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FELBAMATE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Felbamate is a carbamate that is a structurally similar, but non-sedating, relative of meprobamate. It is a broad-spectrum anticonvulsant which raises the seizure threshold and prevents the spread of seizures, although its mechanism is still uncertain.

Specific Substances

    1) AD-03055
    2) Carter-Wallace 554
    3) C11-H14-N2-O4
    4) FBM
    5) W-554
    6) 2-Phenyl-1,3-propanediol dicarbamate
    7) Molecular Formula: C11-H14-N2-O4
    8) CAS 25451-15-4
    1.2.1) MOLECULAR FORMULA
    1) C11H14N2O4

Available Forms Sources

    A) FORMS
    1) Felbamate is available in the United States as 400 mg and 600 mg scored tablets or as an oral suspension 600 mg/5 mL (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    B) USES
    1) Felbamate is indicated in adults as monotherapy or as adjunctive therapy and in children as adjunctive therapy for the treatment of partial seizures, with and without generalization. Felbamate is not indicated as first-line antiepileptic treatment and is only recommended for use in those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable in light of the benefits conferred by its use (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    2) Felbamate is also indicated as adjunctive therapy for the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children 2 to 14 years of age (Prod Info FELBATOL(R) oral tablets, suspension, 2011).

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: Felbamate is recommended for use in adult patients with severe epilepsy refractory to other treatments and the benefit of use is worth the substantial risk of aplastic anemia and/or liver failure. It is NOT indicated as first-line therapy for the treatment of epilepsy. It is also indicated as adjunctive therapy for the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children 2 to 14 years of age.
    B) PHARMACOLOGY: Felbamate is a structural analog of meprobamate. Its mechanism of anticonvulsant action in humans is unknown. In animals, it abolishes the hindlimb tonic extensor phase of maximal electroshock seizures, and elevates the subcutaneous pentylenetetrazole-induced seizure threshold, as well as picrotoxin-induced seizures. These findings suggest that felbamate may reduce seizure spread and increase seizure threshold, effects predictive of efficacy in generalized tonic-clonic or partial seizures and absence seizures, respectively.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects reported, with an incidence rate of at least 5% and at least 5% greater than placebo, include nausea, vomiting, anorexia, dyspepsia, constipation, abdominal pain, decreased weight, palpitations, tachycardia, leukopenia, otitis media, fatigue, headache, somnolence, insomnia, ataxia, depression, upper respiratory tract infection, cough, fever, diplopia, miosis, and taste perversion.
    2) INFREQUENT: Adverse effects that have been reported less frequently, but with a greater incidence rate than placebo, include chest pain, dizziness, anxiety, tremor, paresthesia, rash, dry mouth, purpura, hiccups, diarrhea, elevated liver enzymes, myalgia, sinusitis, pharyngitis, and abnormal vision.
    3) RARE: Thrombocytopenia, anaphylaxis
    4) SEVERE: Aplastic anemia and liver failure are serious adverse effects that have occurred with felbamate therapy and have limited its use.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. In general, overdose effects are anticipated to be an extension of adverse effects at therapeutic doses. One patient, who ingested 12,000 mg in a suicide attempt, developed mild gastric distress and a resting heart rate of 100 bpm. A 3-year-old child developed restlessness, ataxia, tachycardia, crystalluria, and hematuria after ingesting 3.6 grams of felbamate elixir (232 mg/kg).
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Palpitations and tachycardia have been reported following therapeutic doses.
    2) Fever was reported in children following therapeutic doses.
    B) WITH POISONING/EXPOSURE
    1) Increased pulse rate has been reported following overdoses .
    0.2.20) REPRODUCTIVE
    A) No effects on male or female fertility were shown in reproduction and fertility studies in rats.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of felbamate in humans. However, due to the synthesis process, it is possible for there to be small amounts of 2 compounds known to be animal carcinogens (urethane and methyl carbamate) present in felbamate. Although in lifetime carcinogenicity studies, exposure to these compounds at any level did not result in tumorigenicity.

Laboratory Monitoring

    A) Monitor vital signs, CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Obtain an ECG, and institute continuous cardiac monitoring.
    D) Obtain urinalysis for evidence of crystalluria following overdose.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

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. Transfusions as needed for severe thrombocytopenia. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or if airway is protected.
    2) HOSPITAL: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or if airway is protected.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression or severe allergic reactions.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis has not been established as an effective means of removing felbamate from the blood; however, the small volume of distribution and low protein binding suggest that hemodialysis might be of value in severe overdose.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, who remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, should be sent to a healthcare facility for evaluation.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom diagnosis is unclear.
    H) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication. Signs and symptoms of aplastic anemia may be delayed or not evident, so reliable follow-up is imperative.
    I) PHARMACOKINETICS
    1) Well-absorbed after oral administration. Protein binding is 22% to 25%; volume of distribution in adults is approximately 59 to 65 L, or 0.7 to 1 L/kg and, in children, the apparent volume of distribution is reported to be 908 mL/kg. Felbamate is partly metabolized in the liver to inactive metabolites. Approximately 40% to 50% of the absorbed dose appears unchanged in the urine. The terminal half-life is 20 to 23 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression or hepatotoxicity.

