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SUCCINIMIDES-ANTICONVULSANTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Succinimide derivatives are anticonvulsants used for the control of absence (petit mal) seizures.

Specific Substances

    A) ETHOSUXIMIDE
    1) 2-ethyl-2-methylsuccinmide
    2) 3-ethyl-3-methyl-2,5-pyrrolidine-dione
    3) 3-methyl-3-ethylpyrrolidine-2,5-dione
    4) CAS 77-67-8
    METHSUXIMIDE
    1) 1,3-dimethyl-3-phenyl-2,5-dioxopyrrolidine
    2) N,2-dimethyl-2-phenylsuccinimide
    3) mesuximide
    4) CAS 77-41-8
    PHENSUXIMIDE
    1) 1-methyl-3-phenyl-2,5-pyrrolidinedione
    2) N-methyl-2-phenylsuccinimide
    3) CAS 86-34-0

Available Forms Sources

    A) FORMS
    1) Ethosuximide is available as 250 mg liquid-filled capsules and a syrup (250 mg/5 mL) (Prod Info Zarontin(R) oral capsules, 2012)
    2) Methsuximide is available as 300 mg (P-D 525) capsules (Prod Info Celontin(R) oral capsules, 2010)
    B) USES
    1) Ethosuximide is indicated for the control of absence (petit mal) epilepsy in adults and children 3 years of age or older (Prod Info Zarontin(R) oral capsules, 2012).
    2) Methsuximide is indicated for the treatment of REFRACTORY ABSENCE SEIZURES(Prod Info Celontin(R) oral capsules, 2010)

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Succinimide derivatives are anticonvulsants used to control absence (petit mal) seizures.
    B) PHARMACOLOGY: Succinimides suppress activity associated with lapses of consciousness by depressing the motor cortex and elevating the CNS threshold to convulsive stimuli.
    C) TOXICOLOGY: Methsuximide toxicity may follow a biphasic profile with extended CNS depression. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours. The accumulation of the active metabolite N-desmethylmethsuximide may be responsible for the recurrence of coma.
    D) EPIDEMIOLOGY: Overdose is rarely reported.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most frequent adverse effects with succinimide use include: nausea, vomiting, anorexia, diarrhea, weight loss, epigastric pain, abdominal pain, drowsiness, ataxia, and dizziness.
    2) LESS COMMON AND RARE: Less common and rare adverse effects include: leukopenia, agranulocytosis, pancytopenia (with or without bone marrow suppression), eosinophilia, monocytosis, psychosis, depression or suicidal behavior, aggressiveness, Stevens-Johnson syndrome, and sleep disturbances. Gum hypertrophy, tongue swelling, night terrors, lack of concentration, hirsutism, vaginal bleeding, hematuria and systemic lupus erythematosus have been reported with use of ETHOSUXIMIDE. Auditory hallucinations, blurred vision, headache, photophobia, proteinuria, hyperemia, and periorbital edema have been reported with METHSUXIMIDE use.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild to moderate toxicity may cause nausea and vomiting.
    2) SEVERE TOXICITY: Severe effects of acute toxicity include CNS depression, respiratory depression, and coma.
    0.2.7) NEUROLOGIC
    A) Acute overdoses, alone or in combination with other anticonvulsants, produce CNS depression including coma with respiratory depression.
    B) The N-desmethyl metabolite of methsuximide (normethsuximide) may be detected for up to 60 hours after ingestion, and may produce prolonged coma.
    C) Commonly occurring dose-related effects include anorexia, drowsiness, irritability, euphoria, dizziness, headache, ataxia, hiccough, Parkinsonian-like symptoms, and photophobia.
    0.2.8) GASTROINTESTINAL
    A) Nausea and vomiting are common dose-related effects.
    0.2.13) HEMATOLOGIC
    A) Chronic changes associated with the succinimides include eosinophilia, leukopenia, monocytosis, granulocytopenia, agranulocytosis, thrombocytopenia, pancytopenia, and aplastic anemia.
    B) Blood dyscrasias are more commonly seen with ethosuximide than with the other two members of this group.
    0.2.14) DERMATOLOGIC
    A) Skin rashes have been reported.
    0.2.20) REPRODUCTIVE
    A) Ethosuximide, methsuximide, and phensuximide are comparably teratogenic in the mouse although no evidence of teratogenicitiy has been found in humans.

