Sabril

(Vigabatrin)

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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 (
5.1 Permanent Vision Loss
SABRIL can cause permanent vision loss. Because of this
risk and because, when it is effective, SABRIL provides an observable
symptomatic benefit; patient response and continued need for treatment should
be periodically assessed.
Based upon adult studies,
30 percent or more of patients can be affected with bilateral concentric visual
field constriction ranging in severity from mild to severe. Severe cases may be
characterized by tunnel vision to within 10 degrees of visual fixation, which
can result in disability. In some cases, SABRIL also can damage the central
retina and may decrease visual acuity. 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.
Because assessing vision
may be difficult in infants and children, the frequency and extent of vision
loss is poorly characterized in these patients. For this reason, the understanding
of the risk is primarily based on the adult experience. 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.
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.
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.
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should be withdrawn if a substantial clinical benefit is not observed within 3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
Dosage and Administration and Warnings and Precautions ]
.
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spasms, SABRIL should be withdrawn if a substantial clinical benefit is not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 Dosage and Administration and Warnings and Precautions ].
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.
Monitoring of Vision
Monitoring of vision by
an ophthalmic professional with expertise in visual field interpretation
and the ability to perform dilated indirect ophthalmoscopy of the retina is
recommended
[see Warnings and Precautions
].
Because vision testing in infants is difficult, vision loss may not
be detected until it is severe. For patients receiving SABRIL, vision
assessment is recommended 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 therapy. The
diagnostic approach should be individualized for the patient and clinical
situation.
In adults and
cooperative pediatric patients, perimetry is recommended, preferably by
automated threshold visual field testing. Additional testing may also include
electrophysiology (e.g., electroretinography [ERG]), retinal imaging (e.g., optical
coherence tomography [OCT]), and/or other methods appropriate for the patient. In
patients who cannot be tested, treatment may continue according to clinical
judgment, with appropriate patient counseling. Because of variability, results
from ophthalmic monitoring must be interpreted with caution, and repeat assessment
is recommended if results are abnormal or uninterpretable. Repeat assessment in
the first few weeks of treatment is recommended to establish if, and to what
degree, reproducible results can be obtained, and to guide selection of
appropriate ongoing monitoring for the patient.
The onset and progression of
vision loss from SABRIL is unpredictable, and it may occur or worsen
precipitously between assessments. Once detected, vision loss due to SABRIL is
not reversible. It is expected that even with frequent monitoring, some SABRIL patients
will develop severe vision loss. Consider drug discontinuation, balancing
benefit and risk, if vision loss is documented. It is possible that vision loss
can worsen despite discontinuation of SABRIL.
)].
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 (
2.1 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
].
)].

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

(

5.2 Vigabatrin REMS Program

SABRIL is
available only through a restricted distribution program called the Vigabatrin REMS
Program, because of the risk of permanent vision loss.

Notable requirements
of the Vigabatrin REMS Program include the following:

Prescribers
must be certified by enrolling in the program, agreeing to counsel patients on
the risk of vision loss and the need for periodic monitoring of vision, and
reporting any event suggestive of vision loss to Lundbeck.
Patients
must enroll in the program.
Pharmacies must
be certified and must only dispense to patients authorized to receive SABRIL.

Further information is
available at

www.vigabatrinREMS.com,

or call
1-866-244-8175.

)

]

. Further information is available at www.vigabatrinREMS.com or 1-866-244-8175.

SABRIL is indicated for the
treatment of:

Refractory Complex
Partial Seizures as adjunctive therapy in patients 2 years of age and older who have
responded inadequately to several alternative treatments; SABRIL is not
indicated as a first line agent (
1.1 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 -
monotherapy in infants 1 month to 2 years of age for whom the potential
benefits outweigh the potential risk of vision loss (
1.2 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
].
)

Refractory Complex Partial Seizures

Adults (17 years of age and older): Initiate at 1000 mg/day (500 mg twice daily); increase total daily dose weekly in 500 mg/day increments, to the recommended dose of 3000 mg/day (1500 mg twice daily) (

2.2 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 ].

)

Pediatric (2 to 16 years of age): The recommended dosage is based on body weight and administered as two divided doses (

2.2 Refractory Complex Partial Seizures

Adults (Patients 17 Years of Age and Older)

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)

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

[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 ].

)

The dosage may be increased in weekly intervals, depending on response (

2.2 Refractory Complex Partial Seizures

Adults (Patients 17 Years of Age and Older)

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)

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

[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 ].

)

Dose patients weighing more than 60 kg according to adult recommendations (

2.2 Refractory Complex Partial Seizures

Adults (Patients 17 Years of Age and Older)

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)

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

[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

Initiate at a daily dose of 50 mg/kg (25 mg/kg twice daily); increase total daily dose every 3 days, in increments of 25 mg/kg/day to 50 mg/kg/day, up to a maximum daily dose of 150 mg/kg (75 mg/kg twice daily) (

2.3 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)

[

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 ].

)

Renal Impairment

: Dose adjustment recommended (

2.4 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

[

ee Clinical Pharmacology

and

Use in Specific Populations

]

8.5 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 ]

)

Pregnancy: Based on animal data, may cause fetal harm. (
8.1 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/m²basis. 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/m²basis.
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: SABRIL is excreted in human milk (
8.2 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 ]
.
)

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