MOBILE VIEW  | 

TRIMETHADIONE

Classification   |    Detailed evidence-based information

Therapeutic Toxic Class

    A) Trimethadione and paramethadione are oxazolidinedione antiepileptic agents used for the treatment of absence seizures in patients who are unresponsive to other treatment.

Specific Substances

    A) PARAMETHADIONE (SYNONYM)
    1) 5-Ethyl-3,5-dimethyl-1,3-oxazolidine-2,4-dione
    2) Molecular Formula: C7-H11-N-O3
    3) CAS 115-67-3
    TRIMETHADIONE (SYNONYM)
    1) Troxidone
    2) Trimetadiona
    3) Trimethadionum
    4) Trimethinum
    5) 3,5,5-Trimethyl-1,3-oxazolidine-2,4-dione
    6) CAS 127-48-0

Available Forms Sources

    A) FORMS
    1) Paramethadione was available as 150 mg and 300 mg capsules (Prod Info Paradione(R), paramethadione, 1991).
    2) Trimethadione was available as 150 mg chewable tablets, 300 mg capsules, and 40 mg/mL oral solution (Prod Info Tridione(R), trimethadione, 1994).
    B) USES
    1) Paramethadione and trimethadione, formerly important for treating absence epilepsy, now seems to have almost completely disappeared from clinical use (Eadie & Vajda, 1999).
    2) Oral trimethadione has been used for dissolution of pancreatic stones in patients with chronic calcific pancreatitis (Noda et al, 1994).

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) OVERDOSE-
    1) Trimethadione or paramethadione overdose ingestions may cause drowsiness, nausea, dizziness, ataxia, and visual disturbances. Coma may occur following severe overdose ingestions.
    B) ADVERSE EFFECTS AT THERAPEUTIC DOSE-
    1) Adverse effects following therapeutic use of trimethadione may include blood dyscrasias, hepatitis, nephrosis, ocular abnormalities, drug-induced systemic lupus erythematosus, and skin rashes. A myasthenia gravis-like syndrome has been associated with chronic trimethadione use. Abrupt withdrawal of trimethadione or paramethadione may precipitate seizures.
    C) Trimethadione and paramethadione are considered severe teratogens. Maternal ingestions of these drugs during pregnancy may cause a fetal trimethadione syndrome, characterized by developmental delay, speech difficulty, V-shaped eyebrows, low-set ears with anteriorly folded helix, palatal anomaly, and irregular teeth.
    1) Other congenital anomalies may include intrauterine growth retardation, short stature, microcephaly, cardiac anomalies, ocular anomalies, hypospadias, inguinal hernia, and simian creases.
    0.2.7) NEUROLOGIC
    A) Drowsiness, fatigue, and malaise have been associated with trimethadione use and may occur following acute trimethadione or paramethadione overdosage. Hyperactivity occurs infrequently following trimethadione therapy.
    B) Dizziness, ataxia, and coma may occur following an acute overdose of trimethadione or paramethadione.
    C) A myasthenia gravis-like syndrome has been reported following trimethadione therapy.
    D) Seizures may occur during trimethadione therapy or following abrupt discontinuation of trimethadione or paramethadione therapy.
    0.2.10) GENITOURINARY
    A) Nephrosis has been associated with the chronic ingestion of trimethadione and paramethadione and has been fatal in some instances.
    0.2.19) IMMUNOLOGIC
    A) Systemic lupus erythematosus may occur following therapeutic use of trimethadione.
    B) Lymphadenopathies and swelling of the thyroid gland have been reported following trimethadione therapy.
    0.2.20) REPRODUCTIVE
    A) Trimethadione and paramethadione are severe teratogens and may cause fetal trimethadione syndrome, characterized by developmental delay, speech difficulty, V-shaped eyebrows, low-set ears with anteriorly folded helix, palatal anomaly, and irregular teeth.
    B) Other teratogenic effects, caused by maternal ingestion of trimethadione or paramethadione during pregnancy, include intrauterine growth retardation, short stature, microcephaly, cardiac anomaly, ocular anomaly, hypospadias, inguinal hernia, and simian creases.
    C) Trimethadione and paramethadione are categorized as FDA Pregnancy Category D.

