Vigabatrin

Pronunciation: vye-GA-ba-trin
Class: Anticonvulsant

Trade Names

Sabril
- Tablets 500 mg
- Powder for oral solution 500 mg

Pharmacology

Precise mechanism unknown. Possibly inhibition of GABA transaminase, resulting in increased levels of GABA in the CNS.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Completely absorbed. T max is 1 h (2.5 h in infants). Food decreased C max 33% and T max increased to 2 h; AUC was unchanged.

Distribution

Widely distributed throughout the body; no plasma protein binding. Mean Vd is 1.1 L/kg.

Metabolism

Not significantly metabolized.

Elimination

Half-life is 7.5 h in adults and 5.7 h in infants. Eliminated primarily through renal excretion; 80% recovered in the urine as parent drug.

Special Populations

Renal Function Impairment

AUC increased 30% and half-life increased 55% in patients with mild renal impairment (CrCl greater than 50 to 80 mL/min). AUC and half-life increased 2-fold in patients with moderate renal impairment (CrCl greater than 30 to 50 mL/min). In patients with severe renal impairment (CrCl greater than 10 to 30 mL/min), AUC increased 4.5-fold and half-life increased 3.5-fold.

Hepatic Function Impairment

Pharmacokinetics have not been studied.

Elderly

Renal Cl was 36% lower in elderly patients compared with younger patients.

Children

The Cl was 2.4 and 5.7 L/h in infants and children, respectively, compared with 7 L/h in adults.

Gender

No pharmacokinetic differences were observed.

Race

Renal Cl was 25% lower in Japanese patients compared with white patients.

Indications and Usage

Adjunctive therapy for adults with refractory complex partial seizures who have inadequately responded to several alternative treatments (tablets only); monotherapy for children with infantile spasms (oral solution only).

Contraindications

None well documented.

Dosage and Administration

Refractory Complex Partial Seizures
Adults 16 yr of age and older

PO 500 mg twice daily, initially. May increase total daily dose in increments of 500 mg at weekly intervals, depending on patient response. Maintenance dosage, 1,500 mg twice daily.

Infantile Spasms
Infants and Children 1 mo to 2 yr of age

PO Initially, 50 mg/kg twice daily. Titrate by 25 to 50 mg/kg/day every 3 days (max, 150 mg/kg/day).

Renal Function Impairment
CrCl greater than 50 to 80 mL/min

Decrease dose by 25%.

CrCl greater than 30 to 50 mL/min

Decrease dose by 50%.

CrCl greater than 10 to 30 mL/min

Decrease dose by 75%.

General Advice

  • Administer prescribed dose without regard to meals. Administer with food if GI upset occurs.
  • Each 500 mg packet of powder for oral solution should be dissolved with 10 mL of cold or room temperature water only. Each dose should be prepared immediately before use using the oral syringe provided.
  • Continued need for treatment should be periodically assessed.
  • Vigabatrin should be withdrawn gradually. Taper by decreasing the dose by 25 to 50 mg/kg every 3 to 4 days in infants and children with infantile spasms or by decreasing the daily dose 1 g/day on a weekly basis until discontinued in adults with complex partial seizures.

Storage/Stability

Store at 68° to 77°F.

Drug Interactions

Clonazepam

Clonazepam plasma concentrations may be increased while the T max may be reduced, increasing the pharmacologic effects and risk of adverse reactions. Monitor the patient when starting or stopping vigabatrin. Adjust the clonazepam dose as needed.

Drugs associated with serious adverse ophthalmic effects, such as retinopathy (eg, hydroxychloroquine) or glaucoma (eg, corticosteroids [open-angle], tricyclic antidepressants [closed-angle])

Risk of serious adverse ophthalmic effects may be increased. Avoid coadministration unless the benefits clearly outweigh the risks.

Hydantoins (eg, phenytoin)

Coadministration has been reported to decrease phenytoin plasma concentrations 16% to 20%. Monitor the patient when starting or stopping vigabatrin. Be prepared to adjust the hydantoin dose if an interaction is suspected.

Phenobarbital, primidone

On average, phenobarbital plasma concentrations may be reduced 8% to 16%. This change is not likely to be clinically important.

