Included as part of the PRECAUTIONS section.

Vision Loss (see BOXED WARNING)

Because of the risk of vision loss and because SABRIL (vigabatrin oral solution) , when it is effective, provides an observable symptomatic benefit, a patient who fails to show substantial clinical benefit within 3 months of initiation of treatment, should be withdrawn from SABRIL (vigabatrin oral solution) . If in the clinical judgment of the prescriber evidence of treatment failure becomes obvious earlier than 3 months, treatment with SABRIL (vigabatrin oral solution) should be discontinued at that time. Patient response to and continued need for treatment should be periodically assessed.

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 required. Vision testing at baseline (no later than 4 weeks after starting SABRIL (vigabatrin oral solution) ) and at least every 3 months is required for adults on SABRIL (vigabatrin oral solution) . Vision testing is also required about 3 to 6 months after the discontinuation of SABRIL (vigabatrin oral solution) therapy.

The diagnostic approach should be individualized for the patient and clinical situation, but for all patients attempts to monitor vision periodically must be documented under the SHARE program. 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 in whom vision testing is not possible, treatment may continue according to clinical judgment, with appropriate patient counseling and with documentation in the SHARE program of the inability to test vision. Because of variability, results from ophthalmic monitoring must be interpreted with caution, and repeat testing is recommended if results are abnormal or uninterpretable. Repeat testing 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 (vigabatrin oral solution) is unpredictable, and it may occur or worsen precipitously between tests. Once detected, vision loss due to SABRIL (vigabatrin oral solution) is not reversible. It is expected that even with frequent monitoring, some SABRIL (vigabatrin oral solution) patients will develop severe vision loss.

Distribution Program for SABRIL (vigabatrin oral solution)

SABRIL (vigabatrin oral solution) is available only under a special restricted distribution program called the SHARE program. Under the SHARE program, only prescribers and pharmacies registered with the program are able to prescribe and distribute SABRIL (vigabatrin oral solution) . In addition, SABRIL (vigabatrin oral solution) may be dispensed only to patients who are enrolled in and meet all conditions of SHARE. Contact the SHARE program at 1-888-45-SHARE.

To enroll in SHARE, prescribers must understand the risks of SABRIL (vigabatrin oral solution) and complete the SHARE Prescriber Enrollment and Agreement Form indicating agreement to:

• Enroll all patients in SHARE
• Review the SABRIL (vigabatrin oral solution) Medication Guide with every patient
• Educate patients on the risks of SABRIL, including the risk of vision loss [see BOXED WARNING: Vision Loss]
• Order and review vision assessments at initiation of SABRIL (vigabatrin oral solution) treatment and every 3 months during therapy
• Remove patients from SABRIL (vigabatrin oral solution) therapy if the patients do not experience meaningful reduction in seizures
• Counsel patients who fail to comply with the program requirements
• Remove patients from SABRIL (vigabatrin oral solution) therapy who fail to comply with the program requirements after appropriate counseling

Magnetic Resonance Imaging (MRI) Abnormalities

Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated for Infantile Spasms (IS) with vigabatrin. In a retrospective epidemiologic study in infants with IS (N=205), the prevalence of these changes was 21.5% in vigabatrin-treated patients versus 4.1% in patients treated with other therapies.

In the study above, in post marketing experience, and in published literature reports, these changes generally resolved with discontinuation of treatment. In a few patients, the lesion resolved despite continued use. It has been reported that some infants exhibited coincident motor abnormalities, but no causal relationship has been established and the potential for long-term clinical sequelae has not been adequately studied.

Neurotoxicity (including convulsions and hypomyelination) was observed in rats exposed to vigabatrin during late gestation and the neonatal and juvenile periods of development. The relationship between these findings and the abnormal MRI findings in infants treated for IS with vigabatrin is unknown [see WARNINGS AND PRECAUTIONS, Neurotoxicity and Use In Specific Populations, Pregnancy].

The specific pattern of signal changes observed in IS patients was not observed in older children and adult patients treated with vigabatrin for CPS. In a blinded review of MRI images obtained in prospective clinical trials in patients with CPS 3 years and older (N=656), no difference was observed in anatomic distribution or prevalence of MRI signal changes between vigabatrin treated and placebo patients.