Laboratory Monitoring

    A) No specific laboratory studies are needed after overdose, unless otherwise clinically indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    D) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    E) For infants who have been exposed in utero to trimethadione, phytonadione (vitamin K) injections should be given to newborns immediately after delivery in order to prevent hemorrhagic disease.

Range Of Toxicity

    A) Mild photophobia has been reported in patients ingesting trimethadione in doses exceeding 0.9 grams daily.

Summary Of Exposure

    A) OVERDOSE-
    1) Trimethadione or paramethadione overdose ingestions may cause drowsiness, nausea, dizziness, ataxia, and visual disturbances. Coma may occur following severe overdose ingestions.
    B) ADVERSE EFFECTS AT THERAPEUTIC DOSE-
    1) Adverse effects following therapeutic use of trimethadione may include blood dyscrasias, hepatitis, nephrosis, ocular abnormalities, drug-induced systemic lupus erythematosus, and skin rashes. A myasthenia gravis-like syndrome has been associated with chronic trimethadione use. Abrupt withdrawal of trimethadione or paramethadione may precipitate seizures.
    C) Trimethadione and paramethadione are considered severe teratogens. Maternal ingestions of these drugs during pregnancy may cause a fetal trimethadione syndrome, characterized by developmental delay, speech difficulty, V-shaped eyebrows, low-set ears with anteriorly folded helix, palatal anomaly, and irregular teeth.
    1) Other congenital anomalies may include intrauterine growth retardation, short stature, microcephaly, cardiac anomalies, ocular anomalies, hypospadias, inguinal hernia, and simian creases.

Heent

    3.4.3) EYES
    A) HEMERALOPIA (diminished vision in bright light) has been reported as an effect of trimethadione on the neural layers of the retina (Prod Info Tridione(R), trimethadione, 1994).
    B) PHOTOPHOBIA was reported in 80% of patients who ingested trimethadione, greater than 900 mg daily, during a study to determine the efficacy of trimethadione in dissolving pancreatic stones. The patients easily overcame the photophobia by wearing sunglasses outside (Noda et al, 1994).

Neurologic

    3.7.1) SUMMARY
    A) Drowsiness, fatigue, and malaise have been associated with trimethadione use and may occur following acute trimethadione or paramethadione overdosage. Hyperactivity occurs infrequently following trimethadione therapy.
    B) Dizziness, ataxia, and coma may occur following an acute overdose of trimethadione or paramethadione.
    C) A myasthenia gravis-like syndrome has been reported following trimethadione therapy.
    D) Seizures may occur during trimethadione therapy or following abrupt discontinuation of trimethadione or paramethadione therapy.
    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) Drowsiness has been commonly associated with trimethadione use and will usually decrease with continued therapy (Antonovych, 1984; Prod Info Tridione(R), trimethadione, 1994; McNamara, 1996).
    2) WITH POISONING/EXPOSURE
    a) Acute overdosage of trimethadione or paramethadione may cause drowsiness (Prod Info Tridione(R), trimethadione, 1994; Prod Info Paradione(R), paramethadione, 1991).
    B) ATAXIA
    1) Ataxia and dizziness may occur following an acute trimethadione or paramethadione overdose (Prod Info Tridione(R), trimethadione, 1994; Prod Info Paradione(R), paramethadione, 1991).
    C) COMA
    1) Coma may occur following a severe trimethadione or paramethadione overdose (Prod Info Tridione(R), trimethadione, 1994; Prod Info Paradione(R), paramethadione, 1991).
    D) MUSCLE WEAKNESS
    1) A myasthenia gravis-like reaction was described in adult and pediatric patients following chronic trimethadione therapy to treat petit mal seizures. Effects included bilateral ptosis, diplopia, fatigue, dysphagia, nasal speech, respiratory distress, hypotonia, and proximal limb weakness. The patients gradually recovered following administration of anticholinesterase medications and discontinuation of trimethadione (Booker et al, 1970; Gilbert, 1970; Peterson, 1966).
    E) HYPERACTIVE BEHAVIOR
    1) Hyperactivity is an infrequent occurrence following therapeutic administration of trimethadione (Hooshmand, 1974).
    F) SEIZURE
    1) Tonic clonic seizures may be precipitated during trimethadione therapy in patients who have both absence and grand mal seizuries. Seizures may also occue after abrupt withdrawal of trimethadione or paramethadione therapy may result in recurrence of absence seizures(Prod Info Tridione(R), trimethadione, 1994; Prod Info Paradione(R), paramethadione, 1991).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Nausea and vomiting, part of which could be initial episodes of nephrotic syndrome (Northway & West, 1967), have been associated with trimethadione therapy and with acute overdose (Prod Info Tridione(R), trimethadione, 1994).
    B) ABDOMINAL PAIN
    1) Abdominal pain and gastric distress, part of which could be initial episodes of nephrotic syndrome (Northway & West, 1967), have been associated with trimethadione use (Prod Info Tridione(R), trimethadione, 1994).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) Hepatitis has been reported rarely following therapeutic administration of trimethadione (Prod Info Tridione(R), trimethadione, 1994; Antonovych, 1984).