Range Of Toxicity

    A) TOXICITY: ADULT: An overdose of approximately 18 grams along with sodium valproate (12 to 25 grams) resulted in massive crystalluria and acute renal failure. Ingestion of 12,000 mg resulted only in mild gastric distress and tachycardia. PEDIATRIC: An overdose of 6,900 mg resulted in somnolence and tachycardia in a 15-year-old girl. A 3-year-old child developed restlessness, ataxia, tachycardia, crystalluria, and hematuria after ingesting 3.6 grams of felbamate elixir (232 mg/kg).
    B) THERAPEUTIC DOSE: ADULTS and CHILDREN over the age of 14 years: 1200 mg/day orally in 3 to 4 divided doses, may increase dosage in 600 mg/day increments every 2 weeks to 2400 mg/day as needed and thereafter to 3600 mg/day if clinically indicated. PEDIATRIC: For ages 2 to 14 years, initiate at 15 mg/kg/day orally in 3 to 4 divided doses; increase felbamate by 15 mg/kg/day increments at weekly intervals to 45 mg/kg/day.

Clinical Effects

Summary Of Exposure

    A) USES: Felbamate is recommended for use in adult patients with severe epilepsy refractory to other treatments and the benefit of use is worth the substantial risk of aplastic anemia and/or liver failure. It is NOT indicated as first-line therapy for the treatment of epilepsy. It is also indicated as adjunctive therapy for the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children 2 to 14 years of age.
    B) PHARMACOLOGY: Felbamate is a structural analog of meprobamate. Its mechanism of anticonvulsant action in humans is unknown. In animals, it abolishes the hindlimb tonic extensor phase of maximal electroshock seizures, and elevates the subcutaneous pentylenetetrazole-induced seizure threshold, as well as picrotoxin-induced seizures. These findings suggest that felbamate may reduce seizure spread and increase seizure threshold, effects predictive of efficacy in generalized tonic-clonic or partial seizures and absence seizures, respectively.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects reported, with an incidence rate of at least 5% and at least 5% greater than placebo, include nausea, vomiting, anorexia, dyspepsia, constipation, abdominal pain, decreased weight, palpitations, tachycardia, leukopenia, otitis media, fatigue, headache, somnolence, insomnia, ataxia, depression, upper respiratory tract infection, cough, fever, diplopia, miosis, and taste perversion.
    2) INFREQUENT: Adverse effects that have been reported less frequently, but with a greater incidence rate than placebo, include chest pain, dizziness, anxiety, tremor, paresthesia, rash, dry mouth, purpura, hiccups, diarrhea, elevated liver enzymes, myalgia, sinusitis, pharyngitis, and abnormal vision.
    3) RARE: Thrombocytopenia, anaphylaxis
    4) SEVERE: Aplastic anemia and liver failure are serious adverse effects that have occurred with felbamate therapy and have limited its use.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. In general, overdose effects are anticipated to be an extension of adverse effects at therapeutic doses. One patient, who ingested 12,000 mg in a suicide attempt, developed mild gastric distress and a resting heart rate of 100 bpm. A 3-year-old child developed restlessness, ataxia, tachycardia, crystalluria, and hematuria after ingesting 3.6 grams of felbamate elixir (232 mg/kg).