Laboratory Monitoring

    A) Monitor mental status closely. Methsuximide toxicity may follow a biphasic profile with extended CNS depression. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours.
    B) Monitor CBC, particularly if signs or symptoms of infection (eg, sore throat or fever) develop.
    C) Monitor urinalysis for proteinuria or hematuria.
    D) Monitor liver enzymes, serum electrolytes and renal function n symptomatic patients.
    E) Plasma concentrations of these agents are not readily available.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Methsuximide toxicity may follow a biphasic profile with extended CNS depression. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours. Monitor mental status. Perform early intubation in patients with a declining level of consciousness. Patients with mixed types of epilepsy or abrupt withdrawal of these agents can precipitate seizures. Treat seizures with IV benzodiazepines, barbiturates.
    C) DECONTAMINATION
    1) PREHOSPITAL: GI decontamination is not recommended because of the risk of CNS depression and aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is alert and able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with serious toxicity or significant CNS or respiratory depression.
    E) ANTIDOTE
    1) None.
    F) SEIZURE
    1) Administer IV benzodiazepines; barbiturates may be needed if seizures persist or recur.
    G) MYELOSUPPRESSION
    1) Severe neutropenia: Filgrastim 5 mcg/kg/day IV or SubQ or sargramostim 250 mcg/m(2)/day IV infused over 4 hours. Monitor serial CBC with differential. Transfusions as needed for severe thrombocytopenia, bleeding.
    H) ENHANCED ELIMINATION
    1) ETHOSUXIMIDE: Early hemodialysis would be expected to effectively clear ethosuximide. METHSUXIMIDE: Charcoal hemoperfusion may effectively remove the N-desmethyl metabolite of methsuximide. Exchange transfusions and forced diuresis are unlikely to be effective for removing ETHOSUXIMIDE or the N-desmethyl metabolite of METHSUXIMIDE.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Children with inadvertent ingestion of up to the therapeutic pediatric dose, and adults with inadvertent ingestion of an extra dose who have minimal symptoms can be managed at home.
    2) OBSERVATION CRITERIA: Patients with deliberate overdose, those with more than mild symptoms, and children who have ingested more than a therapeutic dose for age should be sent to a healthcare facility for evaluation.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted. Patients who develop CNS depression after methsuximide overdose should be admitted as recurrent CNS depression may develop.
    4) CONSULT CRITERIA: Consult a Poison Center for assistance in managing patients with severe toxicity or for whom diagnosis is unclear.
    J) PITFALLS
    1) METHSUXIMIDE: Toxicity after methsuximide over dose or toxicity may be biphasic, with extended CNS depression. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours. The accumulation of the N-desmethyl metabolite may be responsible for the recurrence of coma.
    K) PHARMACOKINETICS
    1) ETHOSUXIMIDE: Ethosuximide is well absorbed with insignificant protein binding. Peak plasma levels are attained in 2 to 7 hours. The volume of distribution is 0.67 L/kg. Metabolism is 80% hepatic with 10% to 20% renal excretion. The elimination half-life is 25 to 60 hours.
    2) METHSUXIMIDE: Methsuximide is well absorbed and is rapidly metabolized to N-desmethylmethsuximide (normethsuximide), which is primarily responsible for the pharmacologic activity. N-desmethylmethsuximide is approximately 50% protein bound and peak plasma levels are attained in 1 to 4 hours. Elimination half-life: 1.4 hours (parent compound) and 38 and 25.6 hours (N-desmethylsuximide) in adults and children, respectively. Less than 1% of a dose is excreted unchanged in the urine.
    L) TOXICOKINETICS
    1) Methsuximide toxicity may follow a biphasic profile with extended CNS depression. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours. Toxicity may be observed at plasma N-desmethylmethsuximide (active metabolite) concentrations of 40 mcg/mL or greater; coma has been observed at concentrations of 150 mcg/mL or greater. Elimination may be prolonged in overdose.
    2) No correlation between plasma concentrations and toxicity has been established with ethosuximide or phensuximide.
    M) DIFFERENTIAL DIAGNOSIS
    1) Includes effects attributable to other antiepileptic agents. Methsuximide may increase the plasma levels of phenytoin and phenobarbital.

Range Of Toxicity

    A) TOXICITY: Toxic doses are variable depending on the particular agent. Specific toxic doses have not been determined. A 10-year-old boy developed psychiatric symptoms including headaches, insomnia, visual hallucinations, paranoia, and suicidal thoughts following 2 weeks of ETHOSUXIMIDE at 750 mg twice daily.
    B) THERAPEUTIC DOSE: ETHOSUXIMIDE: 6 YEARS OF AGE AND OLDER: Initial dose is 500 mg/day orally. The dose may be increased in small increments (eg, 250 mg every 4 to 7 days) until desired control is achieved. A dose should not exceed 1.5 g daily without strict physician supervision. PEDIATRIC: 3 TO 6 YEARS OF AGE: The optimal dose is 20 mg/kg/day orally. METHSUXIMIDE: ADULT: Therapy must be individualized by trial based on response. A suggested dose for the initial week of therapy is 300 mg/day orally. The dose may be increased by 300 mg/day every week for 3 weeks to a maximum of 1.2 g/day. PEDIATRIC: 10 to 20 mg/kg/day; adjust as necessary to achieve therapeutic drug levels. PHENSUXIMIDE: ADULT: 500 to 1000 mg orally 2 to 3 times daily, titrated to response.