Valproic acid

On average, valproate plasma concentrations may be reduced 8%. This change is not likely to be clinically important.

Laboratory Test Interactions

ALT and AST enzyme activity is suppressed in up to 90% of patients; false positive test for certain rare genetic metabolic diseases (eg, alpha-aminoadipic aciduria).

Adverse Reactions

CNS

Somnolence (45%); fatigue (40%); headache (33%); dizziness (26%); irritability (23%); sedation (19%); abnormal coordination, memory impairment, tremor (16%); confusional state, depression (14%); gait disturbance, insomnia (12%); convulsion (11%); disturbance in attention (9%); abnormal thinking, asthenia, expressive language disorder, lethargy, paresthesia, sensory disturbance (7%); hypotonia, status epilepticus (6%); abnormal behavior, abnormal dreams, depressed mood, hypoesthesia, hyporeflexia, malaise, nervousness, sensory disturbance, sensory loss, vertigo (5%); anxiety, hyperreflexia, peripheral neuropathy (4%); aggression, dysarthria, postictal state (2%); acute psychosis, apathy, delirium, dystonia, encephalopathy, hypertonia, hypomania, hypotonia, muscle spasticity, myoclonus, neonatal agitation, optic neuritis, psychotic disorder (postmarketing).

Dermatologic

Rash (11%); maculopapular rash, pruritus (postmarketing).

EENT

Otitis media (44%); nystagmus (19%); blurred vision, diplopia (16%); ear infection, nasopharyngitis, pharyngolaryngeal pain (14%); nasal congestion (13%); sinusitis, visual field defect (9%); conjunctivitis, eye pain, strabismus (5%); eye disorder other than field or acuity changes (3%); asthenopia, tinnitus (2%); deafness (postmarketing).

GI

Vomiting (20%); diarrhea (16%); constipation (14%); nausea (10%); decreased appetite (9%); viral gastroenteritis (6%); dyspepsia, increased appetite, toothache, upper abdominal pain (5%); stomach discomfort (4%); abdominal pain (3%); abdominal distension, hemorrhoids (2%); esophagitis, GI hemorrhage (postmarketing).

Genitourinary

Dysmenorrhea (9%); UTI (6%); erectile dysfunction (5%).

Metabolic-Nutritional

Weight increased (17%).

Musculoskeletal

Arthralgia (10%); muscle twitching (9%); back pain (7%); pain in extremity (6%); myalgia (5%); joint swelling, muscle spasms (3%); joint sprain, muscle strain, shoulder pain (2%).

Respiratory

Upper respiratory tract infection (51%); bronchitis (30%); cough (14%); pneumonia (13%); sinus headache (6%); pulmonary congestion (5%); dyspnea (2%); laryngeal edema, pulmonary embolism, respiratory failure, stridor (postmarketing).

Miscellaneous

Fever (29%); MRI abnormalities (22%); viral infection (20%); candidiasis (8%); influenza, peripheral edema (7%); anemia (6%); chest pain, contusion, infectious croup (5%); fluid retention, thirst, wound secretion (2%); angioedema, cholestasis, delayed puberty, developmental delay, facial edema, malignant hyperthermia, multiorgan failure (postmarketing).

Precautions

Warnings

Vigabatrin causes permanent vision loss. Onset of vision loss is unpredictable, and can occur within weeks of starting treatment or sooner, or at any time during treatment, even after months or years. The risk increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss. It is possible that vision loss can worsen despite discontinuing vigabatrin. Vigabatrin should be withdrawn from patients with infantile spasms who fail to show substantial clinical benefit within 2 to 4 wk of initiation, within 3 mo of initiation in patients with complex partial seizures who fail to show substantial response, or sooner if treatment failure becomes obvious. Periodically reassess patient response to and continued need for vigabatrin. Once detected, vision loss due to vigabatrin is not reversible. Symptoms of vision loss from vigabatrin are unlikely to be recognized by the patient, parent, or caregiver before vision loss is severe. Vision loss of milder severity, although unrecognized by the caregiver, may still adversely affect function.

