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|WARNING: VISION LOSS
- SABRIL causes permanent bilateral concentric visual field constriction in 30 percent or more of patients that ranges in severity from mild to severe, including tunnel vision to within 10 degrees of visual fixation, and can result in disability. In some cases, SABRIL also can damage the central retina and may decrease visual acuity.
- The onset of vision loss from SABRIL 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 of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss
- Vision Testing at baseline (no later than 4 weeks after starting SABRIL) and at least every 3 months during therapy is required for adults on SABRIL. Vision testing is also required about 3 to 6 months after the discontinuation of SABRIL therapy. Once detected, vision loss due to SABRIL is not reversible. It is expected that, even with frequent monitoring, some patients will develop severe vision loss.
- It is possible that vision loss can worsen despite discontinuation of SABRIL
- Because of the risk of vision loss, SABRIL should be withdrawn from patients who fail to show substantial clinical benefit within 3 months of initiation, or sooner if treatment failure becomes obvious. Patient response to and continued need for SABRIL should be periodically reassessed.
- Symptoms of vision loss from SABRIL are unlikely to be recognized by patients or caregivers before vision loss is severe. Vision loss of milder severity, while often unrecognized by the patient, can still adversely affect function.
- SABRIL should not be used in patients with, or at high risk of, other types of irreversible vision loss unless the benefits of treatment clearly outweigh the risks. The interaction of other types of irreversible vision damage with vision damage from SABRIL has not been well-characterized, but is likely adverse.
- SABRIL should not be used with other drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma unless the benefits clearly outweigh the risks
- The lowest dose and shortest exposure to SABRIL should be used that is consistent with clinical objectives
Because of the risk of permanent vision loss, SABRIL is available only through a special restricted distribution program called SHARE, by calling 1-888-45-SHARE. Only prescribers and pharmacies registered with SHARE may prescribe and distribute SABRIL. In addition, SABRIL may be dispensed only to patients who are enrolled in and meet all conditions of SHARE [see WARNINGS AND PRECAUTIONS, Distribution Program for SABRIL].
| Initial U.S. Approval: 2009
SABRIL (vigabatrin) is available as a white, film-coated tablet for oral administration. Each tablet contains 500 mg vigabatrin. Tablets also contain as inactive ingredients: hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycols, povidone, sodium starch glycolate, and titanium dioxide. Vigabatrin is an oral antiepileptic drug with the chemical name (±) 4-amino-5-hexenoic acid. It is a racemate consisting of two enantiomers. The molecular formula is C6H11NO2 and the molecular weight is 129.16.
Vigabatrin is a white to off-white powder which is freely soluble in water, slightly soluble in methyl alcohol, very slightly soluble in ethyl alcohol and chloroform, and insoluble in toluene and hexane. The pH of a 1% aqueous solution is about 6.9. The n-octanol/water partition coefficient of vigabatrin is about 0.011 (log P=-1.96) at physiologic pH. Vigabatrin melts with decomposition in a 3-degree range within the temperature interval of 171°C to 176°C. The dissociation constants (pKa) of vigabatrin are 4 and 9.7 at room temperature (25°C).
| CLINICAL PHARMACOLOGY
Mechanism of Action
The precise mechanism of vigabatrin's anti-seizure effect is unknown, but it is believed to be the result of its action as an irreversible inhibitor of y-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the metabolism of the inhibitory neurotransmitter GABA. This action results in increased levels of GABA in the central nervous system.
No direct correlation between plasma concentration and efficacy has been established. The duration of drug effect is presumed to be dependent on the rate of enzyme re-synthesis rather than on the rate of elimination of the drug from the systemic circulation
Indications and usage
| INDICATIONS AND USAGE
Refractory Complex Partial Seizures in Adults
SABRIL® is indicated as adjunctive therapy for adult patients with refractory complex partial seizures (CPS) who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss [see WARNINGS AND PRECAUTIONS, Vision Loss]. SABRIL is not indicated as a first line agent for complex partial seizures.
USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm. Pregnancy registry available.
Nursing Mothers: SABRIL is excreted in human milk.
Renal Impairment: Dose adjustment recommended.
| WARNINGS AND PRECAUTIONS
- SABRIL causes permanent vision loss
- Abnormal MRI signal changes have been reported in some infants with IS receiving SABRIL
- Antiepileptic drugs, including SABRIL, increase the risk of suicidal thoughts and behavior
- Dose should be tapered gradually to avoid withdrawal seizures
- SABRIL causes anemia
- SABRIL causes somnolence and fatigue
- SABRIL causes peripheral neuropathy
- SABRIL causes weight gain
- SABRIL causes edema
Decreased phenytoin plasma levels have been reported.
| Most common adverse reactions (change of ≥ 5% over placebo) in addition to permanent vision loss in adult controlled trials with vigabatrin were fatigue, somnolence, nystagmus, tremor, vision blurred, memory impairment, weight gain, arthralgia, abnormal coordination, and confusional state.
To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck Inc. at 1-800-455-1141 or www.lundbeckinc.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Dosage and administration
| DOSAGE AND ADMINISTRATION
Refractory Complex Partial Seizures in Adults
SABRIL 500 mg tablets should be given as twice daily oral administration with or without food. Therapy should be initiated at 1 g/day (500 mg twice daily). Total daily dose may be increased in 500 mg increments at weekly intervals depending on response. The recommended dose of SABRIL in adults is 3 g/day (1.5 g twice daily). A 6 g/day dose has not been shown to confer additional benefit compared to the 3 g/day dose and is associated with an increased incidence of adverse events.
Patients with Renal Impairment
SABRIL is primarily eliminated through the kidney. In patients with renal impairment, dose adjustments should be made as follows:
In patients with mild renal impairment (CLcr >50 to 80 mL/min), the dose should be decreased by 25%; in patients with moderate renal impairment (CLcr >30 to 50 mL/min), the dose should be decreased by 50%; and in patients with severe renal impairment (CLcr >10 to <30 mL/min), the dose should be decreased by 75%.
CLcr in mL/min may be estimated from a serum creatinine (mg/dL) determination using the following formula:
CLcr *= [140-age (years)]× weight (kg)/72× serum creatinine (mg/dL)]
*[× 0.85 for female patients]
The effect of dialysis on SABRIL clearance has not been adequately studied.
General Dosing Considerations
SABRIL should be withdrawn gradually. In controlled clinical studies in adults with CPS, vigabatrin was tapered by decreasing the daily dose 1 g/day on a weekly basis until discontinued [see WARNINGS AND PRECAUTIONS, Withdrawal of Antiepileptic Drugs (AEDs)].
| HOW SUPPLIED/STORAGE AND HANDLING
Each SABRIL film-coated tablet contains 500 mg vigabatrin and is white, film-coated, oval, biconvex, scored on one side, and debossed with OV 111 on the other.
NDC 67386-111-01: Bottles of 100.
Store at 20-25°C (68-77°F). See USP controlled room temperature
| Package Insert data:
Marketed by: Lundbeck Inc., Deerfield, IL 60015, U.S.A.
® Trademark of Lundbeck Inc.
Revised: September 2010
PRINCIPAL DISPLAY PANEL
National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
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