Clinical Effects

Summary Of Exposure

    A) USES: Succinimide derivatives are anticonvulsants used to control absence (petit mal) seizures.
    B) PHARMACOLOGY: Succinimides suppress activity associated with lapses of consciousness by depressing the motor cortex and elevating the CNS threshold to convulsive stimuli.
    C) TOXICOLOGY: Methsuximide toxicity may follow a biphasic profile with extended CNS depression. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours. The accumulation of the active metabolite N-desmethylmethsuximide may be responsible for the recurrence of coma.
    D) EPIDEMIOLOGY: Overdose is rarely reported.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most frequent adverse effects with succinimide use include: nausea, vomiting, anorexia, diarrhea, weight loss, epigastric pain, abdominal pain, drowsiness, ataxia, and dizziness.
    2) LESS COMMON AND RARE: Less common and rare adverse effects include: leukopenia, agranulocytosis, pancytopenia (with or without bone marrow suppression), eosinophilia, monocytosis, psychosis, depression or suicidal behavior, aggressiveness, Stevens-Johnson syndrome, and sleep disturbances. Gum hypertrophy, tongue swelling, night terrors, lack of concentration, hirsutism, vaginal bleeding, hematuria and systemic lupus erythematosus have been reported with use of ETHOSUXIMIDE. Auditory hallucinations, blurred vision, headache, photophobia, proteinuria, hyperemia, and periorbital edema have been reported with METHSUXIMIDE use.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild to moderate toxicity may cause nausea and vomiting.
    2) SEVERE TOXICITY: Severe effects of acute toxicity include CNS depression, respiratory depression, and coma.

Heent

    3.4.3) EYES
    A) ETHOSUXIMIDE: Reports of MYOPIA have occurred with therapeutic doses (Prod Info ZARONTIN(R) oral capsules, 2010).
    B) METHSUXIMIDE: PHOTOPHOBIA, BLURRED VISION, and PERIORBITAL EDEMA have occurred with therapeutic use (Prod Info Celontin(R) oral capsules, 2010).
    3.4.6) THROAT
    A) ETHOSUXIMIDE: GUM HYPERTROPHY and SWELLING OF TONGUE have been associated with therapeutic use (Prod Info ZARONTIN(R) oral capsules, 2010).

Neurologic

    3.7.1) SUMMARY
    A) Acute overdoses, alone or in combination with other anticonvulsants, produce CNS depression including coma with respiratory depression.
    B) The N-desmethyl metabolite of methsuximide (normethsuximide) may be detected for up to 60 hours after ingestion, and may produce prolonged coma.
    C) Commonly occurring dose-related effects include anorexia, drowsiness, irritability, euphoria, dizziness, headache, ataxia, hiccough, Parkinsonian-like symptoms, and photophobia.
    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) Acute overdosage, alone or in combination with other anticonvulsants, produces CNS depression, including coma with respiratory depression.
    b) ETHOSUXIMIDE: Overdose has been associated with CNS depression, including, respiratory depression and coma (Prod Info ZARONTIN(R) oral capsules, 2010).
    c) METHSUXIMIDE: Overdose may result in coma, respiratory depression, and CNS depression with a biphasic course. In some cases, patients have emerged from a comatose state and then relapsed within 24 hours (Prod Info Celontin(R) oral capsules, 2010).
    1) The N-desmethyl metabolite of methsuximide, which may be detected at toxic levels up to 60 hours after ingestion, can cause delayed deep coma after acute overdosage, the onset of which may be sooner in those patients having been on chronic therapy.
    2) Overdose with methsuximide may present initially (within 1 hour) with dizziness and ataxia which progresses to a semistuporous or semicoma-like condition. On occasion coma may be profound (Schulte & Good, 1966; Karch, 1973).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) ETHOSUXIMIDE: Ataxia, dizziness, drowsiness, fatigue, headache, hiccups, hyperactivity, irritability, and lethargy have occurred with ethosuximide therapy (Prod Info ZARONTIN(R) oral capsules, 2010).
    b) METHSUXIMIDE: Commonly occurring neurologic effects reported with therapeutic use include drowsiness, ataxia, and dizziness. Additional effects reported include irritability, nervousness, headache, hiccups, and insomnia (Prod Info Celontin(R) oral capsules, 2010).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and vomiting are common dose-related effects.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are commonly reported adverse events with therapeutic use of these agents (Prod Info Celontin(R) oral capsules, 2010; Prod Info ZARONTIN(R) oral capsules, 2010).
    2) WITH POISONING/EXPOSURE
    a) Acute overdose may produce nausea, vomiting and CNS depression (Prod Info ZARONTIN(R) oral capsules, 2010).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Epigastric pain, abdominal pain, cramps, and gastric upset have been reported with therapeutic use of ETHOSUXIMIDE and METHSUXIMIDE (Prod Info Celontin(R) oral capsules, 2010; Prod Info ZARONTIN(R) oral capsules, 2010).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea and constipation have been reported with therapeutic doses of ETHOSUXIMIDE and METHSUXIMIDE (Prod Info Celontin(R) oral capsules, 2010; Prod Info ZARONTIN(R) oral capsules, 2010).
    D) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia and weight loss have been reported with therapeutic use of ETHOSUXIMIDE and METHSUXIMIDE (Prod Info Celontin(R) oral capsules, 2010; Prod Info ZARONTIN(R) oral capsules, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Ethosuximide has been suspected of causing elevated liver enzymes when used therapeutically (Coulter, 1983), but has not been reported to cause hepatotoxicity (Gilman et al, 1985).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) Succinimides have produced morphological and functional changes in animal livers.

