiring immediate intubation and mechanical ventilation. The patient improved rapidly and was extubated a few hours later and made a complete recovery (Martos et al, 2015).

3) CASE SERIES

a) CARISOPRODOL: In a small study (n=19) of carisoprodol exposure, decreased level of consciousness was observed in 12 individuals, and 8 had developed lethargy. Of 4 patients that were obtunded, only one patient was unresponsive to pain. The authors recognized that the findings may have been confounded by the ingestion of other agents. Supportive care led to recovery in all cases (Bailey & Briggs, 2002).

B) ATAXIA

1) Ataxia and dysmetria may occur at therapeutic doses or in overdose (Goldberg, 1969; Koppel et al, 1991).

C) CENTRAL STIMULANT ADVERSE REACTION

1) SUMMARY

a) CNS excitation and hallucinations are less common effects (Goldberg, 1969) (Kirkham & Edelman, 1986).

D) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizure is rare finding following carisoprodol overdose (Prod Info carisoprodol oral tablets, 2006).
b) TOLPERISONE/TODDLER: A 21-month-old toddler ingested 2700 mg (225 mg/kg) of tolperisone and within 35 minutes developed generalized tonic-clonic seizures, apnea and cardiac arrest. Following prolonged resuscitation efforts, the patient had severe acidosis (pH: 6.98), hypokalemia (2.4 mmol/L) and evidence of cerebral hypoxia with spasticity. Fourteen hours after exposure, the plasma tolperisone concentration was 720 mcg/L (therapeutic range: 64 to 785 mcg/L, Tmax 0.9 hours). Persistent neurological sequelae (ie, developmental impairments and muscle spasticity) was still present 9 months after exposure despite rehabilitation (Martos et al, 2015).

E) DYSTONIA

1) Opisthotonos and torticollis developed in a 24-year-old man taking chlorzoxazone (Badanowski & Powell, 1981).

F) HYPERREFLEXIA

1) Hyperreflexia, ankle clonus, fasciculations, and extensor plantar responses developed in a 32-year-old man who ingested 11 g of chlormezanone (Kirkham & Edelman, 1986).

G) SEROTONIN SYNDROME

1) WITH POISONING/EXPOSURE

a) Four adults developed clinical features of serotonin syndrome after carisoprodol overdose (range, 5.6 to 17.5 g). Mental status alteration, agitation, myoclonus, tremor, fever, tachycardia, and shivering were common; hyperreflexia, diarrhea, sweating, rigidity and mydriasis were less common. All patients recovered with supportive care (Bramness et al, 2005).

Gastrointestinal

3.8.2)

A) APTYALISM

1) Dry mouth may occur as an adverse effect or in overdose (Eyssette et al, 1988) (Hoogstrate et al, 1988) (Stein et al, 1987).

B) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea, vomiting and abdominal pain have occurred at therapeutic doses (Chesrow et al, 1966; Miller, 1976; Preston et al, 1989) .

Hepatic

3.9.2)

A) HEPATIC NECROSIS

1) CHLORZOXAZONE

a) An idiosyncratic non-dose-related hepatotoxic reaction, confirmed by biopsy as centrilobular necrosis, was described in a 55-year-old woman receiving therapeutic doses of a chlorzoxazone-acetaminophen combination.

1) Rechallenge with a single dose of the combination produced jaundice within 5 hours, while a 1 week challenge with APAP alone was tolerated (Powers et al, 1986).

2) At least 21 other cases of hepatitis associated with therapeutic use of chlormezanone have been reported (Ohsawa & Konishi, 1986; Powers et al, 1986).

Acid-Base

3.11.2)

A) RESPIRATORY ACIDOSIS

1) WITH POISONING/EXPOSURE

a) CARISOPRODOL: After ingesting 60 carisoprodol tablets (21 g) and an unknown quantity of chlordiazepoxide and temazepam, a 40-year-old man developed coma (with absent tendon and plantar reflexes), respiratory failure, sinus tachycardia (130 beats per minute) with a prolonged QT interval, mild respiratory acidosis (pH 7.31; pCO2 50.1 mmHg), fever (100.5 degrees F), hypertension (220/118 mmHg; he had a history of hypertension), and dry and warm skin. Following supportive care, he recovered completely without further sequelae (Siddiqi & Jennings, 2004).

Summary Of Exposure

A)

B)

C)

D)

E)

1) At therapeutic dosing, one might expect drowsiness, dizziness, and headache. Carisoprodol, in postmarketing reporting and in case reports, has been associated with seizures and idiosyncratic reactions, including severe weakness, transient quadriplegia, euphoria, and temporary vision loss. Hepatotoxicity has rarely been reported following therapeutic doses of chlorzoxazone.

F)

1) MILD TO MODERATE TOXICITY: Mild to moderate overdose may cause mental status depression, nystagmus, mydriasis, blurred vision, tachycardia, mild hypotension, nausea, vomiting, dry mouth, lethargy, euphoria, confusion, incoordination, hallucinations, ataxia, and muscle weakness. Anticholinergic symptoms are common with some of these medications, including carisoprodol. Serotonin syndrome has been reported with carisoprodol.
2) SEVERE TOXICITY: Severe overdose may rarely cause coma, shock, respiratory depression, and seizures. Death is extremely rare.