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Palpitations and tachycardia have been reported following therapeutic doses.
    2) Fever was reported in children following therapeutic doses.
    B) WITH POISONING/EXPOSURE
    1) Increased pulse rate has been reported following overdoses .
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER
    a) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, fever was reported in 22.6% of patients treated with felbamate (n=31) compared to 11.1% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Palpitations and tachycardia have been reported following therapeutic doses (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    B) WITH POISONING/EXPOSURE
    1) Increased pulse rate has been reported following overdoses (Prod Info FELBATOL(R) oral tablets, suspension, 2011; Meier et al, 2005; Nagel & Schunk, 1995).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) DIPLOPIA
    a) Blurred vision and diplopia may be seen following therapeutic felbamate doses in a significant number of patients (Leppik et al, 1991; Wilensky et al, 1985).
    b) INCIDENCE: Diplopia and abnormal vision were reported in 6.1% and 5.3%, respectively, of patients treated with felbamate (n=114) compared to 0% and 2.3%, respectively, of patients who received placebo (n=43) during clinical trials (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    2) MIOSIS
    a) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, miosis was reported in 6.5% of patients treated with felbamate (n=31) compared to 0% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) OTITIS MEDIA
    a) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, otitis media was reported in 9.7% of patients treated with felbamate (n=31) compared to 0% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) SINUSITIS: During placebo-controlled adjunctive therapy trials in adults, sinusitis was reported in 3.5% of patients treated with felbamate (n=114) compared to 0% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) PHARYNGITIS
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, pharyngitis was reported in 2.6% of patients treated with felbamate (n=114) compared to 0% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    b) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, pharyngitis was reported in 9.7% of patients treated with felbamate (n=31) compared to 3.7% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Palpitations and tachycardia have been frequently reported following therapeutic administration. Rarely, supraventricular tachycardia has been reported (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 15-year-old girl presented with a heart rate of 116 beats/minute 4 hours after ingesting 6900 milligrams of felbamate (Nagel & Schunk, 1995). Tachycardia had resolved by 5 hours post ingestion.
    b) CASE REPORT: A resting heart rate of 100 bpm was reported in a subject following an intentional overdose of 12,000 mg of felbamate (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    c) CASE REPORT: A heart rate of 130 to 150 beats/minute was reported in a 3-year-old child approximately 9 hours after ingesting 3.6 grams of felbamate elixir (232 mg/kg). The patient recovered with supportive care (Meier et al, 2005).
    B) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, chest pain was reported in 2.6% of patients treated with felbamate (n=114) compared to 0% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, upper respiratory tract infection was reported in 45.2% of patients treated with felbamate (n=31) compared to 25.9% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    B) COUGH
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, coughing was reported in 6.5% of patients treated with felbamate (n=31) compared to 0% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, somnolence, fatigue, depression, and stupor were reported in 19.3, 16.8%, 5.3%, and 2.6% of patients, respectively, treated with felbamate (n=114) compared to 7%, 7%, 0%, and 0% of patients, respectively, who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    b) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, somnolence and fatigue were reported in 48.4% and 9.7% of patients, respectively, treated with felbamate (n=31) compared to 11.1% and 3.7% of patients, respectively, who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Somnolence and exhaustion occurred in a 15-year-old girl with documented seizure disorder following an overdose of 6900 mg felbamate (about 8 times her usual bedtime dose). Felbamate was begun 4 months prior to the overdose. Treatment consisted of gastric lavage and one dose of activated charcoal, with resolution of somnolence 7.5 hours after ingestion. No seizure activity occurred (Nagel & Schunk, 1995).
    b) CASE REPORT: Altered mental status was reported following an acute overdose of felbamate (approximately 18 grams) and sodium valproate (12 to 25 grams). The patient became progressively obtunded over a 4 to 5 hour period, requiring endotracheal intubation and mechanical ventilation. The patient made a full recovery following symptomatic therapy (Rengstorff et al, 2000).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, headaches were reported in 36.8% of patients treated with felbamate (n=114) compared to 9.3% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, dizziness was reported in 18.4% of patients treated with felbamate (n=114) compared to 14% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    D) ANXIETY
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, insomnia, nervousness, and anxiety were reported in 17.5%, 7%, and 5.3%, respectively, of patients treated with felbamate (n=114) compared to 7%, 2.3%, and 4.7%, respectively, of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    E) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, insomnia was reported in 17.5% of patients treated with felbamate (n=114) compared to 7% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    b) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, insomnia was reported in 16.1% of patients treated with felbamate (n=31) compared to 14.8% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    F) TREMOR