For adults treated with SABRIL (vigabatrin oral solution) , routine MRI surveillance is unnecessary as there is no evidence that vigabatrin causes MRI changes in this population.

Neurotoxicity

Vacuolization, characterized by fluid accumulation and separation of the outer layers of myelin, has been observed in brain white matter tracts in adult and juvenile rats and adult mice, dogs, and possibly monkeys following administration of vigabatrin. This lesion, referred to as intramyelinic edema (1MB), was seen in animals at doses within the human therapeutic range. A no-effect dose was not established in rodents or dogs. In the rat and dog, vacuolization was reversible following discontinuation of vigabatrin treatment, but, in the rat, pathologic changes consisting of swollen or degenerating axons, mineralization, and gliosis were seen in brain areas in which vacuolation had been previously observed. Vacuolization in adult animals was correlated with alterations in MRI and changes in visual and somatosensory evoked potentials (EP).

Administration of vigabatrin to rats during the neonatal and juvenile periods of development produced vacuolar changes in the gray matter (areas including the thalamus, midbrain, deep cerebellar nuclei, substantia nigra, hippocampus, and forebrain) which are considered distinct from the 1MB observed in vigabatrin treated adult animals. Decreased myelination, retinal dysplasia, and neurobehavioral abnormalities (convulsions, neuromotor impairment, learning deficits) were also observed following vigabatrin treatment of young rats. These effects occurred at doses associated with plasma vigabatrin levels substantially lower than those achieved clinically in infants and children.

In a published study, vigabatrin (200, 400 mg/kg/day) induced apoptotic neurodegeneration in the brain of young rats when administered by intraperitoneal injection on postnatal days 5-7.

Administration of vigabatrin to female rats during pregnancy and lactation at doses below those used clinically resulted in hippocampal vacuolation and convulsions in the mature offspring.

Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated for IS with vigabatrin. Studies of the effects of vigabatrin on MRI and EP in adult epilepsy patients have demonstrated no clear-cut abnormalities [see WARNINGS AND PRECAUTIONS, MRI Abnormalities].

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including SABRIL (vigabatrin oral solution) , increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% Cl:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing SABRIL (vigabatrin oral solution) or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Withdrawal of Antiepileptic Drugs (AEDs)

As with all AEDs, SABRIL (vigabatrin oral solution) should be withdrawn gradually. In controlled clinical studies in adults with CPS, SABRIL (vigabatrin oral solution) was tapered by decreasing the daily dose 1 g/day on a weekly basis until discontinued [see DOSAGE AND ADMINISTRATION, General Dosing Considerations, and PATIENT INFORMATION].

Anemia

In North American controlled trials, 5.7% of patients (16/280) receiving SABRIL (vigabatrin oral solution) and 1.6% of patients (3/188) receiving placebo had adverse events of anemia and/or met criteria for potentially clinically important hematology changes involving hemoglobin, hematocrit, and/or RBC indices. Across U.S. controlled trials, there were mean decreases in hemoglobin of about 3% and 0% in SABRIL (vigabatrin oral solution) and placebo-treated patients, respectively, and in hematocrit of about 1% in Sabril (vigabatrin oral solution) treated patients compared to a gain of about 1% in patients treated with placebo.

In controlled and open label epilepsy trials, 3 SABRIL (vigabatrin oral solution) patients (0.06%, 3/4855) discontinued for anemia and 2 SABRIL (vigabatrin oral solution) patients experienced unexplained declines in hemoglobin to below 8 g/dL and/or hematocrit below 24%.

Somnolence and Fatigue

SABRIL (vigabatrin oral solution) causes somnolence and fatigue. Patients should be advised not to drive a car or operate other complex machinery until they are familiar with the effects of SABRIL (vigabatrin oral solution) on their ability to perform such activities.