Dermatologic

3.14.2)

A) FIXED DRUG ERUPTION

1) Fixed drug eruption has been reported with both chlormezanone and chlorphenesin (Coskey, 1982; McFadden, 1988; Mohamed & Bahru, 1983).

B) CONTACT DERMATITIS

1) MEPHENESIN: Contact dermatitis has been reported with the use of mephenesin-containing ointment (Degreef et al, 1984).

C) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE

1) CHLORMEZANONE: Toxic epidermal necrolysis associated with the use of chlormezanone occurred in a patient with AIDS (Saiag et al, 1992).

D) DRY SKIN

1) WITH POISONING/EXPOSURE

a) Hot, dry skin developed in a 32-year-old man who ingested 11 g of chlormezanone (Kirkham & Edelman, 1986).
b) CARISOPRODOL: After ingesting 60 carisoprodol tablets (21 g) and an unknown quantity of chlordiazepoxide and temazepam, a 40-year-old man developed coma (with absent tendon and plantar reflexes), sinus tachycardia (130 beats/minute) with a prolonged QT interval, mild respiratory acidosis (pH 7.31; pCO2 50.1 mmHg [partially compensated with artificial ventilation]), fever (100.5 degrees F), hypertension (220/118 mmHg; previous history of hypertension), and dry and warm skin. Following supportive care, he recovered completely without further sequelae (Siddiqi & Jennings, 2004).

Reproductive

3.20.1)

A) Carisoprodol/aspirin and carisoprodol/aspirin/codeine are classified as FDA pregnancy category D. Carisoprodol, chlorzoxazone, and methocarbamol are classified as FDA pregnancy category C. There have been reports of fetal and congenital anomalies and defects following in utero exposure to methocarbamol. In animal studies, fetal weight gain and postnatal weight gain and survival were decreased following carisoprodol exposure. Carisoprodol achieves measurable concentrations in breast milk of 2 to 4 times those observed in plasma. In a case report of a nursing mother who was taking carisoprodol, there was no evidence of harm to the nursing infant. In animal studies, methocarbamol has been shown to be excreted in dog milk. In mice studies, there was evidence of longer estrous cycles in female mice and reduced testes weight and sperm motility in male mice.

3.20.2)

A) LACK OF INFORMATION

1) The safe administration of CHLORZOXAZONE or METHOCARBAMOL during pregnancy regarding the potential for fetal harm has not been determined (Prod Info Methocarbamol oral tablets, 2009; Prod Info chlorzoxazone oral tablets, 2008).

B) CONGENITAL ANOMALIES

1) METHOCARBAMOL: There have been reports of fetal and congenital anomalies and defects following in utero exposure to methocarbamol (Prod Info Methocarbamol oral tablets, 2009).

C) ANIMAL STUDIES

1) CARISOPRODOL

a) There was no evidence of teratogenicity in rabbits, rats, or mice exposed to carisoprodol (Prod Info SOMA(R) oral tablets, 2009).
b) In animal studies, carisoprodol crossed the placental barrier. Administration of carisoprodol at doses approximately 1 to 1.5 times the human dose resulted in reduced fetal weights, reduced postnatal weight gain, and reduced postnatal survival. In utero exposure of meprobamate, a metabolite of carisoprodol, in rats resulted in behavioral alterations that continued into adulthood (Prod Info SOMA(R) COMPOUND oral tablets, 2013).

3.20.3)

A) LACK OF INFORMATION

1) The safe administration of CHLORZOXAZONE or METHOCARBAMOL during pregnancy regarding the potential for fetal harm has not been determined (Prod Info Methocarbamol oral tablets, 2009; Prod Info chlorzoxazone oral tablets, 2008).

B) PREGNANCY CATEGORY

1) The manufacturer has classified carisoprodol/aspirin and carisoprodol/aspirin/codeine as FDA pregnancy category D (Prod Info SOMA(R) COMPOUND oral tablets, 2013; Prod Info SOMA(R) COMPOUND with CODEINE oral tablets, 2013).
2) The manufacturers have classified carisoprodol, chlorzoxazone, and methocarbamol as FDA pregnancy category C (Prod Info SOMA(R) oral tablets, 2009; Prod Info Methocarbamol oral tablets, 2009).
3) There are no adequate or well-controlled studies of the carisoprodol, in human pregnancy. Meprobamate is the primary metabolite of carisoprodol. Based on retrospective, postmarketing studies, a consistent association cannot be made between maternal use of meprobamate and an increased risk of congenital malformations. In one study of children exposed to meprobamate in utero, no adverse effects on mental or motor development, or IQ scores were observed (Prod Info SOMA(R) COMPOUND oral tablets, 2013).

C) ANIMAL STUDIES

1) CARISOPRODOL

a) Decreases in fetal weight gain and in postnatal weight gain and survival were reported in animal studies in which carisoprodol exposure was 1 to 1.5 times the human dose based on body surface area (Prod Info SOMA(R) oral tablets, 2009).

3.20.4)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects of exposure to CHLORZOXAZONE or METHOCARBAMOL during lactation in humans (Prod Info Methocarbamol oral tablets, 2009; Prod Info chlorzoxazone oral tablets, 2008).