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, tremor was reported in 6.1% of patients treated with felbamate (n=114) compared to 2.3% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    G) NYSTAGMUS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A constant downbeat nystagmus in the primary position and in downward gaze has been reported in a 44-year-old man following ingestion of an unknown quantity of felbamate (possibly a maximum of 36,000 mg) in a suicide attempt. The nystagmus resolved by the third hospital day (Hwang et al, 1995).
    H) ATAXIA
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, ataxia and abnormal gait were reported in 3.5% and 5.3% of patients, respectively, treated with felbamate (n=114) compared to 0% of patients who received placebo (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    b) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, ataxia and abnormal gait were reported in 6.5% and 9.7% of patients, respectively, treated with felbamate (n=31) compared to 3.7% and 0% of patients, respectively, who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Ataxia, agitation and hostility were observed on admission to the emergency department in a 44-year-old man following an overdose of felbamate. Concomitant medications also included haloperidol and benztropine mesylate (not taken in the overdose). Following increased doses of haloperidol and sertraline, the patient's symptoms resolved over 6 days (Hwang et al, 1995).
    b) CASE REPORT: A 3-year-old child presented to the emergency department with restlessness and ataxia approximately 9 hours after ingesting 3.6 grams of felbamate elixir (232 mg/kg). The ataxia completely resolved within one day following supportive care (Meier et al, 2005).
    I) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, paresthesia was reported in 3.5% of patients treated with felbamate (n=114) compared to 2.3% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    J) DYSTONIA
    1) WITH THERAPEUTIC USE
    a) Involuntary movement disorders, including choreoathetosis and acute dystonia, have been reported following therapeutic felbamate doses used as adjunctive therapy in two children. Symptoms resolved with no recurrence following discontinuation of felbamate (Kerrick et al, 1995).
    K) PAIN
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, pain was reported in 6.5% of patients treated with felbamate (n=31) compared to 0% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, nausea and vomiting were reported in 34.2% and 16.7%, respectively, of patients treated with felbamate (n=114) compared to 2.3% and 4.7%, respectively, of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011). In one study, doses up to 3000 mg/day were decreased to 2600 mg/day due to the high incidence of nausea and vomiting (Leppik et al, 1991).
    b) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, nausea and vomiting were reported in 6.5% and 38.7% of patients, respectively, treated with felbamate (n=31) compared to 0% and 14.8% of patients, respectively, who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: An adult attempting suicide with the ingestion of 12,000 mg felbamate in a 12 hour period experienced mild gastric distress (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    b) Vomiting occurred in a 3-year-old child approximately 9 hours after ingesting 3.6 grams of felbamate elixir (232 mg/kg) (Meier et al, 2005).
    B) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, anorexia was reported in 19.3% of patients treated with felbamate (n=114) compared to 2.3% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    b) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, anorexia was reported in 54.8% of patients treated with felbamate (n=31) compared to 14.8% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011). Anorexia, with weight loss of 3% to 5% of body weight, in children occurs mostly during the first 3 months of therapy (Bourgeois, 1997)
    C) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, dyspepsia was reported in 12.3% of patients treated with felbamate (n=114) compared to 7% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    b) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, dyspepsia was reported in 6.5% of patients treated with felbamate (n=31) compared to 3.7% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    D) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, constipation was reported in 11.4% of patients treated with felbamate (n=114) compared to 2.3% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    b) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, constipation was reported in 12.9% of patients treated with felbamate (n=31) compared to 0% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    E) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, diarrhea was reported in 5.3% of patients treated with felbamate (n=114) compared to 2.3% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    F) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, abdominal pain was reported in 5.3% of patients treated with felbamate (n=114) as compared to 0% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    G) APTYALISM
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, dry mouth was reported in 2.6% of patients treated with felbamate (n=114) compared to 0% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    H) DISORDER OF TASTE
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, taste perversion was reported in 6.1% of patients treated with felbamate (n=114) compared to 0% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    I) HICCOUGHS
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, hiccup was reported in 9.7% of patients treated with felbamate (n=31) compared to 3.7% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) Hepatotoxicity is a potentially serious adverse effect. Pellock (1999) reviewed 18 reported cases of acute hepatic failure associated with felbamate therapy (Pellock, 1999). The overall incidence was 164 per million patients treated. Patients ranged in age from 5 to 61 years, with 78% female and mean time to presentation of 217 days (range, 25 to 939 days). Eliminating 11 patients in whom other complications possibly contributed to hepatotoxicity, the incidence dropped to 64 per million cases treated. Eight fatalities have been reported to the manufacturer (Bourgeois, 1997). The estimated incidence of death is 1 per 26,000 to 34,000 exposures (Pellock & Brodie, 1997).
