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VIGABATRIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Vigabatrin is an anticonvulsant and a synthetic derivative of gamma-aminobutyric acid (GABA).

Specific Substances

    1) Gamma-vinyl aminobutyric acid
    2) Gamma-vinyl GABA
    3) MDL-71754
    4) Vigabatrina
    5) Vigabatrine
    6) Vigabatrinum
    7) RMI-71754
    8) 4-Amino-5-hexenoic acid
    9) 4-Aminohex-5-enoic acid
    10) C(6)H(11)NO(2)
    11) CAS 60643-86-9
    1.2.1) MOLECULAR FORMULA
    1) C6H11NO2

Available Forms Sources

    A) FORMS
    1) Vigabatrin is available as a 500 mg tablet (Prod Info SABRIL(R) oral tablets, 2009) and it is also available as a powder (500 mg) for oral solution (Prod Info SABRIL(R) oral solution, 2009).
    B) USES
    1) Vigabatrin is indicated as an adjunctive anticonvulsant therapy for refractory complex partial seizures in adults with an inadequate response to alternative treatments (Prod Info SABRIL(R) oral tablets, 2009); it has also been indicated as a monotherapy to treat infantile spasms in infants from one month to 2 years of age (Prod Info SABRIL(R) oral solution, 2009).

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: Vigabatrin is used for the treatment of refractory complex partial seizures in adults. It is indicated as an adjunctive therapy in patients that fail to respond to other therapies. It is also used to treat infantile spasms in children 1 month to 2 years.
    B) PHARMACOLOGY: Although the exact mechanism for antiseizure activity is unknown, it is thought to be an irreversible inhibitor of the gamma-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the metabolism of the inhibitory neurotransmitter GABA. This can increase the levels of GABA in the central nervous system.
    C) EPIDEMIOLOGY: Overdose is infrequent. Due to the risk of permanent vision loss, the drug is only available through a restricted distribution program called SHARE (1-888-45-SHARE). When overdose has occurred, it has often been combined with other agents.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Drowsiness and fatigue are the most common adverse events. Exacerbation of psychotic symptoms may develop during treatment with vigabatrin or withdrawal from vigabatrin. As with other antiepileptic drugs, vigabatrin may increase the risk of suicidal thoughts or behavior during therapeutic use. Other events include: fever, seizures, anemia, peripheral edema and neuropathy, weight gain, and headache.
    2) SEVERE EVENTS: Permanent vision loss can develop with therapy, which has led to its restricted use. In postmarketing experience, relatively serious events have included: gastrointestinal hemorrhage, acute psychosis, delirium, neonatal agitation, laryngeal edema, pulmonary embolism, respiratory failure, stridor, angioedema, malignant hyperthermia, dystonia, and multiorgan failure; the frequency of these events is unknown.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited data. Drowsiness and fatigue are likely to occur. Other symptoms may include: vertigo, irritability, agitation, headache, and increased seizure activity.
    2) SEVERE TOXICITY: Coma and unconsciousness may develop. Other events may include: seizures, acute psychosis, delirium, respiratory depression, hypotension and bradycardia. Although not reported in overdose, anemia has developed with therapy.
    0.2.20) REPRODUCTIVE
    A) The manufacturer has classified vigabatrin as FDA pregnancy category C. Since data in humans are lacking, vigabatrin should be used in pregnancy only if the potential benefit outweighs risk. Teratogenic effects (eg; cleft palate) have been reported in toxic doses in rabbits; no teratogenic effects were observed at high doses in rats.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential.

Laboratory Monitoring

    A) Monitor mental status.
    B) Monitor pulse oximetry, initiate cardiac monitoring and obtain an ECG upon initial evaluation and repeat as indicated following a significant overdose.
    C) Monitor fluid status, renal function and a basic metabolic panel, as necessary.
    D) Obtain a CBC as indicated.
    E) ABGs should be obtained in patients with significant respiratory depression.
    F) Creatinine kinase should be measured in patients with prolonged coma or seizures.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment of mild to moderate toxicity is largely supportive. Monitor neuro status and vital signs. Assess respiratory effort; monitor pulse oximetry. Airway protection and management may be indicated. Moderate to severe nausea and vomiting should be treated with antiemetics, as needed.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Supportive care is the mainstay of treatment. Mental status or respiratory depression may require airway protection. Intubation and mechanical ventilation may be indicated. Coma should be treated with airway management and supportive care. Seizures should be treated with benzodiazepines as a first-line therapy. Agitation/delirium should be treated with benzodiazepines, large doses may be required. Treat hypotension initially with isotonic fluids; vasopressor agents, such as norepinephrine or phenylephrine may also be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: Because of the risk of CNS depression and subsequent aspiration, prehospital decontamination should generally be avoided.
    2) HOSPITAL: Activated charcoal should be considered in an asymptomatic patient, if performed soon after exposure and the airway is protected. Airway protection is indicated prior to decontamination in symptomatic patients.
    D) AIRWAY MANAGEMENT
    1) A mild exposure is unlikely to necessitate airway management, however airway protection may be necessary in cases of prominent CNS depression, seizures or significant respiratory depression.
    E) ANTIDOTE
    1) There is no specific antidote.
    F) ENHANCED ELIMINATION
    1) Hemodialysis may be of value following a significant exposure because vigabatrin is not bound to plasma proteins. In limited cases, hemodialysis has reduced vigabatrin plasma concentration by 40% to 60% in patients with renal failure receiving therapeutic doses.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients (adult) with a minor inadvertent ingestion of a therapeutic dose may be observed at home. An inadvertent exposure by a child may require evaluation in a healthcare facility due to the risk of CNS depression. Patients with an intentional exposure should be referred to a health care facility.
    2) OBSERVATION CRITERIA: Patients with a deliberate self-harm ingestion or a large ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients may be discharged to home after 10 to 12 hours, if symptoms improve after treatment and laboratory studies remain normal. Patients who remain symptomatic or develop significant symptoms should be admitted.
    3) ADMISSION CRITERIA: Patients with persistent CNS or respiratory depression, despite adequate treatment should be admitted.
    4) CONSULT CRITERIA: Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    H) PITFALLS
    1) Underlying renal insufficiency may produce more severe toxicity. Monitor renal function. Adequate evaluation to assess the patient's baseline neurologic and psychiatric function (underlying disease vs vigabatrin toxicity).
    I) PHARMACOKINETICS
    1) Vigabatrin is almost completely absorbed. The time to maximum concentration is 1 hour following single and multiple doses. It does not bind to plasma proteins and is widely distributed throughout the body (mean steady state volume of Vd is 1.1 L/kg). Vigabatrin is not significantly metabolized and is primarily eliminated through renal excretion. Half-life is 7.5 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Coingestants (ie, antipsychotics, opioids, antidepressants, anticonvulsants) may produce significant CNS depression. Trauma, infectious disease, underlying seizure or behavioral disorders may also produce alterations in CNS function.