Genitourinary

    3.10.1) SUMMARY
    A) Nephrosis has been associated with the chronic ingestion of trimethadione and paramethadione and has been fatal in some instances.
    3.10.2) CLINICAL EFFECTS
    A) KIDNEY DISEASE
    1) Fatal nephrosis has been reported following therapeutic use of trimethadione or paramethadione (Heymann, 1967; Prod Info Paradione(R), paramethadione, 1991; Prod Info Tridione(R), trimethadione, 1994).
    2) CASE REPORTS
    a) A 43-month-old child developed malaise and periorbital and peripheral edema 4 months after beginning trimethadione therapy to treat petit mal seizures. The trimethadione therapy was discontinued following admission into the hospital. The patient's BUN increased from 19 mg% to 90 mg% and proteinuria was observed, indicating a diagnosis of severe nephrotic syndrome. The nephrosis gradually resolved following treatment with prednisone and cyclophosphamide (Northway & West, 1967).
    b) A 15-year-old male ingested a total dose of approximately 835 grams of trimethadione over a 3-year period and subsequently developed proteinuria and periorbital and peripheral edema. Sixteen months after discontinuation of trimethadione, the patient's proteinuria decreased from 9 g/24 hours to 300 mg/24 hours. A renal biopsy, performed seven months after discontinuation of trimethadione, showed partial fusion of foot processes in the epithelium, indicating nephrotic syndrome (Bar-Khayim et al, 1973).
    1) Although immunofluorescent staining of renal tissue showed an absence of immunoglobulins G, A, and M, the authors speculated that the cellular localization of eosinophils in the glomeruli suggested that an allergic reaction was responsible for the trimethadione-induced nephrosis in the 15-year-old patient.
    3) The renal change reported with trimethadione-induced nephrotic syndrome is membranous glomerulonephritis which may be associated with eosinophilic infiltration in the glomeruli and interstitium (Antonovych, 1984).
    B) ALBUMINURIA
    1) Albuminuria is a common finding in patients who develop nephrotic syndrome (Bar-Khayim et al, 1973; Northway & West, 1967).
    2) CASE REPORT - A 11-year-old female developed proteinuria several months after beginning trimethadione therapy (1200 mg daily) to treat petit mal seizures. Other renal function tests were normal. The proteinuria subsided following discontinuation of the trimethadione (Peterson, 1966).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) Blood dyscrasias, including leukopenia, eosinophilia, thrombocytopenia, pancytopenia, agranulocytosis, hypoplastic anemia, and fatal aplastic anemia have been reported following therapeutic use of trimethadione (Prod Info Tridione(R), trimethadione, 1994; Hooshmand, 1974; Antonovych, 1984).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) Acneiform or morbilliform skin rash that may progress to exfoliative dermatitis or severe forms of erythema multiforme have been associated with trimethadione therapy (Prod Info Tridione(R), trimethadione, 1994; Antonovych, 1984).