B) BREAST MILK

1) CARISOPRODOL

a) Carisoprodol is excreted into breast milk and may reach concentrations 2 to 4 times the maternal plasma concentrations. According to 1 case report, a breastfed infant received about 4% to 6% of the maternal daily dose through breast milk, but did not develop any adverse effects. It was determined that milk production was inadequate and the baby was supplemented with formula. In animal lactation studies, carisoprodol use in mice resulted in decreased female pup survival and decreased pup weight at weaning. Based on this information, the use of carisoprodol by a nursing mother may result in decreased milk production or in reduced or less effective infant feeding, possibly due to sedation (Prod Info SOMA(R) COMPOUND oral tablets, 2013).
b) Averaged over 4 consecutive days, the concentrations of carisoprodol and meprobamate (active metabolite) in the breast milk of one woman taking carisoprodol 700 mg daily were 0.9 mcg/mL and 11.6 mcg/mL. The relative dose to an exclusively breast-fed infant was calculated to be 4.1%. When feeding occurred at times when the maternal plasma level was highest, the maximum relative dose could be 6% of the weight-adjusted maternal dose. The infant of this mother, not fully breast-fed, thrived normally and at 6 months of age had normal psychomotor development (Prod Info SOMA(R) oral tablets, 2009; Nordeng et al, 2001).
c) Carisoprodol achieves measurable concentrations in breast milk of 2 to 4 times those observed in plasma (Prod Info SOMA(R) oral tablets, 2009); however, the drug has been safely administered during the breast-feeding period (White & White, 1980). Until more data are available, use caution when considering the use of carisoprodol in lactating women.

2) METHOCARBAMOL

a) This drug has an extensive first-pass metabolism and is completely absorbed from the gastrointestinal tract. Concentrations of methocarbamol in breast milk are low and unlikely to cause adverse effects in the infant (O'Brien, 1974).

C) ANIMAL STUDIES

1) CARISOPRODOL

a) In animal lactation studies, carisoprodol use in mice resulted in decreased female pup survival and decreased pup weight at weaning (Prod Info SOMA(R) COMPOUND oral tablets, 2013).

2) METHOCARBAMOL

a) DOGS: Methocarbamol and/or its metabolites have been shown to be excreted in dog's milk (Prod Info Methocarbamol oral tablets, 2009).

3.20.5)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to CHLORZOXAZONE or METHOCARBAMOL (Prod Info Methocarbamol oral tablets, 2009; Prod Info chlorzoxazone oral tablets, 2008).

B) ANIMAL STUDIES

1) CARISOPRODOL

a) MICE: There was no evidence of impaired fertility when mice were exposed to carisoprodol; however, reproductive cycles were altered and this was characterized by a longer estrous cycle when female mice were given 1200 mg/kg/day. In a 13-week toxicology study, testes weight and sperm motility in mice were decreased after exposure to 1200 mg/kg/day. In both studies, the no effect level was 750 mg/kg/day (approximately 2.6 times the human equivalent dosage of 350 mg 4 times daily on a mg/m(2) basis (Prod Info SOMA(R) oral tablets, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) No specific laboratory tests are indicated.
B) Monitor patients with significant CNS depression for respiratory insufficiency and rhabdomyolysis.
C) Qualitative or quantitative levels of these agents in the blood or urine may be obtained by certain labs, but are not useful or generally available for clinical management.

Methods

A)

1) GAS CHROMATOGRAPHY-MASS SPECTROMETRY (GC/MS): Qualitative or quantitative levels of these agents in the blood or urine may be obtained through gas chromatograph/mass spectrophotometric analysis. Without this equipment, toxicologic analysis of these drugs is not generally available in the clinical setting.
2) CARISOPRODOL: A colorimetric procedure which does not distinguish between metabolites (Hoffman & Ludwig, 1959) and a specific gas chromatographic method (Siddiqi & Jennings, 2004; Adams et al, 1975) have been described.
3) CHLORZOXAZONE: Ultraviolet spectrophotometry (Conney & Burns, 1960), fluorometry (Stewart & Chan, 1978), and high-pressure liquid chromatography (Honigberg et al, 1979; Lucas et al, 1993; Stiff et al, 1993) have been used to detect chlorzoxazone in biological specimens.

a) A thin-layer chromatography method misinterpreted chlorzoxazone as aprobarbital (Breiner et al, 1984).

4) CHLORPHENESIN: A spectrophotometric method for determining concentrations of chlorphenesin in serum has been described (Forist & Judy, 1971).
5) CHLORMEZANONE: A high performance liquid chromatography method for determining concentrations of chlormezanone in plasma and blood has been described (Koppel et al, 1991).
6) METHOCARBAMOL: Thin layer chromatography, spectrophotometric, gas liquid chromatography and high performance liquid chromatography methods for detecting methocarbamol in biologic fluids have been reported (Kemal et al, 1982).
7) MEPHENESIN: A colorimetric method for detecting mephenesin in plasma has been described (Huf et al, 1959). High performance liquid chromatography with photodiode array detection (DAD) was used to sample all biological fluids in one patient postmortem. It confirmed the presence and concentration of mephenesin; gas chromatography-mass spectrometry was also used for hair analysis and detected mephenesin absorption over the 6 months prior to the patient's death (Fanton et al, 2007).
8) ZOXAZOLAMINE: A spectrophotometric method determining concentrations of zoxazolamine in urine has been described (Conney & Burns, 1960).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) SUMMARY: Patients who are symptomatic after a period of observation should be admitted to the hospital. Depending on the severity of the symptoms, the patient may require an ICU admission. Criteria for discharge should be clear improvement of symptoms (eg, patient is alert and able to ambulate safely).
B) CARISOPRODOL: Symptomatic patients should be observed in a health care facility for at least 24 hours (Ellenhorn & Barceloux, 1988).

