Clinical Data for Refractory CPS in Adults
(as adjunctive therapy)
Below is the refractory complex partial seizures (CPS) data from the 2 US pivotal trials conducted in adults.
Click any of the links below to learn more about the Sabril clinical trials:
Or, click here to see clinical adverse events data.
Overview of Pivotal Trials
- Design: 2 US multicenter, randomized, double-blind, placebo-controlled, parallel-group studies were conducted with adults 18 to 60 years old with refractory CPS, with or without secondary generalization, on an adequate and stable dose of an antiepilepsy drug (AED), and with a history of failure on an adequate regimen of carbamazepine or phenytoin
- Primary measure: The primary measure of efficacy was the patients’ reduction in mean monthly frequency of CPS plus partial seizures secondarily generalized at end of study compared to baseline
- Results: In Study 1 and Study 2, Sabril 3 g/day as adjunctive therapy demonstrated a statistically significant median monthly reduction in seizures vs placebo
- The adverse reactions most commonly associated with treatment discontinuation in ?1% of patients were convulsion (1.4%) and depression (1.5%)
Note: Study 1 and Study 2 were not capable by design of demonstrating direct superiority of Sabril over any other anticonvulsant added to the regimen to which the patient had not adequately responded.
Further, in these studies patients had previously been treated with a limited range of anticonvulsants.
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.
Back to Top
Study 1 Design
- N=174
- 8-week baseline period followed by an 18-week treatment period
- Patients randomized to receive placebo or 1, 3, or 6 g/day Sabril administered BID
- Dose was titrated during the first 6 weeks following randomization
- Doses in the 3 g/day and 6 g/day groups were started at 1 g/day and increased by 0.5 g/day on days 1 and 5 of each subsequent week until the assigned dose was reached
Back to Top
Study 2 Design
- N=183 randomized; N=182 evaluated for efficacy
- 8-week baseline period followed by a 16-week treatment period
- Patients randomized to receive placebo or 3 g/day Sabril administered BID
- Dose was titrated during the first 4 weeks following randomization
- Beginning with 1 g/day and increased by 0.5 g/day on a weekly basis to the maintenance dose of 3 g/day
- 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
Back to Top
Patient Population
Sabril pivotal studies were conducted with a challenging refractory patient population:1,2
- History of failing adequate doses of carbamazepine or phenytoin
- Experienced about 8 seizures per month (median)
- History of epilepsy for about 20 years (median)
Adult patients with refractory CPS failing previous AED classes (Study 1 and 2)2
Note: Study 1 and Study 2 were not capable by design of demonstrating direct superiority of Sabril over any other anticonvulsant added to the regimen to which the patient had not adequately responded.
Further, in these studies patients had previously been treated with a limited range of anticonvulsants.
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.
Back to Top
Study Results
Seizure Frequency
Median Monthly Seizure Frequency
The primary measure of efficacy was the patients’ reduction in mean monthly frequency of CPS plus partial seizures secondarily generalized at end of study compared to baseline.
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.
Due to the risk of Sabril-induced permanent vision loss:
- The lowest dose and shortest exposure to Sabril should be used that is consistent with clinical objectives
- Sabril should be withdrawn from patients who fail to show substantial clinical benefit within 3 months of initiation or sooner. Patient response to and continued need for Sabril should be periodically reassessed
- 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
Back to Top
Responder Rates
Responder Rates from Baseline
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.
- Study 1 and Study 2 were not capable by design of demonstrating direct superiority of Sabril over any other anticonvulsant added to the regimen to which the patient had not adequately responded. Further, in these studies patients had previously been treated with a limited range of anticonvulsants
- The adverse reactions most commonly associated with treatment discontinuation in ?1% of patients were convulsion (1.4%) and depression (1.5%)
Study 1 (n=174)
Study 2 (n=182)
The figures above show the percentage of patients (X-axis) with the associated percent reductions in seizure frequency (responder rate) from baseline to the maintenance phase. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in complex partial seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in complex partial seizure frequency).
Seizure Frequency from Baseline to Study Endpoint
Due to the risk of Sabril-induced permanent vision loss, the lowest dose and shortest exposure to Sabril should be used that is consistent with clinical objectives.
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.
Back to Top
Click the button below to see the adverse event data from the trials.
Important Safety Information
SABRIL® (vigabatrin) Tablets
SABRIL® (vigabatrin) for Oral Solution
Indication
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. SABRIL is not indicated as a first line agent for complex partial seizures.