Immunologic

    3.19.1) SUMMARY
    A) Systemic lupus erythematosus may occur following therapeutic use of trimethadione.
    B) Lymphadenopathies and swelling of the thyroid gland have been reported following trimethadione therapy.
    3.19.2) CLINICAL EFFECTS
    A) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) Lupus erythematosus has been associated with the use of trimethadione (Prod Info Tridione(R), trimethadione, 1994; McNamara, 1996; Drory & Korczyn, 1993).
    2) CASE REPORT - A slide agglutination test for lupus erythematosus (LE) was positive twice, although LE preparations were normal four times, in an 11-year-old female following long-term administration of trimethadione (1200 mg daily) to treat petit mal seizures. A repeat slide agglutination test for LE, performed several months after discontinuation of the trimethadione, was negative (Peterson, 1966).
    B) VASCULITIS
    1) A skin biopsy, performed on a patient receiving trimethadione therapeutically, showed hypersensitivity vasculitis although systemic lupus erythematosus was suspected clinically (Drory & Korczyn, 1993).
    C) LYMPHADENOPATHY
    1) Lymphadenopathies have occurred following trimethadione therapy (Prod Info Tridione(R), trimethadione, 1994; McNamara, 1996).
    D) DISORDER OF THYROID GLAND
    1) CASE REPORT - Diffuse, non-tender swelling of the thyroid gland was reported in an 11-year-old female several months after beginning trimethadione therapy (1200 mg daily) to treat petit mal seizures. The thyroid swelling resolved several weeks after discontinuation of the trimethadione (Peterson, 1966).

