Dosage & Administration
Refractory Complex Partial Seizures
Infantile Spasms
Renal Impairment: Dose adjustment recommended
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Sabril Prescribing Information
- SABRIL can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, SABRIL also can damage the central retina and may decrease visual acuity [see Warnings and Precautions ].
- The onset of vision loss from SABRIL is unpredictable, and can occur within weeks of starting treatment or sooner, or at any time after starting treatment, even after months or years.
- 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 or caregiver, can still adversely affect function.
- 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 assessment is recommended at baseline (no later than 4 weeks after starting SABRIL), at least every 3 months during therapy, and about 3 to 6 months after the discontinuation of 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.
- Consider drug discontinuation, balancing benefit and risk, if visual loss is documented.
- Risk of new or worsening vision loss continues as long as SABRIL is used. It is possible that vision loss can worsen despite discontinuation of SABRIL.
- Because of the risk of visual loss, SABRIL should be withdrawn from patients with refractory complex partial seizures who fail to show substantial clinical benefit within 3 months of initiation and within 2-4 weeks of initiation for patients with infantile spasms, or sooner if treatment failure becomes obvious. Patient response to and continued need for SABRIL should be periodically reassessed.
- 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.
- 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.
- Use the lowest dosage and shortest exposure to SABRIL consistent with clinical objectives [see Dosage and Administration ].
Because of the risk of permanent vision loss, SABRIL is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Vigabatrin REMS Program [see Warnings and Precautions ]. Further information is available at www.vigabatrinREMS.com or 1-866-244-8175.
Refractory Complex Partial Seizures (CPS)
SABRIL is indicated as adjunctive therapy for adults and pediatric patients 2 years of age and older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss [see Warnings and Precautions ]. SABRIL is not indicated as a first line agent for complex partial seizures.
Infantile Spasms (IS)
SABRIL is indicated as monotherapy for pediatric patients with infantile spasms 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss [see Warnings and Precautions ].
Important Dosing and Administration Instructions
Dosing
Use the lowest dosage and shortest exposure to SABRIL consistent with clinical objectives [see Warnings and Precautions ].
The SABRIL dosing regimen depends on the indication, age group, weight, and dosage form (tablets or for oral solution) [see Dosage and Administration ]. Patients with impaired renal function require dose adjustment [see Dosage and Administration ].
Monitoring of SABRIL plasma concentrations to optimize therapy is not helpful.
Administration
SABRIL is given orally with or without food.
SABRIL for oral solution should be mixed with water prior to administration [see Dosage and Administration ]. A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device.
If a decision is made to discontinue SABRIL, the dose should be gradually reduced [see Dosage and Administration and Warnings and Precautions ].
Refractory Complex Partial Seizures
Adults (Patients 17 Years of Age and Older)
Treatment should be initiated at 1000 mg/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 3000 mg/day (1500 mg twice daily). A 6000 mg/day dose has not been shown to confer additional benefit compared to the 3000 mg/day dose and is associated with an increased incidence of adverse events.
In controlled clinical studies in adults with complex partial seizures, SABRIL was tapered by decreasing the daily dose 1000 mg/day on a weekly basis until discontinued [see Warnings and Precautions ].
Pediatric (Patients 2 to 16 Years of Age)
The recommended dosage is based on body weight and administered as two divided doses, as shown in Table 1. The dosage may be increased in weekly intervals to the total daily maintenance dosage, depending on response.
Pediatric patients weighing more than 60 kg should be dosed according to adult recommendations.
Table 1. CPS Dosing Recommendations for Pediatric Patients Weighing 10 kg up to 60 kg†† | ||||
Body Weight [kg] | Total Daily* Starting Dose [mg/day] | Total Daily* Maintenance Dose† [mg/day] | ||
10 kg to 15 kg | 350 mg | 1050 mg | ||
Greater than 15 kg to 20 kg | 450 mg | 1300 mg | ||
Greater than 20 kg to 25 kg | 500 mg | 1500 mg | ||
Greater than 25 kg to 60 kg | 500 mg | 2000 mg | ||
* Administered in two divided doses † Maintenance dose is based on 3000 mg/day adult-equivalent dose †† Patients weighing more than 60 kg should be dosed according to adult recommendations | ||||
In patients with refractory complex partial seizures, SABRIL should be withdrawn if a substantial clinical benefit is not observed within 3 months of initiating treatment. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 3 months, treatment should be discontinued at that time [see Warnings and Precautions ].
In a controlled study in pediatric patients with complex partial seizures, SABRIL was tapered by decreasing the daily dose by one third every week for three weeks [see Warnings and Precautions ].
Infantile Spasms
The initial daily dosing is 50 mg/kg/day given in two divided doses (25 mg/kg twice daily); subsequent dosing can be titrated by 25 mg/kg/day to 50 mg/kg/day increments every 3 days, up to a maximum of 150 mg/kg/day given in 2 divided doses (75 mg/kg twice daily) [see Use in Specific Populations ].