    b) Post-marketing surveillance reported a rate of hepatic failure in the U.S. as 6 cases of hepatic failure leading to death or liver transplantation per 75,000 patient years of felbamate use; however, this rate may be an underestimate due to under reporting (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    1) Of the cases reported, approximately 67% resulted in death or liver transplantation, usually occurring within 5 weeks of onset of signs and symptoms (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    c) Frequent monitoring of liver function tests is recommended with early withdrawal of the drug if laboratory findings indicate possible liver damage (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    d) Increased serum liver enzyme function tests have been reported in patients receiving therapeutic doses of felbamate (Prod Info FELBATOL(R) oral tablets, suspension, 2011). Felbamate is not recommended in patients with pre-existing liver dysfunction.
    e) O'Neil et al (1996) reported a case of massive acute hepatic necrosis resulting in death within 40 days of initiating felbamate therapy (O'Neil et al, 1996).
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, increased serum glutamic pyruvic transaminase (SGPT) concentrations were reported in 3.5% of patients treated with felbamate (n=114) compared to 0% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FUNCTION TESTS ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Patients receiving felbamate in doses of up to 2600 mg/day exhibited slightly lower blood urea nitrogen levels (average 1.25 mg/dL less) than a placebo group (Leppik et al, 1991). The clinical significance of this finding is unknown.
    B) CRYSTALLURIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT (CHILD): A 3-year-old child presented to the emergency department with restlessness, ataxia, and tachycardia after ingesting 3.6 grams of felbamate elixir (232 mg/kg). Urine analysis, performed approximately 13 hours post-ingestion, showed hematuria and numerous needle-shaped crystals. The patient's crystalluria and hematuria resolved after 12 hours of intravenous hydration (Meier et al, 2005).
    b) CASE REPORT (ADULT): An acute overdose of felbamate (approximately 18 grams) and sodium valproate (12 to 25 grams) in a 20-year-old woman resulted in acute renal failure with massive crystalluria. Macroscopic urinary crystals, which formed about 18 hours post-ingestion, were identified by gas chromatography as containing felbamate. The patient recovered following hydration and symptomatic therapy (Rengstorff et al, 2000).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) APLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Aplastic anemia has been reported as an uncommon adverse reaction. Of 33 reported cases of aplastic anemia associated with felbamate therapy, the at-risk patient was a Caucasian female, middle age with a history of previous anticonvulsant allergy and/or a history of previous cytopenia and evidence of underlying immunologic disorder. The mean time to onset was 175 days (range, 23 to 339 days). Dose was not a factor (Pellock, 1999). The manufacturer has reported 10 aplastic anemia-related deaths (Bourgeois, 1997).
    b) INCIDENCE: Kaufman et al (1997) established a most probable incidence of aplastic anemia due to therapeutic felbamate as 127 per one million users based on retrospective case analysis (Kaufman et al, 1997). Pellock (1999) estimated the incidence to be 209 to 300 per million patients based on 33 reported cases (Pellock, 1999). An overall case fatality rate is reported to be in the range of 20% to 30%, although rates as high as 70% have been reported (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    c) Onset of aplastic anemia has ranged from 5 to 30 weeks following initiation of felbamate therapy, although the injury to the bone marrow may have occurred weeks to months prior to the onset of symptoms; therefore patients, who have discontinued felbamate therapy, may continue to be at risk for developing aplastic anemia for an unknown period afterwards (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A serious thrombocytopenia was reported following therapeutic felbamate in conjunction with valproic acid, carbamazepine and phenobarbital in a 26-year-old man. Three days after felbamate was added to his therapy regimen, his platelet count dropped to 23,000 from 312,000 prior to felbamate. Platelet transfusions were administered and felbamate was discontinued (Ney et al, 1994).
    C) PURPURA
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, purpura was reported in 12.9% of patients treated with felbamate (n=31) compared to 7.4% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    D) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, leukopenia was reported in 6.5% of patients treated with felbamate (n=31) compared to of 0% patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC: During a placebo-controlled adjunctive therapy trial in children with Lennox-Gastaut Syndrome, rash was reported in 9.7% of patients treated with felbamate (n=31) compared to 7.4% of patients who received placebo (n=27) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    B) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 33-year-old woman on felbamate 3000 mg/day for 16 days developed toxic epidermal necrolysis involving 45% of her total body surface area. She was not receiving other anticonvulsants (Travaglini et al, 1995).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) ADULT: During placebo-controlled adjunctive therapy trials in adults, myalgia was reported in 2.6% of patients treated with felbamate (n=114) as compared to 0% of patients who received placebo (n=43) (Prod Info FELBATOL(R) oral tablets, suspension, 2011).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Delayed anaphylaxis has been reported following a therapeutic dose of felbamate, and is an uncommon effect. A 46-year-old woman with a pre-existing systemic lupus erythematosus, being treated with prednisone, presented with wheezing, orthostatic hypotension, urticaria, pruritus and facial edema by the fourth felbamate dose (O'Neil et al, 1995).