Range Of Toxicity

    A) TOXICITY: Based on limited data, many cases of vigabatrin overdose involved other agents. Coma, unconsciousness or drowsiness have occurred in overdose. In a single case, a 25-year-old woman ingested 60 g and developed severe delirium; no other severe events were observed. An adult developed a psychotic episode (lasting 36 hours) after an ingesting 8 to 12 g of vigabatrin.
    B) THERAPEUTIC DOSE: ADULT: TABLET: INITIAL: 500 mg orally twice daily; MAINTENANCE: 1.5 g twice daily (3 g total). Maximum: 3 g/day. PEDIATRIC: ORAL SOLUTION: INITIAL DOSE: Children 1 month to 2 years: 50 mg/kg/day orally in 2 divided doses. The dose may be titrated by 25 to 50 mg/kg/day increments every 3 days up to a maximum dose of 150 mg/kg/day.

Clinical Effects

Summary Of Exposure

    A) USES: Vigabatrin is used for the treatment of refractory complex partial seizures in adults. It is indicated as an adjunctive therapy in patients that fail to respond to other therapies. It is also used to treat infantile spasms in children 1 month to 2 years.
    B) PHARMACOLOGY: Although the exact mechanism for antiseizure activity is unknown, it is thought to be an irreversible inhibitor of the gamma-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the metabolism of the inhibitory neurotransmitter GABA. This can increase the levels of GABA in the central nervous system.
    C) EPIDEMIOLOGY: Overdose is infrequent. Due to the risk of permanent vision loss, the drug is only available through a restricted distribution program called SHARE (1-888-45-SHARE). When overdose has occurred, it has often been combined with other agents.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Drowsiness and fatigue are the most common adverse events. Exacerbation of psychotic symptoms may develop during treatment with vigabatrin or withdrawal from vigabatrin. As with other antiepileptic drugs, vigabatrin may increase the risk of suicidal thoughts or behavior during therapeutic use. Other events include: fever, seizures, anemia, peripheral edema and neuropathy, weight gain, and headache.
    2) SEVERE EVENTS: Permanent vision loss can develop with therapy, which has led to its restricted use. In postmarketing experience, relatively serious events have included: gastrointestinal hemorrhage, acute psychosis, delirium, neonatal agitation, laryngeal edema, pulmonary embolism, respiratory failure, stridor, angioedema, malignant hyperthermia, dystonia, and multiorgan failure; the frequency of these events is unknown.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited data. Drowsiness and fatigue are likely to occur. Other symptoms may include: vertigo, irritability, agitation, headache, and increased seizure activity.
    2) SEVERE TOXICITY: Coma and unconsciousness may develop. Other events may include: seizures, acute psychosis, delirium, respiratory depression, hypotension and bradycardia. Although not reported in overdose, anemia has developed with therapy.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) In clinical studies (n=4079), pyrexia has been reported in 6% of patients treated with vigabatrin (Prod Info SABRIL(R) oral tablets, 2009).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) VISION LOSS
    a) Vigabatrin can cause permanent bilateral concentric visual field constriction in 30% or more of patients. Symptoms may be mild to severe, with tunnel vision to within 10 degrees of visual fixation. It may also produce central retina damage, which can decrease visual acuity. Because of the risk for vision loss, patients should be withdrawn from therapy if no significant clinical improvement is observed within 3 months or less (Prod Info SABRIL(R) oral tablets, 2009).
    1) Numerous cases of visual field defects have been reported in adults and children (Comaish et al, 2000; Iannetti et al, 2000; Vanhatalo & Paakkonen, 1999; Wilton et al, 1999; Mackenzie & Klistorner, 1998).
    2) RISK FACTORS: Vision loss is more likely to occur with increasing dose and cumulative exposure; however, the exact dose known to cause vision loss is unknown (Prod Info SABRIL(R) oral tablets, 2009).
    3) DISTRIBUTION/SHARE PROGRAM: Because permanent vision loss can develop with therapy, vigabatrin is only available under a restricted distribution program. Contact the SHARE program at 1-888-45-SHARE for further information (Prod Info SABRIL(R) oral tablets, 2009).
    b) ONSET OF VISUAL LOSS: Variable and unpredictable; weeks to months or even years after the start of treatment (Prod Info SABRIL(R) oral tablets, 2009).
    c) VISION TESTING: Obtain at baseline and repeat every 3 months during therapy for adults; it should be continued for 3 to 6 months after the cessation of therapy. Once detected the effects are irreversible (Prod Info SABRIL(R) oral tablets, 2009).
    d) INCIDENCE: Based on epidemiological studies, the overall incidence is estimated to be 14.5/10,000 patients treated for epilepsy each year. Generally, visual field constriction occurs in combination with other antiepileptic drugs, but can occur with vigabatrin alone (Harding, 1998).