SABRIL is indicated as monotherapy for pediatric patients 1 month to 2 years of age with infantile spasms (IS) for whom the potential benefits outweigh the potential risk of vision loss.
Important Safety Information
WARNING: VISION LOSS
See full Prescribing Information for complete boxed warning
- SABRIL causes progressive and permanent bilateral concentric visual field constriction in a high percentage of patients. In some cases, SABRIL may also reduce visual acuity
- Risk increases with total dose and duration of use, but no exposure to SABRIL is known that is free of risk of vision loss
- Risk of new and worsening vision loss continues as long as SABRIL is used, and possibly after discontinuing SABRIL
- Unless a patient is formally exempted, periodic vision assessment is required for patients on SABRIL. However, this assessment cannot always prevent vision damage
- Because of the risk of permanent vision loss, SABRIL is available only through a special restricted distribution program
SABRIL causes permanent vision loss in infants, children, and adults. Because assessing vision loss is difficult in children, the frequency and extent of vision loss in infants and children is poorly characterized.
In adults, SABRIL causes permanent bilateral concentric visual field constriction in 30% or more of patients that ranges in severity from mild to severe, including tunnel vision to within 10° 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 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 should be withdrawn from patients with IS who fail to show substantial clinical benefit within 2 to 4 weeks of initiation, or sooner if treatment failure becomes obvious, or adult patients treated for refractory CPS as adjunctive therapy 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.
Unless a patient is formally exempted from periodic ophthalmologic assessment as documented in the SHARE program, vision assessment is required at baseline (no later than 4 weeks after starting SABRIL), at least every 3 months while on therapy and about 3-6 months after the discontinuation of SABRIL therapy. Once detected, vision loss is not reversible. It is expected that, even with frequent monitoring, some patients will develop severe vision loss. Drug discontinuation should be considered, balancing benefit and risk, if visual loss is documented.
Symptoms of vision loss from SABRIL 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 patient, parent or caregiver may still adversely affect function. The possibility that vision loss from SABRIL may be more common, more severe, or have more severe functional consequences in infants and children than in adults, cannot be excluded.
SABRIL 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 the benefits 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.
In adult patients treated for CPS, dose adjustment is necessary in patients with renal impairment.
Abnormal MRI signal changes have been observed in some infants treated for IS with SABRIL. These changes generally resolved with discontinuation of treatment and in a few patients the lesion resolved despite continued use.
Antiepileptic drugs (AEDs), including SABRIL, increase the risk of suicidal thoughts or behavior. Adult patients should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior and/or any unusual changes in mood or behavior.
As with all AEDs, SABRIL should be discontinued gradually to avoid withdrawal seizures.
Vigabatrin is excreted in human milk and may cause serious adverse events in nursing infants. SABRIL should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.
Pregnancy Registry: To provide information regarding the effects of in utero exposure to SABRIL, physicians are advised to recommend that pregnant patients taking SABRIL enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
SABRIL has been shown to cause neurotoxicity, anemia, somnolence and fatigue, peripheral neuropathy, weight gain and edema. The most commonly observed adverse reactions reported in 2 add-on clinical studies of adults with refractory CPS treated with SABRIL as adjunctive therapy with the recommended dose of 3 g/day (≥10% and at least 5% greater than placebo, respectively) were dizziness (24% vs 17%), fatigue (23% vs 16%), somnolence (22% vs 13%), tremor (15% vs 8%), blurred vision (13% vs 5%), and arthralgia (10% vs 3%). 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.
The most common adverse events reported by >5% of infants taking SABRIL for IS occurring more frequently than placebo, respectively, in a randomized, placebo-controlled IS study with a 5-day double-blind treatment phase (n=40) were somnolence (45% vs 30%), bronchitis (30% vs 15%), ear infection (10% vs 5%), and acute otitis media (10% vs 0%).
Oral Solution: For more information, please see the full Prescribing Information including Boxed Warning, Medication Guide, and Dosing Instructions.
Solución oral: Para más información, vea por favor la información que prescribe completa incluyendo la advertencia encajonada, guía de la medicación, y las instrucciones de la dosificación.
Tablets: For more information, please see the full Prescribing Information including Boxed Warning and Medication Guide.
Tabletas: Para más información, vea por favor la información que prescribe completa incluyendo la advertencia encajonada, y guía de la medicación.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
- Sabril full Prescribing Information for CPS. Deerfield, IL. Lundbeck.
- Data on file. Lundbeck.