Reproductive

    3.20.1) SUMMARY
    A) No effects on male or female fertility were shown in reproduction and fertility studies in rats.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) There is insufficient information concerning teratogenic effects of felbamate in the literature to recommend its use during pregnancy.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Felbamate is classified as US FDA Pregnancy Category C (Prod Info Felbatol(R), felbamate, 2000).
    B) PLACENTAL BARRIER
    1) Felbamate crosses the placental barrier in rat pups. Human data on placental transfer of felbamate is lacking (Prod Info Felbatol(R), felbamate, 2000); placental transfer would be expected to occur because of its low molecular weight (Briggs et al, 1998).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Felbamate has been reported to pass into human breast milk. The effects on the nursing infant are not yet known (Prod Info Felbatol(R), felbamate, 2000).
    2) A decrease in rat pup weight and increase in deaths occurred during lactation, but the cause of death was unknown (Prod Info Felbatol(R), felbamate, 2000).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) No effects on male or female fertility were shown in reproduction and fertility studies in rats at oral doses of up to 13.9 times the human total daily dose of 3600 mg (Prod Info Felbatol(R), felbamate, 2000).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of felbamate in humans. However, due to the synthesis process, it is possible for there to be small amounts of 2 compounds known to be animal carcinogens (urethane and methyl carbamate) present in felbamate. Although in lifetime carcinogenicity studies, exposure to these compounds at any level did not result in tumorigenicity.
    3.21.3) HUMAN STUDIES
    A) SYNTHESIS PROCESS
    1) The possibility exists for there to be small amounts of two compounds known to be animal carcinogens (genotoxic ethyl carbamate (urethane) and non-genotoxic methyl carbamate) present in felbamate due to the synthesis process. In theory, exposure to urethane and methyl carbamate of up to 0.72 mcg and 1800 mcg, respectively, could occur in a 50-kg patient receiving a 3600-mg felbamate dose. These daily doses are approximately 1/35,000 and 1/5500 on a mg/kg basis and 1/10,000 and 1/1600 on a mg/m(2) basis, respectively, of the levels of exposure shown to be carcinogenic in rodents. However, these compounds in felbamate at any exposure level did not result in tumors in lifetime carcinogenicity studies (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    3.21.4) ANIMAL STUDIES
    A) HEPATIC CELL ADENOMAS
    1) There was a significant increase in hepatic cell adenomas in high-dose male and female rats and in high-dose female rats. Mice were exposed to felbamate as a feed admixture for 92 weeks at doses of 300 mg/kg, 600 mg/kg, and 1200 mg/kg. Rats were exposed to felbamate as a feed admixture for 104 weeks at doses of 30 mg/kg, 100 mg/kg, and 300 mg/kg for males and 10 mg/kg, 30 mg/kg, and 100 mg/kg for females. At the maximum dose, steady-state plasma concentrations were equal to or less than the steady-state plasma concentrations in patients receiving 3600 mg/day for epilepsy. There was a significant dose-related increase in the incidence of hepatic hypertrophy in mice, particularly in males. There was no evidence of hepatic hypertrophy in female rats. There have been no studies to determine if there is an association between benign hepatocellular adenomas and liver hypertrophy resulting from liver enzyme induction. In high-dose male rats, there was a statistically significant increase in benign interstitial cell tumors of the testes. It is not known if any of these findings are relevant in humans (Prod Info FELBATOL(R) oral tablets, suspension, 2011).

Genotoxicity

    A) No evidence of mutagenicity was demonstrated in microbial and mammalian cell assays in the Ames Salmonella/microsome plate test, CHO/HGPRT mammalian cell forward gene mutation assay, sister chromatid exchange assay in CHO cells, and bone marrow cytogenetics assay (Prod Info FELBATOL(R) oral tablets, suspension, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Obtain an ECG, and institute continuous cardiac monitoring.
    D) Obtain urinalysis for evidence of crystalluria following overdose.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Although therapeutic serum levels have not been established, it may be advisable to monitor serum levels. Targeted therapeutic concentrations have ranged from 18 to 52 mcg/mL (Leppik et al, 1991). However, plasma concentrations are not clinically useful in the management of overdose.
    2) Monitor CBC with differential and platelet count, renal function and liver enzyme concentrations in symptomatic patients.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4.1.3) URINE
    A) URINALYSIS
    1) Obtain urinalysis following severe overdose. Massive crystalluria and acute renal failure have been reported after felbamate overdose (Rengstorff et al, 2000).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain an ECG and institute cardiac monitoring. Overdoses may result in ECG abnormalities, including tachycardia (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    2) MONITORING
    a) Monitor vital signs in symptomatic patients.

Methods

    A) CHROMATOGRAPHY
    1) A quantitative rapid isothermal chromatographic assay method for felbamate measurements in human serum is described by Poquette (1995). No significant interference was found with 60 commonly encountered drugs (Poquette, 1995).
    2) Wilensky et al (1985) described a method of high-pressure liquid chromatography using a 39% methanol/water or a 20% acetonitrile/water mobile phase and a C 18 column for determination of felbamate in human serum. The acetonitrile/water mobile phase is used in the presence of carbamazepine metabolites, which cause interference if a methanol/water mobile phase is used .
    3) Behnke & Reddy (1997) described a high-performance liquid chromatography method for the simple and rapid quantitation of felbamate in human plasma/serum. Their method utilizes a HPLC unit equipped with a C18 reverse-phase cartridge, an acetonitrile/water gradient, and detection at 210 nm. Interferences from other common antiepileptic drugs and analgesics are not observed (Behnke & Reddy, 1997).
    4) Thompson et al (1999) developed an isotope-dilution-based LC/MS technique for the quantification of felbamate and its metabolites in human urine. The LC/MS analysis was performed with the use of a Water 2690 HPLC equipped with an autosampler and a Water 486 tunable absorbance detector (Thompson et al, 1999).
    5) Rengstorff et al (2000) used gas chromatography to identify felbamate in macroscopic needle-shaped crystals in a patient's urine following an overdose (Rengstorff et al, 2000).

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.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, who remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, should be sent to a healthcare facility for evaluation.

