Sabril Tablets

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

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


• Unless a patient is formally exempted from periodic ophthalmologic assessment as documented in the SHARE program, vision assessment 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 assessment 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.


• Drug discontinuation should be considered, balancing benefit and risk, if visual loss is documented.


• 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• Because of the risk of vision loss, SABRIL should be withdrawn from patients who fail to show substantial clinical benefit within 3 months of initiation, or sooner if treatment failure becomes obvious.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 (SHARE Program) (5.2)].

Indications and Usage for Sabril Tablets

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 (5.1)]. SABRIL is not indicated as a first line agent for complex partial seizures.

Sabril Tablets 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.

[See CLINICAL PHARMACOLOGY, Pharmacokinetics, Renal Impairment (12.3) and USE IN SPECIFIC POPULATIONS, Renal Impairment (8.6)].

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) (5.6)].

Dosage Forms and Strengths

Tablet

500 mg Tablet.

Contraindications

None.

Warnings and Precautions

Vision Loss (see BOXED WARNING)

Because of the risk of vision loss and because SABRIL, 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. If in the clinical judgment of the prescriber evidence of treatment failure becomes obvious earlier than 3 months, treatment with SABRIL 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, unless a patient is formally exempted from periodic ophthalmologic assessment as documented in the Support, Help And Resources for Epilepsy (SHARE) program. For patients receiving SABRIL who are not exempted, vision assessment is required at baseline (no later than 4 weeks after starting SABRIL) and 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. For all patients, attempts to monitor vision periodically and/or formal exemptions 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, but this additional testing is not required. In patients exempted from vision testing, treatment may continue according to clinical judgment, with appropriate patient counseling and with documentation in the SHARE program of the exemption. 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. Drug discontinuation should be considered, balancing benefit and risk, if visual loss is documented.

Distribution Program for SABRIL (SHARE Program)

SABRIL 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. In addition, SABRIL 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 and complete the SHARE Prescriber Enrollment and Agreement Form indicating agreement to:

• Enroll all patients in SHARE


• Review the SABRIL 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 treatment and every 3 months during therapy


• Remove patients from SABRIL 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 therapy who fail to comply with the program requirements after appropriate counseling

The prescriber may, with appropriate documentation and caregiver counseling, exempt certain patients from vision assessment, using the Ophthalmologic Assessment Form, if:

• The patient is blind (subsequent Ophthalmologic Forms do not need to be submitted to the REMS coordinating center)


• The patient's general neurological and/or mental condition permanently precludes the need for visual assessment (subsequent Ophthalmologic Forms do not need to be submitted to the REMS coordinating center)


• The patient's general neurological condition temporarily precludes the ability to assess visual function. The evaluation, however, may be performed at a later time as clinically appropriate.


• The patient's medical condition prevents visual assessment being performed safely


• For other reasons specified by the prescriber

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 (5.4) and USE IN SPECIFIC POPULATIONS, Pregnancy (8.1)].

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, 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 (IME), 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 IME 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 (5.3)].

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including SABRIL, 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% CI: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

Indication	Placebo Patients with Events per 1000 Patients	Drug Patients with Events per 1000 Patients	Relative Risk: Incidence of Drug Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events per 1000 Patients
Epilepsy	1.0	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1.0	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

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 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 should be withdrawn gradually. In controlled clinical studies in adults with CPS, SABRIL was tapered by decreasing the daily dose 1 g/day on a weekly basis until discontinued [see DOSAGE AND ADMINISTRATION, General Dosing Considerations (2.3), PATIENT COUNSELING INFORMATION, Withdrawal of SABRIL Therapy (17.4)].

Anemia

In North American controlled trials, 5.7% of patients (16/280) receiving SABRIL 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 and placebo-treated patients, respectively, and in hematocrit of about 1% in Sabril treated patients compared to a gain of about 1% in patients treated with placebo.

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

Somnolence and Fatigue

SABRIL 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 on their ability to perform such activities.

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

Peripheral Neuropathy

SABRIL causes symptoms of peripheral neuropathy. In a pool of North American controlled and uncontrolled epilepsy studies, 4.2% (19/457) of SABRIL 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 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 treatment, cumulative dose, or if the findings of peripheral neuropathy were completely reversible upon discontinuation of SABRIL.

Weight Gain

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

Edema

SABRIL causes edema. Pooled data from controlled trials demonstrated increased risk among SABRIL patients compared to placebo patients for peripheral edema (SABRIL 2%, placebo 1%), and edema (SABRIL 1%, placebo 0%). In these studies, one SABRIL 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.

Adverse Reactions

SABRIL causes permanent damage to vision in a high percentage of patients [see BOXED WARNING: VISION LOSS and WARNINGS AND PRECAUTIONS, Vision Loss (5.1)].

Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions in U.S. and Primary Non-U.S. Clinical Studies

In U.S. and primary non-U.S. clinical studies of 4,079 SABRIL treated patients, the most commonly observed (≥ 5%) adverse reactions associated with the use of SABRIL in combination with other AEDs were headache (18%), somnolence (17%), fatigue (16%), dizziness (15%), convulsion (11%), nasopharyngitis (10%), weight increased (10%), upper respiratory tract infection (10%), visual field defect (9%), depression (8%), tremor (7%), nystagmus (7%), nausea (7%), diarrhea (7%), memory impairment (7%), insomnia (7%), irritability (7%), coordination abnormal (7%), vision blurred (6%), diplopia (6%), vomiting (6%), influenza (6%), pyrexia (6%), and rash (6%).

The adverse reactions most commonly associated with SABRIL treatment discontinuation in ≥ 1% of patients were convulsion (1.4%) and depression (1.5%).

Most Common Adverse Reactions in Controlled Clinical Trials

Refractory Complex Partial Seizures in Adults

Table 2 lists the treatment emergent adverse reactions that occurred in ≥ 2% and more than one patient per SABRIL-treated group and that occurred more frequently than in placebo patients from 2 U.S. add-on clinical studies of refractory CPS in adults.

Table 2. Treatment Emergent Adverse Reactions Occurring in ≥ 2% and More than One Patient per SABRIL-Treated Group and More Frequently than in Placebo Patients (Studies 024 and 025)

Body System Preferred Term	SABRIL 3 g/day (N=134) n(%)	SABRIL 6 g/day (N=43) n(%)	Placebo (N=135) n(%)
Ear Disorders
Tinnitus	3 (2)	0 (0)	2 (1)
Vertigo	3 (2)	2 (5)	2 (1)
Eye Disorders
Vision blurred	18 (13)	7 (16)	7 (5)
Diplopia	9 (7)	7 (16)	4 (3)
Asthenopia	3 (2)	1 (2)	0 (0)
Eye pain	0 (0)	2 (5)	0 (0)
Gastrointestinal Disorders
Diarrhoea	14 (10)	7 (16)	10 (7)
Nausea	13 (10)	1 (2)	11 (8)
Vomiting	9 (7)	4 (9)	8 (6)
Constipation	11 (8)	2 (5)	4 (3)
Abdominal pain upper	7 (5)	2 (5)	2 (1)
Dyspepsia	6 (4)	2 (5)	4 (3)
Stomach discomfort	5 (4)	1 (2)	1 (1)
Abdominal pain	4 (3)	1 (2)	2 (1)
Toothache	3 (2)	2 (5)	3 (2)
Abdominal distension	3 (2)	0 (0)	1 (1)
General Disorders
Fatigue	31 (23)	17 (40)	21 (16)
Gait disturbance	8 (6)	5 (12)	9 (7)
Asthenia	7 (5)	3 (7)	2 (1)
Oedema peripheral	7 (5)	3 (7)	1 (1)
Fever	6 (4)	3 (7)	4 (3)
Chest pain	2 (1)	2 (5)	2 (1)
Thirst	3 (2)	0 (0)	0 (0)
Malaise	0 (0)	2 (5)	0 (0)
Infections
Nasopharyngitis	19 (14)	4 (9)	14 (10)
Upper respiratory tract infection	10 (7)	4 (9)	8 (6)
Influenza	7 (5)	3 (7)	5 (4)
Urinary tract infection	5 (4)	2 (5)	0 (0)
Bronchitis	0 (0)	2 (5)	2 (1)
Injury
Contusion	4 (3)	2 (5)	3 (2)
Joint sprain	2 (1)	1 (2)	1 (1)
Muscle strain	1 (1)	1 (2)	2 (1)
Wound secretion	0 (0)	1 (2)	0 (0)
Metabolism and Nutrition Disorders
Increased appetite	2 (1)	2 (5)	1 (1)
Weight increased	8 (6)	6 (14)	4 (3)
Musculoskeletal Disorders
Arthralgia	14 (10)	2 (5)	4 (3)
Back pain	6 (4)	3 (7)	3 (2)
Pain in extremity	8 (6)	1 (2)	5 (4)
Myalgia	4 (3)	2 (5)	2 (1)
Muscle twitching	1 (1)	4 (9)	2 (1)
Muscle spasms	4 (3)	0 (0)	1 (1)
Nervous System Disorders
Headache	44 (33)	11 (26)	42 (31)
Somnolence	29 (22)	11 (26)	18 (13)
Dizziness	32 (24)	11 (26)	23 (17)
Nystagmus	17 (13)	8 (19)	12 (9)
Tremor	20 (15)	7 (16)	11 (8)
Memory impairment	9 (7)	7 (16)	4 (3)
Coordination abnormal	10 (7)	7 (16)	3 (2)
Disturbance in attention	12 (9)	0 (0)	1 (1)
Sensory disturbance	6 (4)	3 (7)	3 (2)
Hyporeflexia	6 (4)	2 (5)	1 (1)
Paraesthesia	9 (7)	1 (2)	1 (1)
Lethargy	6 (4)	3 (7)	3 (2)
Hyperreflexia	5 (4)	1 (2)	4 (3)
Hypoaesthesia	5 (4)	2 (5)	2 (1)
Sedation	5 (4)	0 (0)	0 (0)
Status epilepticus	3 (2)	2 (5)	0 (0)
Dysarthria	3 (2)	1 (2)	1 (1)
Postictal state	3 (2)	0 (0)	1 (1)
Sensory loss	0 (0)	2 (5)	0 (0)
Psychiatric Disorders
Irritability	10 (7)	10 (23)	10 (7)
Depression	8 (6)	6 (14)	4 (3)
Confusional state	5 (4)	6 (14)	1 (1)
Anxiety	6 (4)	0 (0)	4 (3)
Depressed mood	7 (5)	0 (0)	1 (1)
Thinking abnormal	4 (3)	3 (7)	0 (0)
Abnormal behaviour	4 (3)	2 (5)	1 (1)
Expressive language disorder	2 (1)	3 (7)	1 (1)
Nervousness	3 (2)	2 (5)	3 (2)
Abnormal dreams	2 (1)	2 (5)	1 (1)
Reproductive System
Dysmenorrhoea	12 (9)	2 (5)	4 (3)
Erectile dysfunction	0 (0)	2 (5)	0 (0)
Respiratory and Thoracic Disorders
Pharyngolaryngal pain	10 (7)	6 (14)	7 (5)
Cough	3 (2)	6 (14)	9 (7)
Pulmonary congestion	0 (0)	2 (5)	1 (1)
Sinus headache	8 (6)	1 (2)	1 (1)
Skin and Subcutaneous Tissue Disorders
Rash	6 (4)	2 (5)	6 (4)