Pooled data from two SABRIL (vigabatrin oral solution) controlled trials demonstrated that 24% (54/222) of SABRIL (vigabatrin oral solution) patients experienced somnolence compared to 10% (14/135) of placebo patients. In those same studies, 28% of SABRIL (vigabatrin oral solution) patients experienced fatigue compared to 15% (20/135) of placebo patients. Almost 1% of SABRIL (vigabatrin oral solution) patients discontinued from clinical trials for somnolence and almost 1% discontinued for fatigue.

Peripheral Neuropathy

SABRIL (vigabatrin oral solution) causes symptoms of peripheral neuropathy. In a pool of North American controlled and uncontrolled epilepsy studies, 4.2% (19/457) of SABRIL (vigabatrin oral solution) patients developed signs and/or symptoms of peripheral neuropathy. In the subset of North American placebo-controlled epilepsy trials, 1.4% (4/280) of SABRIL (vigabatrin oral solution) treated patients and no (0/188) placebo patients developed signs and/or symptoms of peripheral neuropathy. Initial manifestations of peripheral neuropathy in these trials included, in some combination, symptoms of numbness or tingling in the toes or feet, signs of reduced distal lower limb vibration or position sensation, or progressive loss of reflexes, starting at the ankles. Clinical studies in the development program were not designed to investigate peripheral neuropathy systematically and did not include nerve conduction studies, quantitative sensory testing, or skin or nerve biopsy. There is insufficient evidence to determine if development of these signs and symptoms were related to duration of SABRIL (vigabatrin oral solution) treatment, cumulative dose, or if the findings of peripheral neuropathy were completely reversible upon discontinuation of SABRIL (vigabatrin oral solution) .

Weight Gain

SABRIL (vigabatrin oral solution) causes weight gain. Data pooled from randomized controlled trials found that 17% (77/443) of SABRIL (vigabatrin oral solution) patients versus 8% (22/275) of placebo patients gained ≥ 7% of baseline body weight. In these same trials, the mean weight change among SABRIL (vigabatrin oral solution) patients was 3.5 kg compared to 1.6 kg for placebo patients. In all epilepsy trials, 0.6% (31/4855) of SABRIL (vigabatrin oral solution) patients discontinued for weight gain. The long term effects of SABRIL (vigabatrin oral solution) related weight gain are not known. Weight gain was not related to the occurrence of edema.

Edema

SABRIL (vigabatrin oral solution) causes edema. Pooled data from controlled trials demonstrated increased risk among SABRIL (vigabatrin oral solution) patients compared to placebo patients for peripheral edema (SABRIL (vigabatrin oral solution) 2%, placebo 1%), and edema (SABRIL (vigabatrin oral solution) 1%, placebo 0%). In these studies, one SABRIL (vigabatrin oral solution) and no placebo patients discontinued for an edema related AE. There was no apparent association between edema and cardiovascular adverse events such as hypertension or congestive heart failure. Edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.

Patient Counseling Information

See FDA-Approved Patient Labeling

Patients must be informed of the availability of a Medication Guide. Patients must be instructed to read the Medication Guide prior to initiating treatment with SABRIL (vigabatrin oral solution) and with each prescription refill. Doctors must review the SABRIL (vigabatrin oral solution) Medication Guide with every patient prior to initiation of treatment. Patients should be instructed to take SABRIL (vigabatrin oral solution) only as prescribed.

Vision Loss

Patients should be informed of the risk of permanent vision loss, particularly loss of peripheral vision, from SABRIL (vigabatrin oral solution) , and the need for monitoring vision [see WARNINGS AND PRECAUTIONS, Vision Loss].

Monitoring of vision, including assessment of visual fields and visual acuity, is required for adults at baseline (no later than 4 weeks after starting SABRIL (vigabatrin oral solution) ) and at least every 3 months while on therapy unless after repeated attempts it is not possible. In those patients in whom vision testing is not possible, treatment may continue according to clinical judgment with appropriate patient counseling and with documentation in the SHARE program of the inability to test vision. Patients should be informed that if baseline or subsequent vision is not normal, SABRIL (vigabatrin oral solution) should only be used if the benefits of SABRIL (vigabatrin oral solution) treatment clearly outweigh the risks of additional vision loss.