Monitoring

    A) Monitor vital signs, CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Obtain an ECG, and institute continuous cardiac monitoring.
    D) Obtain urinalysis for evidence of crystalluria following overdose.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) 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).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Transfusions as needed for severe thrombocytopenia. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    B) MONITORING OF PATIENT
    1) Monitor vital signs, CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    2) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    3) Obtain an ECG, and institute continuous cardiac monitoring.
    4) Obtain urinalysis for evidence of crystalluria following overdose.
    5) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    2) CRYSTALLURIA and acute renal failure have been reported following felbamate overdose. Administer parenteral hydration until resolution of the crystalluria and normalization of serum creatinine (Rengstorff et al, 2000).
    D) ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis has not been established as an effective means of removing felbamate from the blood. The small volume of distribution (0.7 to 1 L/kg) and low protein binding (22% to 25%) (Prod Info FELBATOL(R) oral tablets, suspension, 2011) suggest that hemodialysis might be of value in severe overdose.

Abstracts

Case Reports

    A) ADULT
    1) Hwang et al (1995) reported a case of a 44-year-old man who ingested an unknown quantity of felbamate 600 mg tablets. His other medications included haloperidol and carbamazepine. He was admitted to the emergency department with a constant downbeat nystagmus in the primary position and in downward gaze, ataxia, generalized mild motor weakness, and rapid alternating peripheral movements.
    a) Admission laboratory studies within normal limits included CBC, electrolytes, renal and liver function tests, and ESR. 21 hours after the felbamate ingestion, his plasma level was 110 mg/L. The nystagmus resolved by the third hospital day. Over the next 3 days, his ataxia, agitation, and hostility resolved (Hwang et al, 1995).
    B) PEDIATRIC
    1) A 15-year-old girl developed felbamate concentrations of 141 and 111 mcg/mL at 4.5 and 7 hours, respectively, after ingesting 6,900 mg of felbamate. Symptoms included somnolence and tachycardia which resolved over approximately 7.5 hours (Nagel & Schunk, 1995).

Range Of Toxicity

Summary

    A) TOXICITY: ADULT: An overdose of approximately 18 grams along with sodium valproate (12 to 25 grams) resulted in massive crystalluria and acute renal failure. Ingestion of 12,000 mg resulted only in mild gastric distress and tachycardia. PEDIATRIC: An overdose of 6,900 mg resulted in somnolence and tachycardia in a 15-year-old girl. A 3-year-old child developed restlessness, ataxia, tachycardia, crystalluria, and hematuria after ingesting 3.6 grams of felbamate elixir (232 mg/kg).
    B) THERAPEUTIC DOSE: ADULTS and CHILDREN over the age of 14 years: 1200 mg/day orally in 3 to 4 divided doses, may increase dosage in 600 mg/day increments every 2 weeks to 2400 mg/day as needed and thereafter to 3600 mg/day if clinically indicated. PEDIATRIC: For ages 2 to 14 years, initiate at 15 mg/kg/day orally in 3 to 4 divided doses; increase felbamate by 15 mg/kg/day increments at weekly intervals to 45 mg/kg/day.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) PARTIAL SEIZURES
    a) MONOTHERAPY: 1200 mg/day in 3 to 4 divided doses. The dose may be increased by 600 mg/day every 2 weeks. MAX DOSE: 3600 mg/day (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    b) ADJUNCTIVE THERAPY: 200 milligrams/day in 3 to 4 divided doses with a concomitant decrease in the dosage of other antiepileptic drugs by 20%. Further reductions in other anticonvulsants may be required to minimize side effects due to drug interactions. Thereafter, the felbamate is increased at a rate of 1200 mg/day in weekly intervals to a maximum dose of 3600 mg daily (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    7.2.2) PEDIATRIC
    A) PARTIAL SEIZURES
    1) 14 YEARS OF AGE AND OLDER
    a) MONOTHERAPY: 1200 mg/day in 3 to 4 divided doses. The dose may be increased by 600 mg/day every 2 weeks. MAX DOSE: 3600 mg/day (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    b) ADJUNCTIVE THERAPY: 200 milligrams/day in 3 to 4 divided doses with a concomitant decrease in the dosage of other antiepileptic drugs by 20%. Further reductions in other anticonvulsants may be required to minimize side effects due to drug interactions. Thereafter, the felbamate is increased at a rate of 1200 mg/day in weekly intervals to a maximum dose of 3600 mg daily (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    B) LENNOX-GASTAUT SYNDROME
    1) 2 TO 14 YEARS OF AGE
    a) ADJUNCTIVE THERAPY: 15 mg/kg/day in 3 or 4 divided doses. Reduce the dose of concurrent antiepileptic drugs by 20%, further reductions may be required. Thereafter, increase the felbamate dose by 15 mg/kg/day in weekly intervals to a maximum of 45 mg/kg/day (Prod Info FELBATOL(R) oral tablets, suspension, 2011).