6.3.1.2) HOME CRITERIA/ORAL

A) SUMMARY: Patients with mild symptoms after small unintentional ingestions may be watched at home as long as someone else is available to obtain help should the patient deteriorate.

6.3.1.3) CONSULT CRITERIA/ORAL

A) A medical toxicologist or poison center should be consulted for patients with severe toxicity or unclear diagnosis.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) SUMMARY: All patients with intentional overdoses, who are having increasing symptoms or are not safe for home management, should be sent in to a health care facility for observation until symptoms improve.

Monitoring

A)

B)

C)

Oral Exposure

6.5.1)

A) NOT RECOMMENDED

1) Prehospital decontamination is not recommended because of the risk of CNS and respiratory depression and subsequent aspiration.

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).

6.5.3)

A) 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).

B) SEIZURE

1) SUMMARY

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

2) DIAZEPAM

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

3) NO INTRAVENOUS ACCESS

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

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

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

6) OTHER AGENTS

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

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

7) RECURRING SEIZURES

a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:

1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)

b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

C) FLUID/ELECTROLYTE BALANCE REGULATION

1) Fluids and electrolytes should be monitored closely.

D) MONITORING OF PATIENT

1) No specific laboratory tests are indicated.
2) Monitor patients with significant CNS depression for respiratory insufficiency and rhabdomyolysis.
3) Qualitative or quantitative levels of these agents in the blood or urine may be obtained by certain labs, but are not useful or generally available for clinical management.

E) FLUMAZENIL

1) CASE REPORTS

a) Roberge et al (1998) reported the successful use of intravenous flumazenil (0.1 mg followed by 0.25 mg 30 minutes later) after chlorzoxazone overdose (chlorzoxazone levels 39 mcg/mL) in a patient with coma(Roberge et al, 1998). The patient did have a positive benzodiazepine drug screen, but the levels were subtherapeutic or therapeutic and probably not a direct cause of the patient's coma. The authors suggested that chlorzoxazone may interact with benzodiazepine receptors, making flumazenil potentially useful in overdose.
b) A 52-year-old female who was reportedly taking her carisoprodol tablets in an erratic fashion (an estimated 35 extra tablets were taken over a 13 day period) developed stupor (aroused with stimulation) along with confusion and garbled speech. Drug screen was positive for carisoprodol (serum level 7.4 mcg/mL) and meprobamate (serum level 30.7 mcg/mL) only. The patient received naloxone with no noticeable improvement; clinical symptoms improved within minutes of flumazenil (0.2 mg IV) administration. A second dose reversed all symptoms of intoxication (Roberge et al, 2000).

2) SEROTONIN SYNDROME

a) SUMMARY

1) 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).

b) HYPERTHERMIA

1) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
2) 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.
3) Non-depolarizing paralytics may be used in severe cases.

c) CYPROHEPTADINE

1) 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.
2) 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).
3) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).

d) HYPERTENSION

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

e) HYPOTENSION

1) 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.
2) 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.
3) NOREPINEPHRINE

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

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

c) MAINTENANCE DOSE

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

f) SEIZURES

1) DIAZEPAM

a) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
b) 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.
c) 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.
d) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.

2) LORAZEPAM

a) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
b) 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).
c) 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, 2009; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).

3) RECURRING SEIZURES

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

4) PHENOBARBITAL

a) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
b) 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.
c) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
d) 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.
e) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
f) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
g) 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.
h) 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.
i) 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.
j) 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.
k) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.

g) CHLORPROMAZINE

1) 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.
2) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
3) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.

h) NOT RECOMMENDED

1) 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).

Enhanced Elimination

A)

1) For ingestions, there is no role for dialysis, hemoperfusion, urinary alkalinization, or multiple dose activated charcoal.

B)

1) Excretion of the active compounds is NOT known to be enhanced by fluid diuresis.

Abstracts

Case Reports

A)