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) ETHOSUXIMIDE and METHSUXIMIDE: Microscopic hematuria has been reported with therapeutic doses (Prod Info Celontin(R) oral capsules, 2010; Prod Info ZARONTIN(R) oral capsules, 2010).

Hematologic

    3.13.1) SUMMARY
    A) Chronic changes associated with the succinimides include eosinophilia, leukopenia, monocytosis, granulocytopenia, agranulocytosis, thrombocytopenia, pancytopenia, and aplastic anemia.
    B) Blood dyscrasias are more commonly seen with ethosuximide than with the other two members of this group.
    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Hematologic changes associated with prolonged use of succinimides include monocytosis, eosinophilia, leukopenia, thrombocytopenia, granulocytopenia, agranulocytosis, pancytopenia, and aplastic anemia.
    b) ETHOSUXIMIDE: Therapeutic ethosuximide use has been associated with agranulocytosis, bone marrow suppression, eosinophilia, leukopenia, and pancytopenia. Fatal outcomes occurred in some cases (Prod Info ZARONTIN(R) oral capsules, 2010).
    c) METHSUXIMIDE: Complications including bone marrow suppression, eosinophilia, leukopenia, monocytosis, and pancytopenia have occurred with therapeutic doses. Fatal outcomes have been reported (Prod Info Celontin(R) oral capsules, 2010).
    B) APLASTIC ANEMIA
    1) CASE REPORT: An 8-year-old girl who had been receiving ethosuximide for approximately 6 months for absence seizures presented with fatigue, headache, and streptococcal throat infection followed by hematuria, bruising, and petechiae. Hemoglobin was 7.5 mg/dL, hematocrit 22.2%, leukocytes 4.1 x 10(9)/L (6% granulocytes, 86% lymphocytes, 1% monocytes and 1% basophils), and platelets were 1 x 10(9)/L. Bone marrow biopsy indicated aplastic anemia. Ethosuximide was discontinued and the patient received an HLA-identical bone marrow transplant from a sibling and recovered without permanent sequelae (Massey et al, 1994).

Dermatologic

    3.14.1) SUMMARY
    A) Skin rashes have been reported.
    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Urticaria, pruritus, skin eruptions, Stevens-Johnson syndrome, pruritic erythematous rashes, erythema multiforme, alopecia, and hirsutism may occur (Schmidt & Seldon, 1982).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) WITH THERAPEUTIC USE
    a) ETHOSUXIMIDE: Lupus erythematosus has been associated with therapeutic ethosuximide use (Prod Info ZARONTIN(R) oral capsules, 2010).
    b) CASE REPORT: An 11-year-old girl developed systemic lupus erythematosus with renal and cerebral manifestations after chronic treatment with ethosuximide. The patient presented with a 3-week history of weight loss, somnolence, headache, and joint pain. Urinalysis revealed proteinuria and presence of dysmorphic red blood cells. Antinuclear, anti-DNA, and anticardiolipin antibodies were present. The patient was treated with prednisone and did not relapse after 1 year of follow-up (Casteels et al, 1998).
    B) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Allergic reactions have been reported with therapeutic use of ETHOSUXIMIDE (Prod Info ZARONTIN(R) oral capsules, 2010).