    e) PERSISTENT SYMPTOMS: In some cases symptoms improved with drug cessation while other patients continued to have persistent stable defects for a year or more (Nousiainen et al, 2001; Versino & Veggiotti, 1999; Harding, 1998).
    2) DIPLOPIA
    a) Double vision has been reported in approximately 7% (n=9/134) of patients treated with vigabatrin 3 g/day and in 16% (n=7/43) of patients treated with 6 g/day, compared with 3% (n=4/135) in the placebo group (Prod Info SABRIL(R) oral tablets, 2009).
    3) BLURRED VISION
    a) Blurred vision has been reported in approximately 13% (n=18/134) of patients treated with vigabatrin 3 g/day and in 16% (n=7/43) of patients treated with 6 g/day, compared with 5% (n=7/135) in the placebo group (Prod Info SABRIL(R) oral tablets, 2009)
    4) COLOR VISION DEFECTS
    a) Abnormal color perception was reported following vigabatrin monotherapy. The color vision defects appear to be associated with constricted visual fields that are prevalent with vigabatrin therapy (Nousiainen et al, 2000).
    5) RETINAL DISORDER
    a) INCIDENCE: Four of 21 children, with epilepsy, developed retinal defects (ie, retinal pigmentation, hypopigmented spots, vascular sheathing, and optic atrophy) following vigabatrin therapy for 6 to 85 months (Koul et al, 2001).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) Deafness has been reported in postmarketing experience; the frequency of this event is unknown (Prod Info SABRIL(R) oral tablets, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) In two multicenter, double-blind, placebo-controlled, parallel-group clinical studies in adults with complex partial seizures, peripheral edema was reported in 5% and 7% of patients treated with vigabatrin 3 g/day (n=7/134) and 6 g/day (n=3/43) respectively, compared with 1% of patients treated with placebo (n=1/135). No correlation between edema and cardiovascular events such as hypertension or congestive heart failure was found, and laboratory changes suggestive of deterioration of renal or hepatic function did not occur (Prod Info SABRIL(R) oral tablets, 2009).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, laryngeal edema, pulmonary embolism, respiratory failure, and stridor have been reported with therapy; the frequency of these events is unknown (Prod Info SABRIL(R) oral tablets, 2009).
    B) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) In clinical studies (n=4079), upper respiratory traction infection (10%), nasopharyngitis (10%), and influenza (6%) were reported in patients treated with vigabatrin (Prod Info SABRIL(R) oral tablets, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) In clinical studies (n=4079), somnolence was reported in 17% of patients treated with vigabatrin, and is one of the most common adverse events (Prod Info SABRIL(R) oral tablets, 2009).
    b) In two multicenter, double-blind, placebo-controlled, parallel-group clinical studies in adults with complex partial seizures, somnolence was reported in 22% and 26% of patients treated with vigabatrin 3 g/day (n=29/134) and 6 g/day (n=11/43) respectively, compared with 13% of patients treated with placebo (n=18/135) (Prod Info SABRIL(R) oral tablets, 2009).
    c) In a multicenter, randomized, placebo-controlled, parallel-group, partially-blinded study of children with new-onset infantile spasms, somnolence was reported in 17% and 19% of patients treated with low-dose (18 to 36 mg/kg/day; n=114) and high-dose (100 to 148 mg/kg/day; n=108) vigabatrin, respectively (Prod Info SABRIL(R) oral solution, 2009).
    d) In a multicenter, randomized, double-blind, placebo-controlled, parallel group study (n=40) in children with infantile spasms, somnolence was reported in 45% of patients treated with vigabatrin (50 mg/kg/day with titration to 150 mg/kg/day) compared with 30% of patients treated with placebo (Prod Info SABRIL(R) oral solution, 2009).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) In clinical studies (n=4079), seizures were reported in 11% of patients treated with vigabatrin (Prod Info SABRIL(R) oral tablets, 2009).
    b) In a multicenter, randomized, placebo-controlled, parallel-group, partially-blinded study of children with new-onset infantile spasms, seizure was reported in 4% and 7% of patients treated with low-dose (18 to 36 mg/kg/day; n=114) and high-dose (100 to 148 mg/kg/day; n=108) vigabatrin, respectively (Prod Info SABRIL(R) oral solution, 2009).
    C) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) In clinical studies (n=4079), insomnia was reported in 7% of patients treated with vigabatrin (Prod Info SABRIL(R) oral tablets, 2009).
    b) In a multicenter, randomized, placebo-controlled, parallel-group, partially-blinded study of children with new-onset infantile spasms, insomnia was reported in 10% and 12% of patients treated with low-dose (18 to 36 mg/kg/day; n=114) and high-dose (100 to 148 mg/kg/day; n=108) vigabatrin, respectively (Prod Info SABRIL(R) oral solution, 2009).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In clinical studies (n=4079), dizziness was reported in 15% of patients treated with vigabatrin (Prod Info SABRIL(R) oral tablets, 2009).