1) CARISOPRODOL: Following ingestion of 27 350-mg carisoprodol tablets and 24 250-mg carisoprodol tablets in an 18- and 20-year-old men, respectively, both patients developed drowsiness, lethargy, headache, vertigo, diplopia, and nystagmus on lateral gaze. The 20-year-old patient observed objects floating before his eyes, ataxia, and slurred speech, while the 18-year-old, developed extreme agitation and persistent tachycardia. Both patients were given ipecac, and one patient received gastric lavage. IV fluids were administered in both patients. Both patients recovered fully approximately 13 hours postingestion (Goldberg, 1969).
2) CARISOPRODOL: After ingesting 60 carisoprodol tablets (21 g) and an unknown quantity of chlordiazepoxide and temazepam, a 40-year-old man developed coma (with absent tendon and plantar reflexes), sinus tachycardia (130 beats per minute) with a prolonged QT interval, mild respiratory acidosis (pH 7.31; pCO2 50.1 mmHg [partially compensated with artificial ventilation]), fever (100.5 degrees F), hypertension (220/118 mmHg; he had a history of hypertension), and dry and warm skin. In addition, he demonstrated anticholinergic signs; pupils were symmetric, dilated, and sluggishly reactive to light. Breath sounds were coarse with rales on the right side. Abdominal exam showed absent bowel sounds as often seen in an anticholinergic toxidrome. Blood levels were: carisoprodol 107 mg/L (therapeutic range -10 to 40 mg/L) and fell to 47.6 and 22 mg/L on the second and third days, respectively; chlordiazepoxide was 2.3 mg/L (therapeutic range: 0.4 to 1.5 mg/L). Following supportive care, he recovered completely without further sequelae (Siddiqi & Jennings, 2004).
3) CHLORMEZANONE: A 32-year-old man ingested 11 g of chlormezanone and developed prominent anticholinergic effects (ie, mydriasis, hot, dry skin), coma, flaccidity, and absent reflexes. Five hours postingestion, symptoms of coma alternated with periods of excitement and gradually resolved over the next 12 to 30 hours (Kirkham & Edelman, 1986)
4) CHLORMEZANONE: A 36-year-old woman ingested 7 g of chlormezanone and developed coma, hypotension and flaccid muscle tone within 5 hours of exposure. Over the next 15 hours, she regained consciousness and blood pressure normalized (Armstrong et al, 1983).
5) CHLORMEZANONE: A 28-year-old woman ingested 9 g of chlormezanone and became drowsy and vomited, however, vital signs include pulse, blood pressure, and respiration remained normal (Marks, 1961).
6) CHLORZOXAZONE: A 57-year-old man intentionally overdosed on chlorzoxazone twice. During the first episode, the patient ingested 3.5 g and became rapidly comatose. Naloxone was given with a slight increase in responsiveness. The patient was intubated and ventilated; recovery was uneventful. Following the second episode, the patient ingested an unknown amount of chlorzoxazone and became confused, somnolent, then comatose, with 2 mm sluggishly reactive pupils. Naloxone (0.8 mg) was ineffective. Flumazenil was then given with rapid reversal of the patient's obtunded state without a need for intubation. In both episodes, a screen for benzodiazepines was positive, but levels were either subtherapeutic or therapeutic (Roberge et al, 1998).

Range Of Toxicity

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) CARISOPRODOL

a) ADULTS AND ADOLESCENTS 16 YEARS AND OLDER: The recommended oral dose is 250 mg to 350 mg 3 times per day and at bedtime. MAXIMUM DURATION OF USE: Up to 3 weeks (Prod Info SOMA oral tablets, 2013).
b) OVER 65 YEARS: Safety and efficacy have not been established (Prod Info SOMA oral tablets, 2013).

2) CARISOPRODOL/ASPIRIN

a) ADULTS AND ADOLESCENTS 16 YEARS AND OLDER: The recommended oral dose is 1 or 2 tablets (each tablet contains carisoprodol 200 mg/aspirin 325 mg) 4 times per day. MAXIMUM DOSE: 2 tablets 4 times per day (total daily dose, carisoprodol 1600 mg/aspirin 2600 mg); MAXIMUM DURATION OF USE: up to 2 or 3 weeks (Prod Info SOMA(R) COMPOUND oral tablets, 2013).
b) OVER 65 YEARS OF AGE: Safety and efficacy have not been established (Prod Info SOMA(R) COMPOUND oral tablets, 2013).

3) CARISOPRODOL/ASPIRIN/CODEINE

a) ADULTS AND ADOLESCENTS 16 YEARS AND OLDER: The recommended oral dose is 1 or 2 tablets (each tablet contains carisoprodol 200 mg/aspirin 325 mg/codeine phosphate 16 mg) 4 times per day. MAXIMUM DOSE: 2 tablets 4 times per day (total daily dose, carisoprodol 1600 mg/aspirin 2600 mg/codeine phosphate 128 mg); MAXIMUM DURATION OF USE: Up to 2 or 3 weeks (Prod Info SOMA(R) COMPOUND with CODEINE oral tablets, 2013a).
b) OVER 65 YEARS OF AGE: Safety and efficacy have not been established (Prod Info SOMA(R) COMPOUND with CODEINE oral tablets, 2013a).

4) CHLORZOXAZONE

a) The recommended dose is 1 tablet (500 mg) 3 or 4 times per day. If pain is not relieved, increase dose to one and one-half tablets (750 mg) 3 or 4 times per day. Reduce dose as improvement occurs (Prod Info chlorzoxazone oral tablets, 2008).

5) METHOCARBAMOL

a) ORAL:

1) MODERATE ANALGESIA: ADULTS AND ADOLESCENTS 16 YEARS AND OLDER: For the first 48 to 72 hours, the recommended dose is 1500 mg 4 times per day for a total daily dose of 6 g. For more severe conditions, 8 g/day may be given. The recommended maintenance dose is 4000 to 4500 mg/day in equally-divided doses (Prod Info Methocarbamol oral tablets, 2009).
2) TETANUS: After conditions allow for a nasogastric tube to be inserted, crush tablets in water or saline to administer through the tube. Total daily oral dose up to 24 g may be necessary based on patient response (Prod Info ROBAXIN(R) injection, 2003).

b) INJECTION (IV and IM):

1) MODERATE ANALGESIA: A single dose of 1 g (one 10-mL vial) may be adequate. May repeat 1-g doses every 8 hr. MAXIMUM DOSE: Do not exceed 3 g/day for more than 3 consecutive days, except in the treatment of tetanus (Prod Info ROBAXIN(R) injection, 2003).

a) INTRAVENOUS: MAXIMUM RATE: 3 mL/minute (Prod Info ROBAXIN(R) injection, 2003).
b) IM: Not more than 5 mL (one-half vial) should be injected into each gluteal region; dose may be repeated at 8-hr intervals, if needed. After adequate relief is maintained, patient may be maintained on oral tablets (Prod Info ROBAXIN(R) injection, 2003).