Maximum Tolerated Exposure

    A) ADULTS
    1) In a suicidal gesture, a patient ingested 12,000 milligrams felbamate over a 12-hour period. Mild gastric symptoms and a resting heart rate of 100 bpm were the only reported adverse events (Prod Info FELBATOL(R) oral tablets, suspension, 2011).
    2) A 44-year-old man ingested an unknown quantity of felbamate, potentially up to 36,000 milligrams, and experienced a reversible downbeat nystagmus and generalized mild motor weakness and ataxia, which resolved over several days (Hwang et al, 1995).
    3) Following an overdose of felbamate (approximately 18 grams) and sodium valproate (12 to 25 grams), a 20-year-old woman developed acute renal failure. At 18 hours post-ingestion, felbamate was identified by gas chromatography in massive quantities of macroscopic needle-shaped crystals. Following hydration therapy, the patient recovered (Rengstorff et al, 2000).
    B) CHILDREN
    1) A 15-year-old girl ingested 6,900 milligrams of felbamate and experienced somnolence and tachycardia which resolved over 7.5 hours (Nagel & Schunk, 1995).
    2) A 3-year-old child presented to the emergency department with vomiting, restlessness, ataxia, and tachycardia after ingesting 3.6 grams of felbamate elixir (232 mg/kg). Urine analysis, performed approximately 13 hours post-ingestion, showed hematuria and numerous needle-shaped crystals. The serum felbamate level was 138 mg/L approximately 15 hours postingestion. The patient's crystalluria and hematuria resolved after 12 hours of intravenous hydration (Meier et al, 2005).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Therapeutic plasma levels of felbamate have not been established. Normal values have ranged from approximately 18 to 52 mcg/mL (mean 32.5 mcg/mL), 5 days after initiation of felbamate in patients taking a mean felbamate dosage of 2300 mg/day for control of severely refractory partial seizures (Leppik et al, 1991).
    2) Mean plasma concentrations for patients taking felbamate 3600 mg/day as monotherapy has been reported to be 63 +/- 18 mg/L (Faught et al, 1993).
    3) Plasma felbamate concentrations ranged from 9 to 134 mcg/mL in 41 patients on felbamate therapeutically (Harden et al, 1996).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) ACUTE
    a) Twenty-one hours after an overdose of an unknown quantity of felbamate (potentially up to 36,000 mg) plasma levels were 110 mg/L. Since monotherapy half-life is 19 to 20 hours, this patients plasma level of felbamate was probably much higher at the time of his ED admission. Symptoms included reversible downbeat nystagmus, generalized mild motor weakness and ataxia (Hwang et al, 1995).
    b) Felbamate concentrations at 4.5 and 7 hours after an acute overdose of 6,900 mg by a patient on felbamate therapeutically were 141 and 111 mcg/mL, respectively. Symptoms included somnolence and tachycardia (Nagel & Schunk, 1995).
    c) Following an approximate overdose of 18 grams of felbamate, plasma concentrations at 12, 16, and 70 hours post-ingestion were 200, 190, and 110 mcg/mL, respectively (Rengstorff et al, 2000).
    d) CASE REPORT: The serum felbamate level was 138 mg/L approximately 15 hours after a 3-year-old child ingested 3.6 grams of felbamate elixir (232 mg/kg) (Meier et al, 2005).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 4 g/kg ((RTECS, 2000))
    2) LD50- (ORAL)MOUSE:
    a) >5 g/kg ((RTECS, 2000))
    3) LD50- (ORAL)RAT:
    a) >5 g/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Felbamate is a structural analog of meprobamate. Its mechanism of anticonvulsant action in humans is unknown. In animals, it abolishes the hindlimb tonic extensor phase of maximal electroshock seizures, and elevates the subcutaneous pentylenetetrazole-induced seizure threshold, as well as picrotoxin-induced seizures (Leppik et al, 1991; Theodore et al, 1991).
    1) Felbamate is relatively ineffective against bicuculline- and strychnine- induced seizures. In animals, felbamate has a relative lack of toxicity and lethality (Leppik et al, 1991). These findings suggest that felbamate may reduce seizure spread and increase seizure threshold, effects predictive of efficacy in generalized tonic-clonic or partial seizures and absence seizures, respectively (Prod Info felbamate oral suspension, 2015).
    B) It is postulated that felbamate's mechanism of action is due to an interaction with N-methyl-D-aspartate (NMDA) receptors, resulting in decreased excitatory amino acid neurotransmission. In animal studies, Kleckner et al (1999) determined the clinical mechanism of felbamate activity to be due in part to an interaction with the NR1-2B subtype of the NMDA receptor (Kleckner et al, 1999).

Physicochemical

Physical Characteristics

    A) Felbamate is a white to off-white crystalline powder with a characteristic odor, is very slightly soluble in water, slightly soluble in ethanol, sparingly soluble in methanol, and freely soluble in dimethyl sulfoxide(Prod Info FELBATOL(R) oral tablets, suspension, 2011).

Molecular Weight

    A) 238.24 (Prod Info FELBATOL(R) oral tablets, suspension, 2011)

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