Reproductive

    3.20.1) SUMMARY
    A) Ethosuximide, methsuximide, and phensuximide are comparably teratogenic in the mouse although no evidence of teratogenicitiy has been found in humans.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) Phensuximide may be teratogenic (Fedrick, 1973).
    B) LACK OF EFFECT
    1) HUMANS - There is no evidence of teratogenicity in humans, although ethosuximide distributes into the fetus (Koup et al, 1978).
    C) ANIMAL STUDIES
    1) Ethosuximide, methsuximide, and phensuximide are comparably teratogenic in the mouse (Fabro et al, 1982). Although Kao et al (1979) found ethosuximide to have low teratogenicity, and Sullivan and McElhatton (1977) found no teratogenicity in the mouse.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    ETHOSUXIMIDEC
    METHSUXIMIDEC
    PHENSUXIMIDED
    1) Reference: Briggs et al, 1998.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Maternal serum ratio of ethosuximide is 0.8 to 1.0. Infant serum ethosuximide is about 30% of maternal. Toxicity is not expected in an infant nursing an ethosuximide-treated mother (Rane & Tunell, 1981; Kuhnz et al, 1984).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor mental status closely. Methsuximide toxicity may follow a biphasic profile with extended CNS depression. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours.
    B) Monitor CBC, particularly if signs or symptoms of infection (eg, sore throat or fever) develop.
    C) Monitor urinalysis for proteinuria or hematuria.
    D) Monitor liver enzymes, serum electrolytes and renal function n symptomatic patients.
    E) Plasma concentrations of these agents are not readily available.
    4.1.2) SERUM/BLOOD
    A) SPECIFIC AGENT
    1) ETHOSUXIMIDE: Therapeutic range is usually 40 to 100 mcg/mL. No relationship between plasma concentrations and toxicity has been established. (Prod Info ZARONTIN(R) oral capsules, 2010). At steady state each 1 mg/kg orally produces an increase of about 2 mcg ethosuximide/mL serum.
    2) METHSUXIMIDE: Therapeutic range is 20 to 40 mcg/mL of N-desmethyl-methsuximide, the active metabolite, and 0.04 to 0.08 mcg/mL methsuximide (Prod Info Celontin(R) oral capsules, 2010). It is rapidly metabolized to N-desmethylmethsuximide (normethsuximide), which is primarily responsible for its pharmacologic activity (Miles et al, 1989). Methsuximide toxicity may follow a biphasic profile with extended CNS depression. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours (Prod Info Celontin(R) oral capsules, 2010).
    a) Toxicity has been observed when N-desmethyl-methsuximide, have exceeded 40 mcg/mL (Prod Info Celontin(R) oral capsules, 2010).
    b) Coma has been associated with plasma N-desmethylmethsuximide concentrations of 150 mcg/mL or greater (Prod Info Celontin(R) oral capsules, 2010; Gilman et al, 1985; Baehler et al, 1980).
    3) PHENSUXIMIDE: Therapeutic range is 10 to 20 mcg/mL. N-desmethylphensuximide is about 30% of phensuximide.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) ETHOSUXIMIDE: Ethosuximide can be determined by gas chromatography (GC) (Least et al, 1975; Johnson et al, 1976), immunoassays, liquid chromatography (LC) (Kabra et al, 1983), and HPLC (Wad, 1984; Wad, 1985).
    a) IMMUNOASSAYS: Immunoassays available include EMIT (Syva), Ames TDA-SLFIA, aca (DuPont), and the Abbott TDx-FPIA.
    1) The Abbott assay produced lower values than Emit or aca (Stewart & Bottorff, 1986) although they are generally comparable to GC.
    2) METHSUXIMIDE AND NORMETHSUXIMIDE: Have been measured accurately using solid-phase extraction and wide-bore capillary gas chromatography (Cardella et al, 1988).
    a) NORMETHSUXIMIDE has been quantitated via EMIT and TDx-FPIA using ethosuximide reagents (Miles et al, 1989).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted. Patients who develop CNS depression after methsuximide overdose should be admitted as recurrent CNS depression may develop.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Children with inadvertent ingestion of up to the therapeutic pediatric dose, and adults with inadvertent ingestion of an extra dose who have minimal symptoms can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a Poison Center for assistance in managing patients with severe toxicity or for whom diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate overdose, those with more than mild symptoms, and children who have ingested more than a therapeutic dose for age should be sent to a healthcare facility for evaluation.

Monitoring

    A) Monitor mental status closely. Methsuximide toxicity may follow a biphasic profile with extended CNS depression. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours.
    B) Monitor CBC, particularly if signs or symptoms of infection (eg, sore throat or fever) develop.
    C) Monitor urinalysis for proteinuria or hematuria.
    D) Monitor liver enzymes, serum electrolytes and renal function n symptomatic patients.
    E) Plasma concentrations of these agents are not readily available.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital GI decontamination is not recommended because of the risk of CNS depression and subsequent aspiration.
    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).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There is no known antidote.
    B) MONITORING OF PATIENT
    1) Monitor mental status; CNS depression and coma may develop.
    2) Methsuximide toxicity may follow a biphasic profile with extended CNS depression. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours. The accumulation of the active metabolite N-desmethylmethsuximide may be responsible for the recurrence of coma.
    3) Obtain a CBC with differential, particularly if signs or symptoms of infection (eg, sore throat or fever) develop.
    4) Monitor urinalysis for proteinuria or hematuria.
    5) Monitor liver enzymes, serum electrolytes and renal function in symptomatic patients.
    C) SEIZURE
    1) When METHSUXIMIDE or ETHOSUXIMIDE are used as monotherapy in patients with mixed types of epilepsy, the frequency of grand mal seizures may increase. Abrupt withdrawal of any antiepileptic drug may precipitate petit mal seizures (Prod Info Celontin(R) oral capsules, 2010; Prod Info ZARONTIN(R) oral capsules, 2010).
    2) Administer IV benzodiazepines; barbiturates may be needed if seizures persist or recur.
    3) 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).
    4) 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 .
    5) 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).
    6) 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).
    7) 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, 1976a; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    8) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) MYELOSUPPRESSION
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Early hemodialysis would be expected to effectively clear ETHOSUXIMIDE.
    a) The extraction efficiency of ETHOSUXIMIDE was 61% to 100%. Hemodialysis may be useful to treat ethosuximide overdose (Marbury et al, 1981).
    B) HEMOPERFUSION
    1) Charcoal hemoperfusion may effectively remove the N-desmethyl metabolite of METHSUXIMIDE (Prod Info Celontin(R) oral capsules, 2010).
    a) Charcoal hemoperfusion markedly improved a poisoned patient by effectively removing the N-desmethyl metabolite of methsuximide (Baehler et al, 1980).
    C) DIURESIS
    1) Forced diuresis is UNLIKELY to be effective for removing ETHOSUXIMIDE or the N-desmethyl metabolite of METHSUXIMIDE (Prod Info Celontin(R) oral capsules, 2010; Prod Info ZARONTIN(R) oral capsules, 2010).
    2) Forced diuresis is ineffective since only 10% to 20% of ethosuximide and less than 1% of both methsuximide and phensuximide are excreted unchanged in the urine.
    D) EXCHANGE TRANSFUSION
    1) Exchange transfusions are UNLIKELY to be effective for removing ETHOSUXIMIDE or the N-desmethyl metabolite of METHSUXIMIDE (Prod Info Celontin(R) oral capsules, 2010; Prod Info ZARONTIN(R) oral capsules, 2010).