2) TETANUS: An initial dose of up to 30 mL (3 vials) is recommended. Start by injecting 1 or 2 vials directly into the tubing of the previously inserted indwelling needle. Then, an additional 10 to 20 mL may be added to the infusion bottle. Repeat this procedure at 6-hr intervals until a nasogastric tube can be inserted (Prod Info ROBAXIN(R) injection, 2003).

6) VOLUNTARY RECALL

a) CHLORMEZANONE: NOTE: As of November, 1996, Sanofi Winthrop manufacturers worldwide have voluntarily instituted a recall of all products which contain chlormezanone (Trancopal(R), Trancopal(R) compositum, Muskel Trancopal(R), Muskel Trancopal(R) compositum, Muskel Trancopal(R) cum codeino), due to toxic epidermal necrolytic reactions (Prod Info Trancopal(R), chlormezanone, 1996).

7.2.2)

A) SPECIFIC SUBSTANCE

1) CARISOPRODOL

a) 16 YEARS AND OLDER: The recommended oral dose is 250 mg to 350 mg 3 times per day and at bedtime. MAXIMUM DURATION OF USE: Up to 3 weeks (Prod Info SOMA oral tablets, 2013).
b) LESS THAN 16 YEARS: Safety and efficacy have not been established (Prod Info SOMA oral tablets, 2013).

2) CARISOPRODOL/ASPIRIN

a) 16 YEARS AND OLDER: The recommended oral dose is 1 or 2 tablets (each tablet contains carisoprodol 200 mg/aspirin 325 mg) 4 times per day. MAXIMUM DOSE: 2 tablets 4 times per day (total daily dose, carisoprodol 1600 mg/aspirin 2600 mg); MAXIMUM DURATION OF USE: Up to 2 or 3 weeks (Prod Info SOMA(R) COMPOUND oral tablets, 2013).
b) LESS THAN 16 YEARS: Safety and efficacy have not been established (Prod Info SOMA(R) COMPOUND oral tablets, 2013).

3) CARISOPRODOL/ASPIRIN/CODEINE

a) 16 YEARS AND OLDER: The recommended oral dose is 1 or 2 tablets (each tablet contains carisoprodol 200 mg/aspirin 325 mg/codeine phosphate 16 mg) 4 times per day. MAXIMUM DOSE: 2 tablets 4 times per day (total daily dose, carisoprodol 1600 mg/aspirin 2600 mg/codeine phosphate 128 mg); MAXIMUM DURATION OF USE: Up to 2 or 3 weeks (Prod Info SOMA(R) COMPOUND with CODEINE oral tablets, 2013a).
b) LESS THAN 16 YEARS: Safety and efficacy have not been established (Prod Info SOMA(R) COMPOUND with CODEINE oral tablets, 2013a).

4) CHLORZOXAZONE

a) There are no data in the manufacturer's package insert regarding safety and efficacy of chlorzoxazone use in pediatric patients.

5) METHOCARBAMOL

a) ORAL:

1) 16 YEARS AND OLDER: For the first 48 to 72 hours, the recommended dose is 1500 mg 4 times per day for a total daily dose of 6 g. For more severe conditions, 8 g/day may be given. Thereafter, the recommended maintenance dose is 4000 to 4500 mg/day in equally-divided doses (Prod Info Methocarbamol oral tablets, 2009).
2) LESS THAN 16 YEARS: Safety and efficacy have not been established (Prod Info Methocarbamol oral tablets, 2009).

b) INJECTION (IV and IM):

1) MODERATE ANALGESIA: Safety and efficacy have not been established in pediatric patients (Prod Info ROBAXIN(R) injection, 2003).
2) TETANUS: The recommended initial dose is a minimum of 15 mg/kg or 500 mg/m(2) repeated at 6-hr intervals if required. MAXIMUM DOSE: 1.8 g/m(2) for 3 consecutive days. Administer the maintenance dose by injection into tubing or IV infusion with the appropriate quantity of fluid. MAXIMUM RATE FOR IV INFUSION: 3 mL/minute (Prod Info ROBAXIN(R) injection, 2003).

B) VOLUNTARY RECALL

1) CHLORMEZANONE: NOTE: As of November, 1996, Sanofi Winthrop manufacturers worldwide have voluntarily instituted a recall of all products which contain chlormezanone (Trancopal(R), Trancopal(R) compositum, Muskel Trancopal(R), Muskel Trancopal(R) compositum, Muskel Trancopal(R) cum codeino), due to toxic epidermal necrolytic reactions (Prod Info Trancopal(R), chlormezanone, 1996).

Minimum Lethal Exposure

A)

1) Acute poisoning with these agents is rarely fatal, and a lethal dose is not established.