Post Marketing Experience

The following serious adverse events have been reported since approval and use of SABRIL worldwide. All serious adverse events that are not listed above as adverse events reported in clinical trials, that are not relatively common in the population and are not too vague to be useful are listed in this section. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure. Events are categorized by system organ class.

Birth Defects: Congenital cardiac defects, congenital external ear anomaly, congenital hemangioma, congenital hydronephrosis, congenital male genital malformation, congenital oral malformation, congenital vesicoureteric reflux, dentofacial anomaly, dysmorphism, fetal anticonvulsant syndrome, hamartomas, hip dysplasia, limb malformation, limb reduction defect, low set ears, renal aplasia, retinitis pigmentosa, supernumerary nipple, talipes

Ear: Deafness

Endocrine: Delayed puberty

Gastrointestinal: Gastrointestinal hemorrhage, esophagitis

General: Developmental delay, facial edema, malignant hyperthermia, multi-organ failure

Hepatobiliary: Cholestasis

Nervous System: Dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis

Psychiatric: Acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorder

Respiratory: Laryngeal edema, pulmonary embolism, respiratory failure, stridor

Skin and Subcutaneous Tissue: Angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN). Rare cases of SJS and TEN coincident with SABRIL administration have been reported. These reports involved the coadministration of other medications that include SJS/TEN as part of their prescribing information.

Drug Interactions

For detailed information about Drug Interactions see CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug Interactions (12.3).

Phenytoin

A 16% to 20% average reduction in total phenytoin plasma levels was reported in controlled clinical studies.

Other AEDs

There are no clinically significant pharmacokinetic interactions between SABRIL and either phenobarbital or sodium valproate. Based on population pharmacokinetics, carbamazepine, clorazepate, primidone, and sodium valproate appear to have no effect on plasma concentrations of vigabatrin.

Clonazepam

In a study of 12 healthy volunteers, clonazepam (0.5 mg) co-administration had no effect on SABRIL (1.5 g twice daily) concentrations. SABRIL increases the mean Cmax of clonazepam by 30% and decreases the mean tmax by 45%.

Oral Contraceptives

SABRIL is unlikely to affect the efficacy of steroid oral contraceptives.

Drug-Laboratory Test Interactions

SABRIL decreases alanine transaminase (ALT) and aspartate transaminase (AST) plasma activity in up to 90% of patients. In some patients, these enzymes become undetectable. The suppression of ALT and AST activity by SABRIL may preclude the use of these markers, especially ALT, to detect early hepatic injury.

SABRIL may increase the amount of amino acids in the urine, possibly leading to a false positive test for certain rare genetic metabolic diseases (e.g., alpha aminoadipic aciduria).

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