Range Of Toxicity

Summary

    A) TOXICITY: Toxic doses are variable depending on the particular agent. Specific toxic doses have not been determined. A 10-year-old boy developed psychiatric symptoms including headaches, insomnia, visual hallucinations, paranoia, and suicidal thoughts following 2 weeks of ETHOSUXIMIDE at 750 mg twice daily.
    B) THERAPEUTIC DOSE: ETHOSUXIMIDE: 6 YEARS OF AGE AND OLDER: Initial dose is 500 mg/day orally. The dose may be increased in small increments (eg, 250 mg every 4 to 7 days) until desired control is achieved. A dose should not exceed 1.5 g daily without strict physician supervision. PEDIATRIC: 3 TO 6 YEARS OF AGE: The optimal dose is 20 mg/kg/day orally. METHSUXIMIDE: ADULT: Therapy must be individualized by trial based on response. A suggested dose for the initial week of therapy is 300 mg/day orally. The dose may be increased by 300 mg/day every week for 3 weeks to a maximum of 1.2 g/day. PEDIATRIC: 10 to 20 mg/kg/day; adjust as necessary to achieve therapeutic drug levels. PHENSUXIMIDE: ADULT: 500 to 1000 mg orally 2 to 3 times daily, titrated to response.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) ETHOSUXIMIDE
    a) ORAL: INITIAL: 500 mg/day, increased in increments of 250 mg/day every 4 to 7 days, titrated to response. Doses greater than 1.5 g/day are not recommended without strict medical supervision (Prod Info ZARONTIN(R) oral capsules, 2010).
    2) METHSUXIMIDE
    a) ORAL: INITIAL: 300 mg/day, increased in increments of 300 mg/day at weekly intervals, up to a maximum of 1.2 g/day (Prod Info Celontin(R) oral capsules, 2010).
    3) PHENSUXIMIDE
    a) ORAL: INITIAL: 500 to 1000 mg 2 to 3 times daily, titrated to response (Prod Info, 1989b).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) ETHOSUXIMIDE
    a) INITIAL DOSE
    1) CHILDREN 3 TO 6 YEARS OF AGE: 250 mg/day orally initially, increasing in increments of 250 mg/day at 4 to 7 day intervals (Prod Info ZARONTIN(R) oral capsules, 2010).
    2) CHILDREN 6 YEARS OF AGE AND OLDER: 500 mg/day orally, with incremental increases of 250 mg/day at 4 to 7 day intervals (Prod Info ZARONTIN(R) oral capsules, 2010).
    b) MAINTENANCE
    1) The optimal dose for most pediatric patients is 20 mg/kg/day to achieve therapeutic drug concentrations (Prod Info ZARONTIN(R) oral capsules, 2010).