Table 2 provides the volume of the 50 mg/mL dosing solution that should be administered as individual doses in infants of various weights.
| Table 2. Infant Dosing Table | ||||
| Weight [kg] | Starting Dose 50 mg/kg/day | Maximum Dose 150 mg/kg/day | ||
| 3 | 1.5 mL twice daily | 4.5 mL twice daily | ||
| 4 | 2 mL twice daily | 6 mL twice daily | ||
| 5 | 2.5 mL twice daily | 7.5 mL twice daily | ||
| 6 | 3 mL twice daily | 9 mL twice daily | ||
| 7 | 3.5 mL twice daily | 10.5 mL twice daily | ||
| 8 | 4 mL twice daily | 12 mL twice daily | ||
| 9 | 4.5 mL twice daily | 13.5 mL twice daily | ||
| 10 | 5 mL twice daily | 15 mL twice daily | ||
| 11 | 5.5 mL twice daily | 16.5 mL twice daily | ||
| 12 | 6 mL twice daily | 18 mL twice daily | ||
| 13 | 6.5 mL twice daily | 19.5 mL twice daily | ||
| 14 | 7 mL twice daily | 21 mL twice daily | ||
| 15 | 7.5 mL twice daily | 22.5 mL twice daily | ||
| 16 | 8 mL twice daily | 24 mL twice daily | ||
In patients with infantile spasms, SABRIL should be withdrawn if a substantial clinical benefit is not observed within 2 to 4 weeks. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 2 to 4 weeks, treatment should be discontinued at that time [see Warnings and Precautions ].
In a controlled clinical study in patients with infantile spasms, SABRIL was tapered by decreasing the daily dose at a rate of 25 mg/kg to 50 mg/kg every 3 to 4 days [see Warnings and Precautions ].
Patients with Renal Impairment
SABRIL is primarily eliminated through the kidney.
Infants
Information about how to adjust the dose in infants with renal impairment is unavailable.
Adult and pediatric patients 2 years and older
- Mild renal impairment (CLcr >50 to 80 mL/min): dose should be decreased by 25%
- Moderate renal impairment (CLcr >30 to 50 mL/min): dose should be decreased by 50%
- Severe renal impairment (CLcr >10 to 30 mL/min): dose should be decreased by 75%
CLcr in mL/min may be estimated from serum creatinine (mg/dL) using the following formulas:
- Patients 2 to <12 years old: CLcr (mL/min/1.73 m2) = (K × Ht) / Scr
height (Ht) in cm; serum creatinine (Scr) in mg/dL
K (proportionality constant): Female Child (<12 years): K=0.55;
Male Child (<12 years): K=0.70
- Adult and pediatric patients 12 years or older: CLcr (mL/min) = [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 [see Clinical Pharmacology and Use in Specific Populations ].
Preparation and Administration Instructions for SABRIL for oral solution
If using SABRIL fororal solution, physicians should review and discuss the Medication Guide andinstructions for mixing and giving SABRIL with the patient or caregiver(s).Physicians should confirm that patients or caregiver(s) understand how to mixSABRIL powder with water and administer the correct daily dose.
Empty the entire contents ofeach 500 mg packet into a clean cup, and dissolve in 10 mL of cold or roomtemperature water per packet. Administer the resulting solution using the 3 mL or 10 mLoral syringe provided by the pharmacy [see How Supplied/Storage and Handling ]. The concentration of the final solutionis 50 mg/mL.
Table 3 below describes howmany packets and how many milliliters (mL) of water will be needed to prepareeach individual dose. The concentrationafter reconstitution is 50 mg/mL.
| Table 3. Number of SABRIL Packets and mL of Water Needed for Each Individual Dose | ||
Individual Dose [mg] [Given Twice Daily] | Total Number of SABRIL Packets | Total mL of Water Required for Dissolving |
| 0 to 500 | 1 Packet | 10 mL |
| 501 to 1000 | 2 Packets | 20 mL |
| 1001 to 1500 | 3 Packets | 30 mL |
Discard the resultingsolution if it is not clear (or free of particles) and colorless. Eachindividual dose should be prepared and used immediately. Discard any unusedportion of the solution after administering the correct dose.
Tablet: 500 mg: white, oval, film-coated, biconvex, scored on one side, and debossed with OV 111 on the other.
For oral solution: 500 mg packet containing a white to off-white granular powder.
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including SABRIL, during pregnancy. Encourage women who are taking SABRIL during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. This must be done by the patient herself.
Risk Summary
There are no adequate data on the developmental risk associated with the use of SABRIL in pregnant women. Limited available data from case reports and cohort studies pertaining to SABRIL use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, based on animal data, SABRIL use in pregnant women may result in fetal harm.