B)

1) SPECIFIC SUBSTANCE

a) CARISOPRODOL: Ingestion of 3.5 g by a 5-year-old child was reported to result in coma, and death 40 hours postingestion (Adams et al, 1975).
b) CHLORMEZANONE: It has been reported in combination with other drugs in 3 fatal overdoses. Chlormezanone blood levels in these cases ranged from 9 to 53 mcg/mL (Koppel et al, 1991).

Maximum Tolerated Exposure

A)

1) In a retrospective study of 56 cases involving acute skeletal muscle relaxant exposure during a one year period, it was concluded that morbidity and mortality associated with pure skeletal muscle relaxant ingestion are low (Lebby et al, 1990).

B)

1) SPECIFIC SUBSTANCE

a) CARISOPRODOL

1) CASE SERIES/ADULT: In a prospective study of 34 patients who abused carisoprodol, most patients were introduced to the drug by their friends or other addicts and were taking the drug to get a better "high" or to help with the withdrawal of other drugs (mainly opioids). Most individuals were using up to 10 tablets in a day (3500 mg) in 2 to 3 divided doses. Dose-dependent effects were reported by most individuals. In most cases, ingestion of 1 to 3 tablets (each tablet 350 mg) produced a general feeling of wellbeing; ingestion of 4 to 10 tablets produced hypomania (ie, excessive cheerfulness, psychomotor excitation) and greater than 10 tablets produced confusion, disorientation and partial amnesia of events. In addition, most individuals gradually developed craving (97%) and tolerance (85%) for carisoprodol. Withdrawal symptoms (70%) were also likely to occur and included restlessness (35%), weakness/reduced energy (23%), aches and pains (20.5%), irritability (20%), reduced sleep (17.6%) lack of pleasure (11.7%), drowsiness (5.8%), watery stools (5.8%) and reduced appetite (2.9%) (Nebhinani et al, 2013).
2) ADULT: Adults have ingested between 8.4 and 9.5 g of carisoprodol and survived (Goldberg, 1969). After ingesting 60 carisoprodol tablets (21 g) and an unknown quantity of chlordiazepoxide and temazepam, a 40-year-old man recovered completely following supportive care. Blood levels were: carisoprodol 107 mg/L (therapeutic range, 10 to 40 mg/L); chlordiazepoxide 2.3 mg/L (therapeutic range, 0.4 to 1.5 mg/L) (Siddiqi & Jennings, 2004).
3) YOUNG ADULT: A 19-year-old ingested 14.7 g and developed seizures for 17 hours and coma for 33 hours, but survived (Brandslung et al, 1976).
4) TODDLER: A 2-year-old developed respiratory and central nervous system depression after ingesting 700 mg of carisoprodol. The patient recovered completely following airway management and supportive care (Green & Caravati, 2001).

b) CHLORMEZANONE

1) SUMMARY: Coma, hypotension, and/or anticholinergic effects have been seen, and survival has been seen with doses ranging from 7 to 11 g. A more severe clinical picture, with coma and anticholinergic effects, was seen after ingestion of 11 g (Kirkham & Edelman, 1986).
2) ADULT: Ingestion of 7 g chlormezanone in an adult resulted in coma and hypotension (Armstrong et al, 1983).
3) ADULT: Ingestion of 9 g chlormezanone in an adult resulted in drowsiness and vomiting (Marks, 1961).

c) CHLORZOXAZONE

1) SUMMARY: Severe symptoms have been reported in one adult after ingestion of 10 g (Prod Info, 1978). (CHECK)
2) LACK OF EFFECT: Ingestion of 5 g in an adult resulted in no adverse effect.

d) TOLPERISONE

1) CASE SERIES: In retrospective review conducted between 1995 and 2013, 75 cases of acute tolperisone overdose were identified. Of these cases, 72 were tolperisone alone ingestions and the remaining 3 cases included a coingestion of NSAIDs (ie, ibuprofen (max 6000 mg in one and 3600 mg in one) and acemetacin 1200 mg). A total of 23 patients (6 adults and 17 children) remained asymptomatic; mild symptoms were observed in 35 patients (25 adults and 10 children); moderate symptoms occurred in 9 adults and severe symptoms occurred in 8 patients (5 adults and 3 children). Of the 3 cases that developed severe symptoms, 2 had coingested NSAIDs. No fatalities were reported. Somnolence was the most frequent adverse event. Other common events included generalized tonic-clonic seizures, coma and apnea. A decrease in level of consciousness, seizures, respiratory depression and acidosis, apnea, tachycardia, and prolonged QTc interval were observed in severe cases. Cardiac arrest occurred in a toddler. Although most adults reported the amount they had ingested, there was no clear dose-effect relationship. In adults, the minimal dose for seizure activity was 1500 mg and 3700 mg for coma. The onset of seizures was likely to occur within the first hour following ingestion (Martos et al, 2015).