Reproductive

    3.20.1) SUMMARY
    A) Trimethadione and paramethadione are severe teratogens and may cause fetal trimethadione syndrome, characterized by developmental delay, speech difficulty, V-shaped eyebrows, low-set ears with anteriorly folded helix, palatal anomaly, and irregular teeth.
    B) Other teratogenic effects, caused by maternal ingestion of trimethadione or paramethadione during pregnancy, include intrauterine growth retardation, short stature, microcephaly, cardiac anomaly, ocular anomaly, hypospadias, inguinal hernia, and simian creases.
    C) Trimethadione and paramethadione are categorized as FDA Pregnancy Category D.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) A fetal trimethadione syndrome has been described following chronic maternal ingestion of trimethadione or paramethadione during pregnancy. The syndrome is characterized by developmental and growth delays, low-set ears with anteriorly folded helix, palatal anomalies, a broad and low nasal bridge, irregular teeth, V-shaped eyebrows, and speech disturbances. Other teratogenic effects may also include intrauterine growth retardation, cardiac anomalies, ocular anomalies, GI abnormalities, simian creases, hypospadias, and microcephaly (Dalessio, 1985; Chernoff & Jones, 1981; Cordero & Oakley, 1983; German et al, 1970; Cohen, 1990).
    2) CASE REPORTS
    a) A 17-year-old female gave birth to a full-term infant who presented with a cleft lip and palate, ruptured omphalocele, lumbosacral meningomyelocele, and congenital heart disease. The mother had continuously received trimethadione therapy for 5 years including throughout her pregnancy. The infant developed multiple petechiae and became hypothermic two days after the repair of the omphalocele. The infant died six days after birth (Nichols, 1973).
    b) A woman chronically ingested barbiturates and trimethadione during her pregnancies and she gave birth to two children with malformations including facial dysmorphism, myopia, inguinal hernias, clinodactyly, short stature, and developmental delays (Rosen & Lightner, 1978).
    c) A-25-year-old female ingested trimethadione and phenobarbital for 9 years including throughout her pregnancy and she gave birth to a full-term infant. Over time the infant was noted as having bilateral hip dislocation, palatal anomaly, bilateral simian creases on hands, iris hypoplasia, underdeveloped musculature with decreased muscle tone, and marked hyperlaxity of all joints except the hip (Zellweger, 1974).
    d) A woman became pregnant seven times while receiving long-term trimethadione and barbiturate therapy. Four infants with congenital defects, typical of maternal anticonvulsant use, developed respiratory distress and died within hours of birth. Three pregnancies resulted in spontaneous abortions. After maternal discontinuation of all anticonvulsant medications, two pregnancies resulted in two normal children (Feldman et al, 1977).
    3) The specific anomalies, in children, of V-shaped eyebrows, low-set ears with anteriorly folded helix, and lack of phalangeal hypoplasia help to distinguish maternal ingestions of trimethadione from other anticonvulsant ingestions during pregnancy (Goldman & Yaffe, 1978).
    B) HEART MALFORMATION
    1) Specific cardiac anomalies including transposition of the great vessels, tetralogy of Fallot, hypoplastic left heart, and ventricular septal defects have been reported in as many as 15 to 30% of fetuses exposed to trimethadione in utero (Copel et al, 1986; Harned, 1983) Anderson, 1976).
    2) A persistent fifth aortic arch with patent arteriosus ductus was seen in a 2-year-old child who had been prenatally exposed to trimethadione. The child also had multiple congenital defects including left hip dislocation, low-set ears, and developmental delays (Lawrence & Stiles, 1975).
    C) HEMORRHAGE
    1) Bleeding tendencies have been described in newborns due to maternal ingestion of trimethadione during pregnancy. The tendency to hemorrhage may occur in the newborn 24 hours after delivery and may be due to the decreased levels of vitamin K-dependent clotting factors (Montouris et al, 1979).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    PARAMETHADIONED
    TRIMETHADIONED
    References: Prod Info Paradione(R), 1991; Prod Info Tridione(R), 1994.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, it is not known whether paramethadione or trimethadione is excreted into human breast milk (Prod Info Paradione(R), paramethadione, 1991; Prod Info Tridione(R), trimethadione, 1994).

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory studies are needed after overdose, unless otherwise clinically indicated.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum trimethadione levels may be clinically useful in determining possible toxicity.
    a) Therapeutic serum trimethadione levels are 20 to 35 mcg/mL (Bruni & Albright, 1984).
    2) No specific laboratory studies are needed after overdose, unless otherwise clinically indicated.

Methods

    A) CHROMATOGRAPHY
    1) Gas chromatography, gas-liquid chromatography, and high performance liquid chromatography have been performed for determination of trimethadione, dimethadione, and paramethadione in serum (Booker & Darcy, 1971; (Cremers & Verheesen, 1973; Griffiths et al, 1973; Loscher & Gobel, 1978; Tanaka et al, 1984; Tanaka & Misawa, 1992).
    2) The detection limit in a gas chromatographic method, for determination of trimethadione and dimethadione in human serum, was 10 ng/mL for trimethadione and 50 ng/mL for dimethadione (Tanaka & Misawa, 1992).
    B) SPECTROSCOPY/SPECTROMETRY
    1) An infrared-spectrometric method was described for the simultaneous determination of trimethadione and its major metabolite, dimethadione. The coefficient of variation for both trimethadione and dimethadione is less than 1% when the concentration of both compounds is 0.5 mmol/L, indicating that the accuracy and precision of this method is greater than ultraviolet spectrometry or gas-liquid chromatography.
    a) This method may be used clinically to determine the trimethadione/ dimethadione ratio as a check of patient compliance, and for the determination of dimethadione as an indicator of mean body intracellular pH (Zweens & Frankena, 1984).