    b) In two multicenter, double-blind, placebo-controlled, parallel-group clinical studies in adults with complex partial seizures, dizziness was reported in 24% and 26% of patients treated with vigabatrin 3 g/day (n=32/134) and 6 g/day (n=11/43) respectively, compared with 17% of patients treated with placebo (n=23/135) (Prod Info SABRIL(R) oral tablets, 2009).
    c) Vigabatrin has caused dizziness in less than 10% of patients being treated for refractory epilepsy. This effect tends to diminish with continued therapy (Tartara et al, 1986; Browne et al, 1989; Sander et al, 1990; Browne et al, 1991; Tartara et al, 1989; Levinson & Devinsky, 1999).
    E) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In clinical studies (n=4079), headache was reported in 18% of patients treated with vigabatrin (Prod Info SABRIL(R) oral tablets, 2009).
    b) In two multicenter, double-blind, placebo-controlled, parallel-group clinical studies in adults with complex partial seizures, headache was reported in 33% and 26% of patients treated with vigabatrin 3 g/day (n=44/134) and 6 g/day (n=11/43) respectively, compared with 31% of patients treated with placebo (n=42/135) (Prod Info SABRIL(R) oral tablets, 2009).
    F) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) In clinical studies (n=4079), memory impairment, tremor and abnormal coordination were each reported in 7% of patients treated with vigabatrin (Prod Info SABRIL(R) oral tablets, 2009).
    b) In two multicenter, double-blind, placebo-controlled, parallel-group clinical studies in adults with complex partial seizures, memory impairment, tremor and abnormal coordination were reported in 7% and 16% of patients treated with vigabatrin 3 g/day (n=9/134) and 6 g/day (n=7/43) respectively (Prod Info SABRIL(R) oral tablets, 2009).
    G) NUCLEAR MAGNETIC RESONANCE ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Abnormal MRI changes (increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum) have been reported in infants receiving vigabatrin for infantile spasms. A retrospective epidemiologic study (n=205) in infants with infantile spasms reported that these changes occurred at an incidence of 21.5% in vigabatrin-treated patients compared with 4.1% in patients receiving other therapies. These changes usually resolved with therapy discontinuation, but in some cases the lesion persisted. Some infants displayed coincident motor abnormalities, but a causal relationship could not be determined (Prod Info SABRIL(R) oral tablets, 2009).
    H) ALTERED MENTAL STATUS
    1) WITH THERAPEUTIC USE
    a) Symptoms suggestive of a prepsychotic state have included behavioral disturbances, irritability or agitation, and anxiety which occurred in approximately 5% of patients (Grant & Heel, 1991).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) BRAIN STEM DISORDER
    a) In one year toxicology studies, vigabatrin caused microvacuolization of the white matter tracts throughout the brain (Hammond & Wilder, 1985).
    b) Animals treated with high doses of vigabatrin for prolonged periods have developed microvacuolization in various areas of white matter in the brain as a result of intramyelinic edema. These lesions have been reversible upon cessation of treatment. Similar lesions have not been reported in humans treated with the drug chronically (Hauw et al, 1988) (Graham, 1989) (Butler, 1989).
    c) Increases in central latencies of evoked potentials have been detected in animals which parallel development of intramyelinic edema (Liegeois- Chauvel et al, 1989) (Grant & Heel, 1991).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH THERAPEUTIC USE
    a) In 2 multicenter, double-blind, placebo-controlled, parallel-group clinical studies in adults with complex partial seizures, vomiting was reported in 7% and 9% of patients treated with vigabatrin 3 g/day (n=9/134) and 6 g/day (n=4/43) respectively, compared with 6% of patients treated with placebo (n=8/135) (Prod Info SABRIL(R) oral tablets, 2009).
    b) In a multicenter, randomized, placebo-controlled, parallel-group, partially-blinded study of children with new-onset infantile spasms, vomiting was reported in 14% and 20% of patients treated with low-dose (18 to 36 mg/kg/day; n=114) and high-dose (100 to 148 mg/kg/day; n=108) vigabatrin, respectively (Prod Info SABRIL(R) oral solution, 2009).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In clinical studies (n=4079), nausea was reported in 7% of patients treated with vigabatrin (Prod Info SABRIL(R) oral tablets, 2009).
    b) In 2 multicenter, double-blind, placebo-controlled, parallel-group clinical studies in adults with complex partial seizures, nausea was reported in 10% and 2% of patients treated with vigabatrin 3 g/day (n=13/134) and 6 g/day (n=1/43) respectively, compared with 8% of patients treated with placebo (n=11/135) (Prod Info SABRIL(R) oral tablets, 2009).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In clinical studies (n=4079), diarrhea was reported in 7% of patients treated with vigabatrin (Prod Info SABRIL(R) oral tablets, 2009).