Maximum Tolerated Exposure

    A) Specific toxic doses have not been determined.
    B) ETHOSUXIMIDE: A 10-year-old boy with absence epilepsy treated with ethosuximide 500 mg twice daily for 2 weeks followed by 750 mg twice daily for 2 weeks developed psychiatric symptoms including headaches, insomnia, visual hallucinations, paranoia, and suicidal thoughts over a 2-week period. The ethosuximide dose was titrated down to 250 mg daily by day 2 of admission and discontinued completely within 1 week. Valproic acid was started on day 2 of admission and continued after discharge. At a 1-month follow-up, psychiatric symptoms had not recurred and his seizures were controlled (Chien, 2011).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ETHOSUXIMIDE
    a) Therapeutic plasma concentrations of ethosuximide are 40 to 100 mcg/mL (Prod Info ZARONTIN(R) oral capsules, 2010; Troupin, 1984). Plasma concentrations up to 150 mcg/mL have been reported without signs of toxicity (Prod Info ZARONTIN(R) oral capsules, 2010).
    2) METHSUXIMIDE
    a) The therapeutic range of the metabolite N-desmethylmethsuximide is 10 to 40 mcg/mL (Strong et al, 1974).
    3) PHENSUXIMIDE
    a) Therapeutic plasma phensuximide levels are 10 to 20 mcg/mL (50 to 100 micromoles/L) (Kempe et al, 1987).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) ETHOSUXIMIDE
    1) Toxic effects of ethosuximide do not correlate well with plasma concentrations of the parent compound (Ellenhorn & Barceloux, 1988). Plasma levels up to 150 mcg/mL have been reported without signs of toxicity (Prod Info ZARONTIN(R) oral capsules, 2010).
    b) METHSUXIMIDE
    1) N-desmethylmethsuximide is the metabolite primarily responsible for the pharmacologic activity in methsuximide toxicity (Miles et al, 1989). Plasma levels of the metabolite in excess of 40 mcg/mL have caused toxicity and levels of 150 mcg/mL have produced coma (Prod Info Celontin(R) oral capsules, 2010). However, levels of 40 to 50 mcg/mL have been well tolerated in children (Miles et al, 1989a).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ETHOSUXIMIDE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 1.65 g/kg
    2) LD50- (ORAL)MOUSE:
    a) 1.75 g/kg
    B) METHSUXIMIDE
    1) LD50- (ORAL)MOUSE:
    a) 1.55 g/kg
    C) PHENSUXIMIDE
    1) LD50- (ORAL)MOUSE:
    a) 960 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The succinimides appear to suppress the paroxysmal three-cycle-per-second spike and wave EEG activity associated with lapses of consciousness common in absence seizures .
    1) Succinimides ETHOSUXIMIDE and METHSUXIMIDE suppress activity associated with lapses of consciousness by depressing the motor cortex and elevating the CNS threshold to convulsive stimuli (Prod Info Celontin(R) oral capsules, 2010; Prod Info ZARONTIN(R) oral capsules, 2010).
    2) The frequency of attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli (Prod Info, 1989a).