When administered to pregnant animals, vigabatrin produced developmental toxicity, including an increase in fetal malformations and offspring neurobehavioral and neurohistopathological effects, at clinically relevant doses. In addition, developmental neurotoxicity was observed in rats treated with vigabatrin during a period of postnatal development corresponding to the third trimester of human pregnancy (see Data).
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Data
Animal Data
Administration of vigabatrin (oral doses of 50 to 200 mg/kg/day) to pregnant rabbits throughout the period of organogenesis was associated with an increased incidence of malformations (cleft palate) and embryofetal death; these findings were observed in two separate studies. The no-effect dose for adverse effects on embryofetal development in rabbits (100 mg/kg/day) is approximately 1/2 the maximum recommended human dose (MRHD) of 3 g/day on a body surface area (mg/m2) basis. In rats, oral administration of vigabatrin (50, 100, or 150 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. The no-effect dose for adverse effects on embryo-fetal development in rats (50 mg/kg/day) is approximately 1/5 the MRHD on a mg/m2 basis. Oral administration of vigabatrin (50, 100, 150 mg/kg/day) to rats from the latter part of pregnancy through weaning produced long-term neurohistopathological (hippocampal vacuolation) and neurobehavioral (convulsions) abnormalities in the offspring. A no-effect dose for developmental neurotoxicity in rats was not established; the low-effect dose (50 mg/kg/day) is approximately 1/5 the MRHD on a mg/m2 basis.
In a published study, vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to a mutant mouse strain on a single day during organogenesis (day 7, 8, 9, 10, 11, or 12). An increase in fetal malformations (including cleft palate) was observed at both doses.
Oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg/day) was associated with plasma vigabatrin exposures (AUC) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg.
Lactation
Risk Summary
Vigabatrin is excreted in human milk. The effects of SABRIL on the breastfed infant and on milk production are unknown. Because of the potential for serious adverse reactions from vigabatrin in nursing infants, breastfeeding is not recommended. If exposing a breastfed infant to SABRIL, observe for any potential adverse effects [see Warnings and Precautions ].
Pediatric Use
The safety and effectiveness of SABRIL as adjunctive treatment of refractory complex partial seizures in pediatric patients 2 to 16 years of age have been established and is supported by three double-blind, placebo-controlled studies in patients 3 to 16 years of age, adequate and well-controlled studies in adult patients, pharmacokinetic data from patients 2 years of age and older, and additional safety information in patients 2 years of age [see Clinical Pharmacology and Clinical Studies ]. The dosing recommendation in this population varies according to age group and is weight-based [see Dosage and Administration ]. Adverse reactions in this pediatric population are similar to those observed in the adult population [see Adverse Reactions ]. The safety and effectiveness of SABRIL as monotherapy for pediatric patients with infantile spasms (1 month to 2 years of age) have been established [see Dosage and Administration and Clinical Studies ].
Safety and effectiveness as adjunctive treatment of refractory complex partial seizures in pediatric patients below the age of 2 and as monotherapy for the treatment of infantile spasms in pediatric patients below the age of 1 month have not been established.
Duration of therapy for infantile spasms was evaluated in a post hoc analysis of a Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in infantile spasms patients. This analysis suggests that a total duration of 6 months of vigabatrin therapy is adequate for the treatment of infantile spasms. However, prescribers must use their clinical judgment as to the most appropriate duration of use [see Clinical Studies ].
Abnormal MRI signal changes and Intramyelinic Edema (IME) in infants and young children being treated with SABRIL have been observed [see Warnings and Precautions ].
Juvenile Animal Toxicity Data
Oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain gray matter vacuolation, decreased myelination, and retinal dysplasia) abnormalities. The no-effect dose for developmental neurotoxicity in juvenile rats (the lowest dose tested) was associated with plasma vigabatrin exposures (AUC) substantially less than those measured in pediatric patients at recommended doses. In dogs, oral administration of vigabatrin (30 or 100 mg/kg/day) during selected periods of juvenile development (postnatal days 22-112) produced neurohistopathological abnormalities (brain gray matter vacuolation). Neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. A no-effect dose for neurohistopathology was not established in juvenile dogs; the lowest effect dose (30 mg/kg/day) was associated with plasma vigabatrin exposures lower than those measured in pediatric patients at recommended doses [see Warnings and Precautions ].
Geriatric Use
Clinical studies of vigabatrin did not include sufficient numbers of patients aged 65 and over to determine whether they responded differently from younger patients.
Vigabatrin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Oral administration of a single dose of 1.5 g of vigabatrin to elderly (≥65 years) patients with reduced creatinine clearance (<50 mL/min) was associated with moderate to severe sedation and confusion in 4 of 5 patients, lasting up to 5 days. The renal clearance of vigabatrin was 36% lower in healthy elderly subjects (≥65 years) than in young healthy males. Adjustment of dose or frequency of administration should be considered. Such patients may respond to a lower maintenance dose [see Dosage and Administration and Clinical Pharmacology and Clinical Pharmacology ].
None.