Patients should understand that vision testing may be insensitive and may not detect vision loss before it is severe. Patients should also understand that if vision loss is documented, such loss is irreversible.

Patients should be informed that if changes in vision are suspected, they should notify their physician immediately.

Suicidal Thinking and Behavior

Patients, their caregiver(s), and families should be counseled that AEDs, including SABRIL (vigabatrin oral solution) , may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the 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. Behaviors of concern should be reported immediately to healthcare providers [see WARNINGS AND PRECAUTIONS, Suicidal Behavior and Ideation].

Use in Pregnancy

Patients should be instructed to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breast feeding or intend to breast feed during therapy [see Use In Specific Populations, Pregnancy, and Nursing Mothers].

Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use In Specific Populations, Pregnancy]. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Withdrawal of SABRIL (vigabatrin oral solution) Therapy

Patients should be told not to suddenly discontinue SABRIL (vigabatrin oral solution) therapy. As with all AEDs, withdrawal should be gradual. 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Vigabatrin showed no carcinogenic potential in mouse or rat when given in the diet at doses up to 150 mg/kg/day for 18 months (mouse) or at doses up to 150 mg/kg/day for 2 years (rat). These doses are less than the maximum recommended human dose (MRHD) of 3 g/day on a mg/m² basis.

Vigabatrin was negative in in vitro (Ames, CHO/HGPRT mammalian cell forward gene mutation, chromosomal aberration in rat lymphocytes) and in in vivo (mouse bone marrow micronucleus) assays.

No adverse effects on male or female fertility were observed in rats at oral doses up to 150 mg/kg/day (approximately 1/2 the MRHD on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category C. Vigabatrin produced developmental toxicity, including teratogenic and neurohistopathological effects, when administered to pregnant animals 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. There are no adequate and well-controlled studies in pregnant women. SABRIL (vigabatrin oral solution) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Administration of vigabatrin (oral doses of 50 to 200 mg/kg) to pregnant rabbits throughout the period of organogenesis was associated with an increased incidence of malformations (cleft palate) and embryo-fetal death; these findings were observed in two separate studies. The no-effect dose for teratogenicity and embryolethality in rabbits (100 mg/kg) 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) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. The no-effect dose for embryo-fetal toxicity in rats (50 mg/kg) is approximately 1/5 the MRHD on a mg/m² basis. Oral administration of vigabatrin (50, 100, 150 mg/kg) 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) 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 malformations (including cleft palate) was observed at both doses.

Oral administration of vigabatrin (5, 15, or 50 mg/kg) 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) 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.

Pregnancy Registry: To provide information regarding the effects of in utero exposure to SABRIL (vigabatrin oral solution) , physicians are advised to recommend that pregnant patients taking SABRIL (vigabatrin oral solution) 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/.

Nursing Mothers

Vigabatrin is excreted in human milk. Because of the potential for serious adverse reactions from vigabatrin in nursing infants [see WARNINGS AND PRECAUTIONS, MRI Abnormalities and Neurotoxicity], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of SABRIL (vigabatrin oral solution) in pediatric patients ( < 16 years of age) with CPS has not been established.

Abnormal MRI signal changes were observed in infants [seeWARNINGS AND PRECAUTIONS,, MRI Abnormalities and Neurotoxicity].

Oral administration of vigabatrin (5, 15, or 50 mg/kg) 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 no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg) 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.

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 CLINICAL PHARMACOLOGY, Pharmacokinetics, Renal Impairment and DOSAGE AND ADMINISTRATION, Patients with Renal Impairment].

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Renal Impairment

Dose adjustment, including initiating treatment with a lower dose, is necessary in patients with mild (creatinine clearance > 50-80 mL/min), moderate (creatinine clearance > 30-50 mL/min) and severe (creatinine clearance > 10-30 mL/min) renal impairment [see CLINICAL PHARMACOLOGY, Pharmacokinetics, Renal Impairment and DOSAGE AND ADMINISTRATION, Patients with Renal Impairment].

Last reviewed on RxList: 3/7/2011
This monograph has been modified to include the generic and brand name in many instances.