    b) In 2 multicenter, double-blind, placebo-controlled, parallel-group clinical studies in adults with complex partial seizures, diarrhea was reported in 10% and 16% of patients treated with vigabatrin 3 g/day (n=14/134) and 6 g/day (n=7/43) respectively, compared with 7% of patients treated with placebo (n=10/135) (Prod Info SABRIL(R) oral tablets, 2009).
    c) In a multicenter, randomized, placebo-controlled, parallel-group, partially-blinded study of children with new-onset infantile spasms, diarrhea was reported in 13% and 12% of patients treated with low-dose (18 to 36 mg/kg/day; n=114) and high-dose (100 to 148 mg/kg/day; n=108) vigabatrin, respectively (Prod Info SABRIL(R) oral solution, 2009).
    D) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In 2 multicenter, double-blind, placebo-controlled, parallel-group clinical studies in adults with complex partial seizures, abdominal pain was reported in 3% and 2% of patients treated with vigabatrin 3 g/day (n=4/134) and 6 g/day (n=1/43) respectively, compared with 1% of patients treated with placebo (n=2/135) (Prod Info SABRIL(R) oral tablets, 2009).
    E) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, gastrointestinal hemorrhage and esophagitis have been reported; the frequency of these events are unknown (Prod Info SABRIL(R) oral tablets, 2009).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Acute fatal hepatotoxicity, possibly related to vigabatrin, occurred in a 3-year-old boy with a history of severe prematurity, developmental delay, microcephaly, generalized leukomalacia and symptomatic epilepsy. Liver failure and death occurred 9 months after initiation of therapy (50 mg/kg/day for 6 months; 100 mg/kg/day for 3 months). Autopsy revealed massive parenchymal necrosis with no inflammatory reactions. The child was also receiving phenobarbitone (Kellerman et al, 1996).
    B) CHOLESTASIS
    1) WITH THERAPEUTIC USE
    a) In postmarketing surveillance, cholestasis has been reported in patients treated with vigabatrin (Prod Info SABRIL(R) oral tablets, 2009).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In controlled clinical studies, anemia and/or criteria for potentially clinically important hematological changes involving hemoglobin, hematocrit, and/or red blood cell indices was reported in 5.7% of patients receiving vigabatrin (16/280) compared with 1.6% of patients receiving placebo (3/188). Mean decreases in hemoglobin were 3% and 0% in vigabatrin and placebo groups, respectively. Mean decreases in hematocrit were 1% in vigabatrin-treated patients compared to a gain of 1% in placebo-treated patients. In controlled and open-label epilepsy clinical trials (n=4855), treatment discontinuation due to anemia was reported in 3 patients, and hemoglobin decreases to less than 8 g/dL and/or hematocrit below 24% occurred in 2 patients (Prod Info SABRIL(R) oral tablets, 2009).(Prod Info SABRIL(R) oral solution, 2009).
    B) NORMOCYTIC HYPOCHROMIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Decreases of 2.5 g/dL in hemoglobin levels have been reported in 6 children receiving high doses (250 to 600 mg/kg/day) of vigabatrin (Livingston et al, 1989).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In clinical studies (n=4079), rash was reported in 6% of patients treated with vigabatrin (Prod Info SABRIL(R) oral tablets, 2009).
    b) In 2 multicenter, double-blind, placebo-controlled, parallel-group clinical studies in adults with complex partial seizures, rash was reported in 4% and 5% of patients treated with vigabatrin 3 g/day (n=6/134) and 6 g/day (n=2/43) respectively, compared with 4% of patients treated with placebo (n=6/135) (Prod Info SABRIL(R) oral tablets, 2009).
    c) In a multicenter, randomized, placebo-controlled, parallel-group, partially-blinded study of children with new-onset infantile spasms, rash was reported in 8% and 11% of patients treated with low-dose (18 to 36 mg/kg/day; n=114) and high-dose (100 to 148 mg/kg/day; n=108) vigabatrin, respectively (Prod Info SABRIL(R) oral solution, 2009).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In 2 multicenter, double-blind, placebo-controlled, parallel-group clinical studies in adults with complex partial seizures, arthralgia was reported in 10% and 5% of patients treated with vigabatrin 3 g/day (n=14/134) and 6 g/day (n=2/43) respectively, compared with 3% of patients treated with placebo (n=4/135) (Prod Info SABRIL(R) oral tablets, 2009).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) In 2 multicenter, double-blind, placebo-controlled, parallel-group clinical studies in adults with complex partial seizures, myalgia was reported in 3% and 5% of patients treated with vigabatrin 3 g/day (n=4/134) and 6 g/day (n=2/43) respectively, compared with 1% of patients treated with placebo (n=2/135) (Prod Info SABRIL(R) oral tablets, 2009).
    C) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In 2 multicenter, double-blind, placebo-controlled, parallel-group clinical studies in adults with complex partial seizures, back pain was reported in 4% and 7% of patients treated with vigabatrin 3 g/day (n=6/134) and 6 g/day (n=3/43) respectively, compared with 2% of patients treated with placebo (n=3/135) (Prod Info SABRIL(R) oral tablets, 2009).