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) No specific laboratory studies are needed after overdose, unless otherwise clinically indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED -
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    B) ACTIVATED CHARCOAL -
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    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.
    6.5.3) TREATMENT
    A) SUPPORT
    1) For trimethadione overdose ingestions, treatment is SYMPTOMATIC and SUPPORTIVE.
    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, 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).
    C) BLOOD COAGULATION DISORDER
    1) HEMORRHAGIC DISEASE PREVENTION - For infants who have been exposed in utero to trimethadione, 1 milligram of phytonadione (vitamin K) should be administered intramuscularly or subcutaneously into the newborn after delivery to prevent hemorrhagic disease (Montouris et al, 1979).
    a) Clotting studies of the newborn, who was exposed to trimethadione in utero, should be obtained 2 to 4 hours after administration of the phytonadione. If the clotting factors remain abnormal, an additional phytonadione dose should be administered with this process being repeated until the clotting factors are normal.
    b) If hemorrhage has occurred, fresh frozen plasma should be given.

Enhanced Elimination

    A) OTHER
    1) Alkalinization of the urine may enhance the renal excretion of the active metabolites of trimethadione and paramethadione (Prod Info Tridione(R), trimethadione, 1994; Prod Info Paradione(R), paramethadione, 1991). There are no reports of the use of urinary alkalinization in the treatment of overdose. Routine use is not recommended.

Summary

    A) Mild photophobia has been reported in patients ingesting trimethadione in doses exceeding 0.9 grams daily.

Therapeutic Dose

    7.2.1) ADULT
    A) TRIMETHADIONE
    1) Initial Dose: 0.9 g/day orally; increase weekly by 300 mg until therapeutic response is seen. The usual dose is 0.9 to 2.4 g/day orally in 3 or 4 divided doses (300 to 600 mg 3 to 4 times daily) (Prod Info TRIDIONE(R) oral chewable tablets, 2013).
    B) PARAMETHADIONE
    1) Usual Dose: 0.9 to 2.4 g daily in 3 or 4 divided doses (300 to 600 mg 3 to 4 times daily). Initially the dose should be administered as 0.9 g daily, then increased by 300 mg at weekly intervals until therapeutic results are achieved or until toxic symptoms appear (Prod Info Paradione(R), paramethadione, 1991).
    7.2.2) PEDIATRIC
    A) TRIMETHADIONE
    1) Usual dose: 0.3 to 0.9 g/day orally in 3 or 4 divided doses (Prod Info TRIDIONE(R) oral chewable tablets, 2013).
    B) PARAMETHADIONE
    1) Usual Dose: 0.3 to 0.9 g daily in 3 or 4 divided doses (Prod Info Paradione(R), paramethadione, 1991).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) TRIMETHADIONE - Mild photophobia has been reported in patients ingesting trimethadione in doses exceeding 0.9 grams daily (Noda et al, 1994).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) TRIMETHADIONE - Plasma levels needed to achieve good seizure control are 20 to 35 micrograms/milliliter (Bruni & Albright, 1984).
    b) DIMETHADIONE (active metabolite of trimethadione) - Plasma level needed to achieve good seizure control is approximately 700 micrograms/milliliter (Bruni & Albright, 1984).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) PARAMETHADIONE-
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 750 mg/kg (RTECS, 2000)
    2) LD50- (ORAL)MOUSE:
    a) 1 g/kg (RTECS, 2000)
    B) TRIMETHADIONE-
    1) LD50- (ORAL)MOUSE:
    a) 2100 mg/kg (RTECS, 2000)
    2) LD50- (ORAL)RAT:
    a) 2140 mg/kg (RTECS, 2000)

Physical Characteristics

    A) Trimethadione is a white crystalline powder and is poorly soluble in water (Bruni & Albright, 1984).
    B) Paramethadione is a synthetic, oily, slightly water-soluble liquid (Prod Info Paradione(R), paramethadione, 1991).

Molecular Weight

    A) TRIMETHADIONE - 143.14 (Budavari et al, 1996)
    B) PARAMETHADIONE - 157.17 (Budavari et al, 1996)

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