Vigabatrin should not be used in patients with, or at high risk of, other types of irreversible vision loss, or with other drugs associated with serious adverse ophthalmic effects, such as retinopathy or glaucoma, unless benefits clearly outweigh risks. The lowest dose and shortest exposure should be used.

Because of the risk of permanent vision loss, vigabatrin is only available through a special restricted distribution program called SHARE. Only prescribers and pharmacies registered with SHARE may prescribe and distribute vigabatrin. Vigabatrin may be dispensed only to patients who are enrolled in and meet all conditions of SHARE. Contact SHARE at 1-888-457-4273.


Monitor

Assess vision at baseline (no later than 4 wk after starting vigabatrin), at least every 3 mo during therapy, and about 3 to 6 mo after discontinuation of therapy with vigabatrin. Assessment should include visual activity and visual field defect whenever possible. Monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.


Pregnancy

Category C .

Lactation

Excreted in breast milk.

Children

For the treatment of refractory complex partial seizures, safety and efficacy not established for patients younger than 16 yr of age. Safety and efficacy not established in patients younger than 1 mo of age or older than 2 yr of age with infantile spasms.

Elderly

Consider adjustment of dose or frequency of administration. May respond to a lower maintenance dose.

Renal Function

Use with caution; adjust doses for patients with renal impairment.

Hazardous Tasks

May cause fatigue or somnolence.

Anemia

Anemia and potentially clinically important changes in hemoglobin, hematocrit, or RBC indices have occurred.

Birth defects

Birth defects have occurred and include congenital cardiac defects, congenital external ear anomaly, congenital hemangioma, congenital hydronephrosis, congenital male genital malformation, congenital oral malformation, congenital vesicoureteric reflux, dentofacial anomaly, dysmorphism, fetal anticonvulsant syndrome, hamartomas, hip dysplasia, limb malformation, limb reduction defect, low-set ears, renal aplasia, retinitis pigmentosa, supernumerary nipple, and talipes.

Edema

May occur.

MRI abnormalities

Observed in some infants treated with vigabatrin. Changes generally resolved with discontinuation of therapy.

Peripheral neuropathy

Manifestations of peripheral neuropathy, including numbness or tingling in the toes or feet and progressive loss of reflexes, have occurred.

Suicidal behavior and ideation

Antiepileptic drugs, including vigabatrin, increase the risk of suicidal thoughts or behavior. Balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

Weight gain

May occur.

Overdosage

Symptoms

Abnormal behavior, agitation, apnea or respiratory depression, bradycardia, coma, confusion, drowsiness, headache, hypotension, increased seizure activity, irritability, psychosis, speech disorder, status epilepticus, unconsciousness, vertigo.

Patient Information

  • Advise patient, family, or caregiver to read the Medication Guide before starting therapy and with each refill.
  • Inform patients or caregivers of the risk of permanent vision loss, particularly loss of peripheral vision and the need for regular monitoring of vision. Patients and caregivers should understand that if vision loss is documented, such loss is irreversible. Instruct patient, family, or caregiver to contact health care provider immediately if any changes in vision are suspected.
  • Instruct patient or caregiver on proper reconstitution of vigabatrin for oral solution.
  • Advise patient, family, or caregiver that medication will be started at a low dose and then gradually increased as tolerated until maximum benefit has been obtained.
  • Advise patient, family, or caregiver that each dose may be taken without regard to meals but to take with food if stomach upset occurs.
  • Instruct patient, family, or caregiver to be alert for abnormal changes in mood or thinking and to immediately report any of the following to health care provider: emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm.
  • Inform patients or caregivers of the possibility of developing abnormal MRI signal changes of unknown clinical significance.
  • Advise patient, family, or caregiver that if medication needs to be discontinued, it will be slowly withdrawn.
  • Caution patient that drug may cause fatigue or drowsiness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
  • Instruct patient, family, or caregiver to contact health care provider if they develop numbness or tingling in the toes or feet, loss of reflexes, swelling in the extremities, or unusual weight gain, if seizures get worse, or if new types of seizures occur.
  • Advise patient, family, or caregiver to contact health care provider if bothersome adverse reactions occur.

Copyright © 2009 Wolters Kluwer Health.

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