Reproductive

    3.20.1) SUMMARY
    A) The manufacturer has classified vigabatrin as FDA pregnancy category C. Since data in humans are lacking, vigabatrin should be used in pregnancy only if the potential benefit outweighs risk. Teratogenic effects (eg; cleft palate) have been reported in toxic doses in rabbits; no teratogenic effects were observed at high doses in rats.
    3.20.2) TERATOGENICITY
    A) ABNORMALITIES
    1) The manufacturer reports that in pregnancies occurring during vigabatrin use, normal outcomes were seen in 72%; 18% had abnormal outcomes, and 10% ended in spontaneous abortion (a 10% to 15% spontaneous abortion rate is seen in the general population) (Pers Comm, 1994). Vigabatrin was used in combination with other antiepileptic agents in all cases with abnormal outcomes. Reported abnormalities included hip dysplasia, hypospadia, absent diaphragm, bilateral cleft palate, small left hemisphere associated with "fits", club feet, intracerebral hemorrhage, conjoined twins, and spina bifida/microcephaly/intraventricular agenesis of heart septum/pulmonary artery atresia. Some of these cases involved a family history of similar conditions.
    B) LACK OF EFFECT
    1) A series of observational cohort studies by Wilton and colleagues (1998) suggested that vigabatrin does not cause an increased rate of congenital anomalies when used during pregnancy. Eighty-one women were treated with vigabatrin with 88 resultant pregnancies. During seven pregnancies, the drug was discontinued before the last menstrual period, 76 were exposed during the first trimester, four during the second or third trimester, and exposure for one was unknown. Of the 76 exposed during the first trimester, there were 47 births, 17 spontaneous abortions, one missed abortion and eleven pregnancies intentionally terminated. Of the 47 births, two full-term infants were born with congenital anomalies. One infant had bowed tibiae and increased tone (mother also exposed to sodium valproate and carbamazepine); one infant had occipital plagiocephaly, premature fusion of lamboid suture and clicky hips (mother also exposed to phenytoin and folic acid) (Wilton et al, 1998).
    C) ANIMAL STUDIES
    1) DEVELOPMENTAL TOXICITY
    a) Developmental toxicity, including teratogenic and neurohistopathological effects have been observed in pregnant animals at clinically relevant doses. Pregnant rabbits receiving 50 mg/kg to 200 mg/kg of vigabatrin throughout organogenesis showed an increased incidence of malformations, including cleft palate and embryo-fetal death. In rabbits, the no-effect dose (100 mg/kg) for teratogenicity and embryolethality is approximately 1/2 the maximum recommended human dose (MRHD) of 3 g/day on a mg/m(2) basis. Vigabatrin at doses of 50 mg/kg, 100 mg/kg, or 150 mg/kg administered to rats throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. The no-effect dose (50 mg/kg) for embryo-fetal toxicity in rats is approximately 1/5 the MRHD on a mg/m(2) basis. Vigabatrin administered to rats during the latter part of pregnancy through weaning resulted in long-term neurohistopathological (hippocampal vacuolation) and neurobehavioral (convulsions) abnormalities in offspring. The no-effect dose for developmental neurotoxicity in rats has not been established (Prod Info SABRIL(R) oral tablets, 2009; Prod Info SABRIL(R) oral solution, 2009).
    2) CLEFT PALATE
    a) Teratogenic effects (cleft palate) have been reported in toxic doses in rabbits; no teratogenic effects were observed at high doses in rats. Since data in humans are lacking, vigabatrin should be used in pregnancy only if the potential benefit outweighs risk (Grant & Heel, 1991).
    3) POSTNATAL DEVELOPMENT
    a) In an experimental evaluator-blind, placebo-controlled study in the rat, the effects of maternal exposure to vigabatrin on the postnatal motor-cognitive behavior of the offspring were evaluated. Ten pregnant rats were treated with different doses (2 rats in each group) of vigabatrin (250, 500, 750, 1000 mg/kg/day) or placebo during the organogenesis (gestation day 6 to 10). It was found that vigabatrin at lower doses (250 or 500 mg/kg/day) did not cause any significant behavioral impairment. When vigabatrin 750 mg/kg/day was given to rats during the period of organogenesis, body weight of pups and young rats were significantly lower both at birth and during the whole postnatal life as compared to the control group. Reduced food consumption was observed in the rats treated with 750 mg/kg/day (88.2%-93.3%) and 1000 mg/kg/day (88.2-89.1%). In addition, young rats exhibited impaired performance in both the open-field and water maze tasks and brain GABA content was dramatically increased in this group of rats. Abortions were observed in rats treated with 500 mg/kg/day (one rat) and 1000 mg/kg/day (two rats) (Lombardo et al, 2005).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified vigabatrin as FDA pregnancy category C (Prod Info SABRIL(R) oral tablets, 2009; Prod Info SABRIL(R) oral solution, 2009).
    2) Vigabatrin use during pregnancy may result in fetal harm. Therefore, if vigabatrin is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be counseled regarding effective contraceptive during vigabatrin therapy (Prod Info SABRIL(R) oral tablets, 2009; Prod Info SABRIL(R) oral solution, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Vigabatrin is excreted in human breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue vigabatrin, taking into consideration the importance of the drug to the nursing mother (Prod Info SABRIL(R) oral tablets, 2009; Prod Info SABRIL(R) oral solution, 2009).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) RATS
    a) There were no effects on male or female fertility in rats when administered oral doses of vigabatrin up to 150 mg/kg/day (approximately 1/2 the maximum recommended human dose (MRHD) of 3 g/day on a mg/m(2) basis) (Prod Info SABRIL(R) oral tablets, 2009; Prod Info SABRIL(R) oral solution, 2009).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) There was no evidence of carcinogenicity in mice or rats given vigabatrin orally at doses up to 150 mg/kg/day for 18 months or 150 mg/kg/day for 2 years, respectively. These doses were less than the maximum recommended human dose of 3 g/day on a mg/m(2) basis (Prod Info SABRIL(R) oral tablets, 2009).

Genotoxicity

    A) There was no evidence of mutagenicity or genotoxicity in in vitro Ames test, CHO/HGPRT mammalian cell forward gene mutation assay, chromosomal aberration in rat lymphocytes or in in vivo mouse bone marrow micronucleus assays (Prod Info SABRIL(R) oral tablets, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor mental status.
    B) Monitor pulse oximetry, initiate cardiac monitoring and obtain an ECG upon initial evaluation and repeat as indicated following a significant overdose.
    C) Monitor fluid status, renal function and a basic metabolic panel, as necessary.
    D) Obtain a CBC as indicated.
    E) ABGs should be obtained in patients with significant respiratory depression.
    F) Creatinine kinase should be measured in patients with prolonged coma or seizures.

Radiographic Studies

    A) Ocular Coherence Tomography
    1) A cross-sectional prospective observational study was conducted to quantify retinal nerve fiber layer thickness (RNFLT) and macular thickness (MT) in patients exhibiting vigabatrin-attributed visual field loss. Vigabatrin has been associated with bilateral constriction of the visual field and the estimated prevalence ranges from 14% to 92%. In this study, ocular coherence tomography (OCT) was able to assess retinal nerve fiber layer thickness as a clinical indicator of vigabatrin-attributed damage. The authors concluded that OCT may be particularly useful in adults or children with learning disabilities and in those patients in whom visual field results are equivocal to detect vigabatrin-associated toxicity (Wild et al, 2006).

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 with persistent CNS or respiratory depression, despite adequate treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients (adult) with a minor inadvertent ingestion of a therapeutic dose may be observed at home. An inadvertent exposure by a child may require evaluation in a healthcare facility due to the risk of CNS depression. Patients with an intentional exposure should be referred to a health care facility.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate self-harm ingestion or a large ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients may be discharged to home after 10 to 12 hours, if symptoms improve after treatment and laboratory studies remain normal. Patients who remain symptomatic or develop significant symptoms should be admitted.

Monitoring

    A) Monitor mental status.
    B) Monitor pulse oximetry, initiate cardiac monitoring and obtain an ECG upon initial evaluation and repeat as indicated following a significant overdose.
    C) Monitor fluid status, renal function and a basic metabolic panel, as necessary.
    D) Obtain a CBC as indicated.
    E) ABGs should be obtained in patients with significant respiratory depression.
    F) Creatinine kinase should be measured in patients with prolonged coma or seizures.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) DECONTAMINATION/NOT RECOMMENDED
    1) Because of the risk of CNS depression and subsequent aspiration, prehospital decontamination should generally be avoided.
    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. Monitor neuro status and vital signs. Airway protection and management may be indicated.
    B) MONITORING OF PATIENT
    1) Monitor mental status.
    2) Monitor pulse oximetry, initiate cardiac monitoring and obtain an ECG upon initial evaluation and repeat as indicated following a significant overdose.
    3) Monitor fluid status, renal function and a basic metabolic panel, as necessary.
    4) Obtain a CBC as indicated.
    5) ABGs should be obtained in patients with significant respiratory depression.
    6) Creatinine kinase should be measured in patients with prolonged coma or seizures.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) DELIRIUM
    1) DELIRIUM/AGITATION: May be controlled with benzodiazepines.
    2) DIAZEPAM
    a) ADULT: 5 to 10 mg IV repeat every 10 to 15 minutes as needed. CHILD: 0.2 to 0.4 mg/kg IV.
    3) LORAZEPAM
    a) ADULT: 2 mg IV repeat every 10 to 15 minutes as needed. CHILD: 0.05 to 0.1 mg/kg.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis may be of value following a significant exposure because vigabatrin is not bound to plasma proteins and has a low volume of distribution. In limited cases, hemodialysis has reduced vigabatrin plasma concentration by 40% to 60% in patients with renal failure receiving therapeutic doses (Prod Info SABRIL(R) oral tablets, 2009).

Range Of Toxicity

Summary

    A) TOXICITY: Based on limited data, many cases of vigabatrin overdose involved other agents. Coma, unconsciousness or drowsiness have occurred in overdose. In a single case, a 25-year-old woman ingested 60 g and developed severe delirium; no other severe events were observed. An adult developed a psychotic episode (lasting 36 hours) after an ingesting 8 to 12 g of vigabatrin.
    B) THERAPEUTIC DOSE: ADULT: TABLET: INITIAL: 500 mg orally twice daily; MAINTENANCE: 1.5 g twice daily (3 g total). Maximum: 3 g/day. PEDIATRIC: ORAL SOLUTION: INITIAL DOSE: Children 1 month to 2 years: 50 mg/kg/day orally in 2 divided doses. The dose may be titrated by 25 to 50 mg/kg/day increments every 3 days up to a maximum dose of 150 mg/kg/day.

Therapeutic Dose

    7.2.1) ADULT
    A) REFRACTORY COMPLEX PARTIAL SEIZURES
    1) 17 YEARS OF AGE AND OLDER: Initial dose: 500 mg twice daily; increase total daily dose weekly in 500 mg/day increments to the recommended dose of 1500 mg twice daily by mouth (Prod Info SABRIL(R) oral tablets, oral powder for solution, 2015).
    2) Withdrawal should be gradual; daily dose was decreased by 1000 mg on a weekly basis in clinical trials (Prod Info SABRIL(R) oral tablets, oral powder for solution, 2015).
    7.2.2) PEDIATRIC
    A) INFANTILE SPASM
    1) ORAL SOLUTION: ONE MONTH TO 2 YEARS OF AGE: Vigabatrin is used as a monotherapy for infants 1 month to 2 years of age with infantile spasm. Initial dosage: 50 mg/kg day in 2 divided doses; titrate dose by 25 to 50 mg/kg/day as necessary every 3 days up to a MAXIMUM of 150 mg/kg/day. Discontinue in patients who fail to demonstrate a significant clinical benefit within 2 to 4 weeks. Withdrawal should be gradual; daily dose was decreased by 25 to 50 mg/kg every 3 to 4 days in a clinical trial. Each 500 mg packet of vigabatrin should be dissolved in 10 mL of cold or room temperature water per packet, which yields a final solution of 50 mg/mL. The following list contains the infant dose based on 50 mg/kg daily with a maximum dose of 150 mg/kg daily (Prod Info Sabril(R) oral solution, 2012):
    1) Infant dosing schedule by weight (Prod Info Sabril(R) oral solution, 2012):
    a) 3 kg: 1.5 mL twice daily; maximum 4.5 mL twice daily
    b) 4 kg: 2 mL twice daily; maximum 6 mL twice daily
    c) 5 kg: 2.5 mL twice daily; maximum 7.5 mL twice daily
    d) 6 kg: 3 mL twice daily; maximum 9 mL twice daily
    e) 7 kg: 3.5 mL twice daily; maximum 10.5 mL twice daily
    f) 8 kg: 4 mL twice daily; maximum 12 mL twice daily
    g) 9 kg: 4.5 mL twice daily; maximum 13.5 mL twice daily
    h) 10 kg: 5 mL twice daily; maximum 15 mL twice daily
    i) 11 kg: 5.5 mL twice daily; maximum 16.5 mL twice daily
    j) 12 kg: 6 mL twice daily; maximum 18 mL twice daily
    k) 13 kg: 6.5 mL twice daily; maximum 19.5 mL twice daily
    l) 14 kg: 7 mL twice daily; maximum 21 mL twice daily
    m) 15 kg: 7.5 mL twice daily; maximum 22.5 mL twice daily
    n) 16 kg: 8 mL twice daily; maximum 24 mL twice daily
    B) REFRACTORY COMPLEX PARTIAL SEIZURES
    1) AGES 10 TO 16 YEARS AND WEIGHING 25 TO 60 KG: The initial recommended dose is 250 mg orally twice daily; may increase dose at weekly intervals of 500 mg/day to a maintenance dose of 1000 mg twice daily (Prod Info SABRIL(R) oral tablets, oral powder for solution, 2015).
    2) AGES 10 TO 16 YEARS AND WEIGHTING GREATER THAN 60 KG OR OVER 16 YEARS OF AGE: The initial recommended dose is 500 mg orally twice daily; may increase total daily dose in 500 mg increments at weekly intervals, depending upon response, up to 1500 mg twice daily (Prod Info SABRIL(R) oral tablets, oral powder for solution, 2015).
    3) Withdrawal should be gradual; daily dose was decreased by one-third on a weekly basis in a clinical trial (Prod Info SABRIL(R) oral tablets, oral powder for solution, 2015).

Maximum Tolerated Exposure

    A) SUMMARY
    1) Based on limited data, most cases of vigabatrin overdose involved other agents; no overdoses resulted in death. Coma, unconsciousness or drowsiness have occurred in overdose (Prod Info SABRIL(R) oral tablets, 2009).
    B) CASE REPORTS
    1) CASE REPORT: A total of 60 g was ingested by a 25-year-old woman. Severe delirium resulted with no other remarkable clinical effects (Davie et al, 1996).
    2) CASE SERIES: A 40-year-old man with a long history of seizures inadvertently ingested 8 to 12 g of vigabatrin during postictal confusion and developed a psychotic episode that lasted 36 hours. The onset of symptoms occurred approximately 24 hours after exposure. In the remaining patients (n=13), the mean dose of vigabatrin at the onset of psychosis was 2500 mg (range: 500 mg to 4000 mg). Each patient made a complete recovery. Most improved with the withdrawal of vigabatrin, while 3 patients required neuroleptic therapy (Sander et al, 1991).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) SUMMARY
    a) No direct correlation between serum concentrations of vigabatrin and clinical efficacy in epilepsy has been observed (Grant & Heel, 1991).
    b) Oral, solution: time to peak concentration, 2.5 hours (infants); 1 hour (children) (Prod Info SABRIL(R) oral solution, 2009)
    c) Oral, tablets: time to peak concentration, 1 hour (adults) (Prod Info SABRIL(R) oral tablets, 2009)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The exact mechanism of vigabatrin is unknown. Vigabatrin inhibits the metabolism of GABA by GABA transaminase, thereby increasing brain levels of GABA (Grant & Heel, 1991). Activated vigabatrin binds covalently (irreversibly) to the active site of GABA transaminase. Although vigabatrin is administered clinically in its racemic form, only the S(+)enantiomer is pharmacologically active with respect to GABA transaminase inhibition.
    B) Vigabatrin administration has been demonstrated to increase GABA levels in brain tissue and cerebrospinal fluid of animals, and in cerebrospinal fluid of epileptic patients, in dose-related fashion (Hammond & Wilder, 1985; Grant & Heel, 1991) (Schechter et al, 1984) (Reikkinen et al, 1989).
    C) Significant elevations of homocarnosine (dipeptide of GABA and histidine) have also been reported (Petroff et al, 1998; Grant & Heel, 1991). Elevations of these markers of GABA-ergic transmission are associated with a significant reduction in seizure frequency in patients with refractory seizures (Hammond & Wilder, 1985; Grant & Heel, 1991). Brain homocarnosine increases linearly in proportion to daily vigabatrin dose and remains elevated with continued therapy. Total GABA concentrations in human cerebral spinal fluid and brain also increase and correlate well with improved seizure control (Petroff et al, 1998).

Physicochemical

Physical Characteristics

    A) Vigabatrin is an off-white to white powder, which is freely soluble in water, less soluble in methyl alcohol, very slightly soluble in ethyl alcohol and chloroform, and insoluble in toluene and hexane (Prod Info SABRIL(R) oral tablets, 2009; Prod Info SABRIL(R) oral solution, 2009).

Ph

    A) 6.9 (1% aqueous solution) (Prod Info SABRIL(R) oral tablets, 2009; Prod Info SABRIL(R) oral solution, 2009)

Molecular Weight

    A) 129.16 (Prod Info SABRIL(R) oral tablets, 2009; Prod Info SABRIL(R) oral solution, 2009)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
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    3) Browne TR, Mattson RH, Penry JK, et al: A multicenter study of vigabatrin for drug-resistant epilepsy. Br J Clin Pharmacol 1989; 27:95S-100S.
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    6) 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.
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    9) Comaish IF, Gorman C, & Galloway NR: Visual field defect associated with vigabatrin: many more patients may be affected than were found in the study. Br Med J 2000; 320:1403.
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    12) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
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    16) Haegele KD & Schechter PJ: Kinetics of the enantiomers of vigabatrin after an oral dose of the racemate or the active S-enantiomer. Clin Pharmacol Ther 1986; 40:581-586.
    17) Hammond EJ & Wilder BJ: Gamma-vinyl GABA: a new antiepileptic drug. Clin Neuropharmacol 1985; 8:1-12.
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