Physicochemical

Molecular Weight

    A) ETHOSUXIMIDE: 141.17 (Budavari, 1989)
    B) METHSUXIMIDE: 203.23 (Budavari, 1989)
    C) PHENSUXIMIDE: 189.21 (Budavari, 1989)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Baehler RW, Wark J, & Smith W: Charcoal hemoperfusion in the therapy for methsuximide and phenytoin overdose. Arch Intern Med 1980; 140:1466-1468.
    3) Baselt RC & Cravey RH: Disposition of Toxic Drugs and Chemicals in Man, 3rd ed, Year Book Medical Publishers, Chicago, IL, 1989.
    4) Bauer LA, Harris C, Wilensky AJ, et al: Ethosuximide kinetics: possible interaction with valproic acid. Clin Pharmacol Ther 1982; 31:741-745.
    5) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    6) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    7) Buchanan RA, Fernandez L, & Kinkel AW: Absorption and elimination of ethosuximide in children. J Clin Pharmacol 1969; 9(6):393-398.
    8) Buchanan RA, Kinkel AW, & Smith TC: The absorption and excretion of ethosuximide. Int J Clin Pharmacol 1973; 7(2):213-221.
    9) Budavari S: The Merck Index, 11th ed, Merck & Co, Inc, Rahway, NJ, 1989.
    10) Cardella DS, Levtzow CB, & Rifai N: Measurement of methsuximide and N-desmethylmethsuimide using solid-phase extraction and wide-bore capillary gas chromatography. Clin Biochem 1988; 21:329-331.
    11) Casteels K, Van Geet C, & Wouters K: Ethosuximide-associated lupus with cerebral and renal manifestations. Eur J Pediatr 1998; 157:780-782.
    12) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    13) Chien J: Ethosuximide-induced mania in a 10-year-old boy. Epilepsy Behav 2011; 21(4):483-485.
    14) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    15) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    16) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    17) Coulter DL: Ethosuximide-induced liver dysfunction. Arch Neurol 1983; 40:393-394.
    18) Ellenhorn MJ & Barceloux DG: Medical Toxicology: Diagnosis and Treatment of Human Poisoning, Elsevier, New York, NY, 1988.
    19) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    20) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    21) Fabro S, Schull G, & Brown NA: The relative teratogenic index and teratogenic potency: proposed components of developmental toxicity risk assessment. Teratogenesis Carcinog Mutagen 1982; 2:61-76.
    22) Fedrick J: Epilepsy and pregnancy: a report from the Oxford Record Linkage Study. Br Med J 1973; 2:442-448.
    23) Gilman AF, Goodman LS, & Rall TW: The Pharmacological Basis of Therapeutics, 7th Ed, MacMillan, New York, NY, 1985.
    24) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    25) Goulet JR: Metabolism of ethosuximide. Clin Pharmacol Ther 1976; 19:213.
    26) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    27) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    28) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    29) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    30) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    31) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976a; 1:161.
    32) Johnson GF, Least AW, & Smith TC: Monitoring drug concentration in a case of combined overdosage with primidone and methsuximide. Clin Chem 1976; 22:915-921.
    33) Kabra PM, Nelson MA, & Marton LJ: Simultaneous very fast liquid chromatographic analysis of ethosuximide, primidone, phenobarbital, phenytoin and carbamazepine in serum. Clin Chem 1983; 29:473-476.
    34) Karch SB: Methsuximide overdose: delayed onset of profound coma. JAMA 1973; 223:1463-1465.
    35) Kempe CH, Silver HK, & O'Brien D: Current Pediatric Diagnosis and Treatment, 9th ed, Lange Medical Publications, Los Altos, CA, 1987.
    36) Koup JR, Rose JQ, & Cohen ME: Ethosuximide pharmacokinetics in a pregnant patient and her newborn. Epilepsia 1978; 19:535-539.
    37) Kuhnz W, Koch S, & Jacob S: Ethosuximide in epileptic women during pregnancy and lactation period. Placental transfer, serum concentrations in nursed infants and clinical status. Br J Clin Pharmacol 1984; 18:671-677.
    38) Kutt H: Plasma clearance of nor-methsuximide in a uremic patient. In: Metabolism of Antiepileptic Drugs. RH Levy et al (eds), Raven Press, New York, NY, 1984.
    39) Least CJ, Johnson GF, & Solomon HM: A quantitative gas chromatographic determination of ethosuximide based on N-butylation. Clin Chim Acta 1975; 60:285-292.
    40) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    41) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    42) Marbury TC, Lee CS, & Perchalski RJ: Hemodialysis clearance of ethosuximide in patients with chronic renal disease. Am J Hosp Pharm 1981; 38:1757-1760.
    43) Massey GV, Dunn NL, & Heckel JL: Aplastic anemia following therapy for absence seizures with ethosuximide. Pediatr Neurol 1994; 11:59-61.
    44) Miles MV, Howlett CM, & Tennison MB: Determination of N-desmethylmethsuximide serum concentrations using enzyme-multiplied and fluorescence polarization immunoassays. Ther Drug Monit 1989; 11:337-342.
    45) Miles MV, Tennison MB, & Greenwood RS: Pharmacokinetics of N-desmethylmethsuximide in pediatric patients. J Pediatr 1989a; 114:647-649.
    46) Miles MV, Tennison MB, & Greenwood RS: Pharmacokinetics of N-desmethylsuximide in pediatric patients. J Pediatrics 1989a; 114:647-650.
    47) Morrow JI & Routledge PA: Poisoning by anticonvulsants. Adverse Drug React Acute Poisoning Rev 1989; 8:97-109.
    48) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    49) Penry JK: Determinations of plasma ethosuximide (Zarontin(R)) concentration and the management of absence (petit mal) seizures. Neurology 1972; 22:410.
    50) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    51) Porter RJ, Penry JK, Lacy JR, et al: Plasma concentrations of phensuximide, methsuximide, and their metabolites in relation to clinical efficacy. Neurology 1979; 29:1509-1513.
    52) Product Information: Celontin(R) oral capsules, methsuximide oral capsules. Pfizer, New York, NY, 2010.
    53) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    54) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    55) Product Information: ZARONTIN(R) oral capsules, ethosuximide oral capsules. Pfizer, New York, NY, 2010.
    56) Product Information: Zarontin(R) oral capsules, ethosuximide oral capsules. Parke-Davis (Per FDA), New York, NY, 2012.
    57) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    58) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    59) Rane A & Tunell R: Ethosuximide in human milk and in plasma of a mother and her nursed infant. Br J Clin Pharmacol 1981; 12:855-858.
    60) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    61) Schmidt D & Seldon L: Adverse effects of antiepileptic drugs, Raven Press, New York, NY, 1982.
    62) Schulte CJA & Good TA: Acute intoxication due to methsuximide and diphenylhydantoin. J Pediatr 1966; 68:635.
    63) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    64) Sherwin AL: Pharmacology of ethosuximide in petit mal epilepsy. Clin Res 1971; 19:800.
    65) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    66) Stewart CF & Bottorff MB: Fluorescence polarization immunoassay for ethosuximide evaluated and compared with two other immunoassay techniques. Clin Chem 1986; 32:1781-1783.
    67) Strong JM, Abe T, Gibbs EL, et al: Plasma levels of methsuximide and N-desmethylmethsuximide during methsuximide therapy. Neurology 1974; 24(3):250-255.
    68) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    69) Troupin AS: The measurement of anticonvulsant agent levels. Ann Intern Med 1984; 100:854-858.
    70) Wad N: Rapid extraction method for ethosuximide and other antiepileptics in serum for determination by high-performance liquid chromatography. Chromatogr 1985; 338:460-462.
    71) Wad N: Simultaneous determination of eleven antiepileptic compounds in serum by high-performance liquid chromatography. J Chromatogr 1984; 305:127-133.
    72) van der Kleijn E, Collste P, Norlander B, et al: Gas chomatographic determination of ethosuximide and phensuximide in plasma and urine of man. J Pharm Pharmacol 1973; 25(4):324-327.