a) TODDLER: A 21-month-old toddler ingested 2700 mg (225 mg/kg) of tolperisone and within 35 minutes developed generalized tonic-clonic seizures, apnea and cardiac arrest. Following prolonged resuscitation efforts, the patient had severe acidosis (pH: 6.98), hypokalemia (2.4 mmol/L) and evidence of cerebral hypoxia with spasticity. Fourteen hours after exposure, the plasma tolperisone concentration was 720 mcg/L (therapeutic range: 64 to 785 mcg/L, Tmax 0.9 hours). Persistent neurological sequelae (ie, developmental impairments and muscle spasticity) was still present 9 months after exposure despite rehabilitation (Martos et al, 2015).
b) TODDLER: A 19-month-old toddler ingested up to 1500 mg (150 mg/kg) of tolperisone and developed a rapid decrease in level of consciousness. Within one hour of ingestion, the patient was admitted to the ED in a coma (Glasgow Coma Scale score of 3). Respiratory acidosis (pH 6.90) was present requiring immediate intubation and mechanical ventilation. The patient improved rapidly and was extubated a few hours later and made a complete recovery (Martos et al, 2015).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CONCENTRATION LEVEL

a) SPECIFIC SUBSTANCE

1) CARISOPRODOL

a) Blood concentrations and clinical effects are summarized in the table below:

AGE (yr)	BLOOD CONCENTRATION (mg/L)	TIME POST- INGESTION (hr)	CLINICAL EFFECT	REFERENCE
-	31	unk*	Stupor	Maes, 1970
5	36	4.5	Death	Adams, 1975
18	38	4.5	Drowsy	Goldberg, 1969
19	13.4	19	Coma	Brandslung, 1976
20	37	5	Drowsy	Goldberg, 1969
40	107	unk*	Coma	Siddiqi et al, 2004
43	39.3	unk*	Death	Backer, 1990
36	6.5	unk*	Death	Backer, 1990
34	7.9	unk*	Death	Backer, 1990
unk* - unknown

2) CARISOPRODOL: After ingesting sixty carisoprodol tablets (21 g) and an unknown quantity of chlordiazepoxide and temazepam, a 40-year-old man developed coma and respiratory failure, but recovered fully following supportive care and mechanical ventilation. The blood level of carisoprodol was 107 mg/L (therapeutic range: 10 to 40 mg/L) and the blood level of chlordiazepoxide was 2.3 mg/L (therapeutic range: 0.4 to 1.5 mg/L) (Siddiqi & Jennings, 2004).
3) CHLORMEZANONE: Has been reported in combination with other drugs in 3 fatal overdoses. Chlormezanone blood levels in these cases ranged from 9 to 53 mcg/mL (Koppel et al, 1991).
4) MEPHENESIN: In one fatal case, the blood concentration of mephenesin was 15.81 mcg/mL (approximately 15-fold greater than the maximum concentration following a single 500-mg dose). Other concentrations included: 3.5 mcg/mL gastric content, 69.75 mcg/mL (after dilution ) in pericardiac liquid, and 73.97 mcg/mL (after dilution) in pleural effusion liquid. Postmortem findings revealed that the cause of death was due to bronchial inhalation syndrome secondary to mephenesin intoxication (Fanton et al, 2007).
5) METHOCARBAMOL: In 3 fatal cases blood concentrations were 320 mg/L (with secobarbital 55 mg/L) (Baselt, 1982), 525 mg/L (with ethanol 140 mg/dL) (Kemal et al, 1982), and 257 mg/L (ethanol 135 mg/dL) (Ferslew et al, 1990).

Toxicity Information

7.7.1)

A) CARISOPRODOL

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 800 mg/kg (RTECS , 2001)

2) LD50- (ORAL)MOUSE:

a) 1800 mg/kg (RTECS , 2001)

3) LD50- (INTRAPERITONEAL)RAT:

a) 450 mg/kg (RTECS , 2001)

4) LD50- (ORAL)RAT:

a) 1320 mg/kg (RTECS , 2001)

B) CHLORPHENESIN

1) LD50- (SUBCUTANEOUS)MOUSE:

a) 911 mg/kg (RTECS , 2001)

2) LD50- (ORAL)RAT:

a) 748 mg/kg

C) CHLORZOXAZONE

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 50 mg/kg (RTECS , 2001)

2) LD50- (ORAL)MOUSE:

a) 440 mg/kg (RTECS , 2001)

3) LD50- (SUBCUTANEOUS)MOUSE:

a) 170 mg/kg (RTECS , 2001)

4) LD50- (INTRAPERITONEAL)RAT:

a) 150 mg/kg (RTECS , 2001)

5) LD50- (ORAL)RAT:

a) 763 mg/kg (RTECS , 2001)

D) MEPEHENSIN

1) LD50- (ORAL)MOUSE:

a) 990 mg/kg

2) LD50- (ORAL)RAT:

a) 945 mg/kg

Summary

A)

B)

Pharmacology Toxicology

Pharmacologic Mechanism

A)

1) Drugs in this group act on the central nervous system and are claimed to relieve skeletal muscle spasms. Many are similar in chemical structure to drugs used primarily to treat anxiety and tension.

a) They appear to be most effective in relieving acute muscular spasm of local origin, but their exact pharmacological mechanism of action is still poorly demonstrated.

2) Most of these agents are simple nervous system depressants which exhibit a blocking action on the interneurons and appear to modify perception of pain without abolishing peripheral pain reflexes. They do not affect the pain threshold (De Lee & Rockwood, 1980).

Physicochemical

Physical Characteristics

A)

B)

C)

Molecular Weight

A)

B)

C)

Animal Toxicology

References

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SKELETAL MUSCLE RELAXANTS - CENTRAL ACTING

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Acid-Base

Summary Of Exposure

Dermatologic

Reproductive

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicity Information

Summary

Pharmacologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography