— Treatment in combination with another anti-epileptic drug for patients with resistant partial epilepsy with or without secondary generalization when all other appropriate drug combinations have proved inadequate or were poorly tolerated.
— Single-agent therapy in the treatment of infantile spasms (West syndrome).

Sabril® treatment may only be initiated by a specialist in epileptology, neurology or pediatric neurology. Follow-up should be carried out under the supervision of a specialist in epileptology, neurology or pediatric neurology.
Sabril® is intended for oral administration once or twice daily and can be taken before or after meals. The tablets should be swallowed with half a glass of water.
If there is no clinically significant improvement in epileptic symptoms following well-conducted initial treatment, vigabatrin must not be continued. Vigabatrin should gradually be withdrawn under close medical supervision.
Tablets are not suitable for children under the age of 6 years, because of the risk of choking.
Adults
Maximum efficacy is usually obtained with a daily dose of 2 to 3 g. A starting dose of 1 g daily should be added to the patient's current anti-epileptic drug regimen. The daily dose must then be increased in 0.5 g increments at weekly intervals depending on clinical response and tolerability. The maximum recommended dose is 3 g/day.
There is no correlation between the plasma concentrations and efficacy. The duration of action of the drug is dependent on the rate of GABA-T resynthesis rather than plasma drug concentrations (see Sections 5.1 and 5.2).
Pediatric population
Treatment of drug-resistant partial epilepsy
The recommended initial dose in newborns, children and adolescents is 40 mg/kg/day. Recommendations in relation to bodyweight for maintenance treatment are as follows:
The maximum recommended dose in each of these bodyweight categories must not be exceeded.
Single-agent therapy in the treatment of infantile spasms (West syndrome).
The recommended initial dosage is 50 mg/kg/day. This dosage may be reached gradually over a period of one week if necessary. Doses of up to 150 mg/kg/day have been well tolerated.
Elderly subjects and patients with renal failure
Since vigabatrin is eliminated via the kidney, special caution should be exercised when administering the drug to the elderly and more particularly in patients with creatinine clearance less than 60 ml/min. Adjustment of dose or frequency of administration must be considered. These patients may respond to a lower maintenance dose. Patients must be closely monitored for possible undesirable effects such as sedation or confusion (see Sections 4.4 and 4.8.).

Except for the treatment of infantile spasms, Sabril® must not be instituted as single-agent therapy.
Visual field defects have been reported in patients receiving vigabatrin with a high prevalence (about 1/3 of patients). The incidence of visual field defects (VFD) determined in an open-label clinical study are presented in Section 5.1. These disorders generally occur months to years after starting vigabatrin therapy. The degree of visual field narrowing may be significant and this may have practical consequences for the patient. Most patients with perimetry-confirmed defects are asymptomatic. This undesirable effect can therefore only be reliably detected by systematic perimetry which is usually possible only in patients with a developmental age of more than 9 years. A specially developed method based on field specific Visual Evoked Potentials (VEP) is available from the Company on request to assess peripheral vision in children aged 3 years and older. At present this method has not been validated for the detection of vigabatrin-related visual field defects. Electroretinography may be useful but should be used only in adults who are unable to cooperate with perimetry or in very young children (see Visual Field Defects). Available data suggest that visual field defects are irreversible even after discontinuation of vigabatrin. Worsening of VFD after treatment discontinuation cannot be ruled out. Therefore, vigabatrin should only be used after careful assessment of the benefits and risks compared with available therapeutic alternatives.
Vigabatrin is not recommended for use in patients with any pre-existing clinically significant visual field defect. Patients should undergo systematic screening examinations from the start of vigabatrin treatment, then at regular intervals to detect visual field defects. Visual field testing should continue at 6-month intervals for the whole duration of treatment (see Visual Field Defects).
Visual Field Defects (VFD)
Based on available data, the usual pattern of visual field defects is a concentric bilateral narrowing of the visual field, which is generally more marked nasally than temporally. In the central visual field (within 30 degrees of eccentricity), frequently an annular nasal defect is seen. However, the VFDs reported in patients receiving vigabatrin have ranged from mild to severe. Severe cases are potentially disabling.
Most patients with perimetry-confirmed defects had not spontaneously noticed any symptoms beforehand, even in cases where a severe defect was observed in perimetry. Available evidence suggests that the VFDs are irreversible even after discontinuation of vigabatrin. A worsening of the VFD after treatment discontinuation cannot be ruled out.
Pooled data from prevalence surveys suggest that as many as 1/3 of patients receiving vigabatrin therapy have VFDs. Men may be at greater risk than women. The incidence of VFDs observed in an open-label clinical study are presented in Section 5.1. The study showed a possible relationship between the risk of visual field defects and the extent of vigabatrin exposure, in terms of daily dose (from 1 g to more than 3 g) and duration of treatment (maximum during the first three years).
All patients must be referred to an ophthalmologist for a visual field examination before the initiation of vigabatrin treatment.
Appropriate visual field testing (perimetry) using standard static perimetry (Humphrey or Octopus) or kinetic perimetry (Goldmann) must be performed before treatment initiation then at six-month intervals for the whole duration of treatment. Static perimetry is the preferred method for detecting vigabatrin-associated visual field defects.
Electroretinography may be useful but must only be used in adults who are unable to cooperate with perimetry. Based on the available data, the first oscillatory potential and 30 Hz flicker responses of the electroretinogram appear to be correlated with vigabatrin-related VFDs. These responses are delayed and of lower amplitude than normal. Such changes have not been seen in vigabatrin-treated patients without VFDs.
The patient and/or family and friends must be given thorough information on the frequency and implications of the development of VFDs during vigabatrin treatment. Patients should be instructed to report any new visual problems and symptoms which may be associated with visual field narrowing. If visual symptoms develop, the patient should be referred to an ophthalmologist.
If visual field narrowing is observed during follow-up, gradual discontinuation of vigabatrin treatment should be considered. If it is decided to continue treatment, more frequent follow-up (perimetry) should be considered in order to detect progression of the narrowing or potentially sight-threatening defects.
Vigabatrin must not be used concomitantly with other retinotoxic drugs.
Pediatric population
Perimetry is seldom possible in children with a developmental age of less than 9 years. The risks of treatment must be very carefully weighed against the possible benefit in children. Currently, there is no established method to diagnose or rule out visual field defects in children in whom standard perimetry cannot be performed. A specially developed method based on field specific Visual Evoked Potentials (VEP) is available from the Company on request to assess peripheral vision in children aged 3 years and older. At present this method has not been validated for the detection of vigabatrin-related visual field defects. If the method reveals normal central visual field response but no peripheral response, the benefit versus risk of vigabatrin must be reassessed and gradual discontinuation considered. Peripheral vision does not rule out the possibility of developing VFDs.
Electroretinography may be useful but must be used only in children under 3 years of age.
Neurological and psychiatric conditions
In view of the results from animal safety studies (see Section 5.3), it is recommended that patients treated with vigabatrin be closely monitored for neurological adverse effects.
Rare reports of encephalopathic symptoms such as marked sedation, stupor and confusion associated with non- specific slow wave activity on electroencephalogram have been described soon after the initiation of vigabatrin treatment. Risk factors for the development of these reactions include administration of a higher-than- recommended starting dose, faster dose escalation and/or dose escalation using higher levels than recommended, and also renal failure. These effects have proved to be reversible following dose reduction or discontinuation of vigabatrin (see Section 4.8).
Cases of abnormal brain MRI findings have been reported, in particular in young children treated for infantile spasms with high doses of vigabatrin. The clinical significance of these findings is currently unknown.
Movement disorders including dystonia, dyskinesia and hypertonia, have been reported in patients treated for infantile spasms. The benefit/risk of vigabatrin should be evaluated on an individual patient basis. If new movement disorders occur during treatment with vigabatrin, dose reduction or gradual treatment discontinuation should be considered.
As with other antiepileptic drugs, some patients taking vigabatrin may experience an increase in seizure frequency or the onset of new types of seizures (see Section 4.8.). These effects may also occur as a result of an overdose, a decrease in plasma concentrations of concomitant antiepileptic treatment, or a paradoxical effect.
As with other antiepileptic drugs, abrupt withdrawal may lead to rebound seizures. If vigabatrin treatment is to be discontinued, it is recommended to do so by gradual dose reduction over a 2 to 4-week period.
Vigabatrin must be used with caution in patients with a history of psychosis, depression or behavioral disorders. Adverse psychiatric effects (e.g., agitation, depression, abnormal ideation, paranoid reactions) have been reported during vigabatrin treatment. These reactions occurred in patients with or without a psychiatric history, and were usually reversible when vigabatrin doses were reduced or gradually discontinued.
Suicide risk
Suicidal ideation and behavior have been reported in patients receiving antiepileptic treatment in various indications. A meta-analysis of randomized, placebo-controlled studies of antiepileptic drugs also showed a slight increase in the risk of suicidal ideation and behavior. The causes of the risk are unknown and the possibility of an increased risk with vigabatrin cannot be ruled out based on available data.
Patients must therefore be closely monitored for any signs of suicidal ideation or behavior and appropriate treatment considered. Patients (and their care-givers) should be advised to seek medical advice if signs of
suicidal ideation and behavior occur.
Elderly subjects and patients with renal failure
Since vigabatrin is eliminated via the kidney, particular caution should be exercised in patients with creatinine clearance of less than 60 ml/min and in elderly subjects. These patients must be monitored closely for undesirable effects such as sedation and confusion (see Section 4.2).

As vigabatrin is neither metabolized, nor protein bound and is not an inducer of hepatic cytochrome P450 drug metabolizing-enzymes, interactions with other drugs are unlikely. During controlled clinical studies, a gradual reduction of 16 to 33% in phenytoin plasma concentrations was sometimes observed. The exact mechanism underlying this interaction is not known; however, in the majority of cases, it had no clinical impact.
The plasma concentrations of carbamazepine, phenobarbital, and sodium valproate have also been monitored during controlled clinical trials and no clinically significant interactions have been detected.
Vigabatrin may lead to decreased plasma alanine aminotransferase (ALT) levels, and to a lesser extent, to decreased aspartate aminotransferase (AST) levels. The decrease in ALT levels was between 30% and 100%. Therefore, these liver tests may be quantitatively unreliable in patients taking vigabatrin (see Section 4.8).
Vigabatrin may cause an increase in amino acid levels in the urine possibly leading to false positive results when testing for certain rare genetic metabolic disorders (e.g., alpha-aminoadipic aciduria).

Pregnancy
Risks related to epilepsy and anti-epileptics in general
In children born to mothers treated with anti-epileptic drugs, the prevalence of malformations is 2 to 3 times higher than in the general population. The most frequently reported malformations are cleft lip, cardiovascular malformations and neural tube defects.
Treatment combining several anti-epileptic drugs could be associated with a higher risk of congenital malformations than single-agent therapy. Single-agent therapy should therefore be used whenever possible.
Medical advice should be given to women starting a pregnancy or of child-bearing age. The need for antiepileptic treatment must be re-evaluated when a woman is considering pregnancy. In the event of pregnancy in women treated for epilepsy, sudden interruption of antiepileptic treatment should be avoided, as it may lead to an increase in seizures, which could have serious consequences for the women and the fetus.
Risks related to vigabatrin
Data on exposure to vigabatrin during pregnancy from spontaneous notifications showed cases of defects in the offspring of mothers taking vigabatrin (congenital defects or spontaneous abortions). Due to limited available data and concomitant administration of other antiepileptic medication during the reported pregnancies, no definitive conclusion can be drawn regarding a possibly increased teratogenic effect with the use of vigabatrin during pregnancy.
Studies in animals have demonstrated that vigabatrin has reproductive toxicity (see Section 5.3). Sabril® should only be used during pregnancy if absolutely necessary.
There is very little available data on the possibility of a visual field defect occurring in children exposed to vigabatrin in utero.
Breast-feeding
Vigabatrin is excreted in breast milk. Data on the effects of vigabatrin on newborns and infants are currently insufficient. The decision to either stop breast-feeding or to stop or not take Sabril® treatment should be made by considering the benefit of breast-feeding for the child compared to the benefit of the treatment for the mother.
Fertility
Fertility studies in rats did not show any effects on fertility in males or females (see Section 5.3).

As a general rule, patients with uncontrolled epilepsy are not able to drive or handle potentially dangerous machinery. As drowsiness has been observed in clinical trials with Sabril®, patients must be informed of this risk at the start of treatment.
Visual field defects which can significantly affect the ability to drive and use machines have frequently been reported with Sabril®. Patients should be examined for visual field defects (see Section 4.4). Special care should be taken by patients who drive, operate machinery or perform any hazardous task.

Summary of safety data
Mild to severe visual field defects have frequently been reported in patients receiving vigabatrin. Severe cases are potentially disabling. These reactions usually occur months to years after starting vigabatrin therapy. Pooled data from prevalence surveys suggest that as many as 1/3 of patients receiving vigabatrin therapy develop visual field defects (see Section 4.4).
Approximately 50% of patients in controlled clinical studies experienced undesirable effects during vigabatrin treatment. In adults, these were mostly central nervous system-related such as sedation, drowsiness, fatigue and impaired concentration. However, in children, excitation or agitation is frequent. The incidence of these undesirable effects is generally higher at the beginning of treatment and decreases with time.
As with other antiepileptic drugs, some patients treated with vigabatrin may experience an increase in seizure frequency, or even status epilepticus. Patients with myoclonic seizures are particularly likely to have these reactions. New-onset myoclonus and exacerbation of existing myoclonus have been observed in rare cases..
Summary table of undesirable effects:
Undesirable effects are ranked in order of incidence as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); frequency not known
(cannot be estimated from the available data).
* Psychiatric reactions have been reported during vigabatrin therapy. These reactions occurred in patients with and without a psychiatric history and were generally reversible when vigabatrin doses were reduced or treatment gradually discontinued (see Section 4.4). Depression was a commonly observed psychiatric reaction in clinical trials but seldom required discontinuation of vigabatrin.
** Rare reports of encephalopathic symptoms such as marked sedation, stupor and confusion associated with non-specific slow wave activity on electroencephalogram have been described soon after the initiation of vigabatrin treatment. Such reactions have proved to be fully reversible following dose reduction or discontinuation of vigabatrin (see Section 4.4).
***Laboratory data indicate that vigabatrin treatment does not lead to renal toxicity. Decreases in ALT and AST, which are considered to be a result of inhibition of these aminotransferases by vigabatrin, have been observed.
Pediatric population:
Psychiatric disorders
• Very common: excitation, agitation
To report any side effect(s):
• Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc
• Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com

Symptoms
Some cases of vigabatrin overdose have been reported. When known, doses were most commonly between 7.5 and 30 g; however, overdoses up to 90 g have also been reported. Nearly half of the cases involved multiple-drug overdose. The most commonly reported symptoms include drowsiness or coma.
Other symptoms were less frequently reported and included dizziness, headache, psychosis, respiratory depression or apnea, bradycardia, hypotension, agitation, irritability, confusion, behavioral disorders, and speech disorders. None of the cases of overdose was fatal.
Management
There is no specific antidote. The usual symptomatic measures should be employed. Measures to remove unabsorbed drug must be considered. In an in vitro study, activated charcoal was shown not to significantly adsorb vigabatrin. The effectiveness of hemodialysis in the treatment of vigabatrin overdose is unknown. In isolated case reports in renal failure patients receiving therapeutic doses of vigabatrin, hemodialysis reduced plasma vigabatrin concentrations by 40% to 60%.

Antiepileptics, ATC code: N03AG04, (N: Central nervous system)
Vigabatrin is an antiepileptic drug with a clearly defined mechanism of action. Treatment with vigabatrin leads to an increase in the concentration of GABA (gamma aminobutyric acid), the major inhibitory neurotransmitter in the brain. Vigabatrin is a selective irreversible inhibitor of GABA-transaminase, the enzyme responsible for the catabolism of GABA.
Controlled and long-term clinical trials have shown that vigabatrin is an effective anticonvulsant agent when given as supportive therapy in patients with epilepsy not controlled satisfactorily by conventional therapy. This efficacy is particularly marked in patients with partial seizures.
The epidemiology of VFD in patients with refractory partial epilepsy was examined in an observational, open- label, multicenter, comparative, parallel group, Phase IV study, including 734 patients, at least 8 years old, with refractory partial epilepsy for at least one year.
Patients were divided into three treatment groups: patients currently treated with vigabatrin (group I), patients previously exposed to vigabatrin (group II) and patients never exposed to vigabatrin (group III).
The following table presents the main findings at inclusion and at the first and last evaluations in the evaluable population (n=524):

 

Absorption
Vigabatrin is a water-soluble compound and it is rapidly and completely absorbed from the gastrointestinal tract. Food intake does not alter vigabatrin absorption. The time needed to reach peak plasma concentrations (tmax) is approximately 1 hour.
Distribution
The drug is widely distributed with an apparent volume of distribution slightly greater than total body water. Plasma and cerebrospinal fluid concentrations are dose-proportional over the recommended dose range.
Biotransformation
Vigabatrin is not significantly metabolized. No metabolites have been identified in the plasma.
Elimination
Vigabatrin is eliminated by renal excretion, with a terminal elimination half-life of 5 to 8 hours. Oral clearance (CL/F) is approximately 7 Lh (i.e. 0.10 L/h/kg). Approximately 70% of a single oral dose is excreted unchanged in the urine 24 hours post-dose.
Vigabatrin does not induce the hepatic cytochrome P450 enzymes nor is it metabolized or protein bound. Therefore, drug interactions are unlikely.
Pharmacokinetic/pharmacodynamic relationship
There is no direct correlation between plasma concentrations and efficacy. The duration of action of the drug is dependent on the GABA-T resynthesis rate.
Pediatric population
The pharmacokinetic properties of vigabitrin were studied in groups of six newborns (aged 15 to 26 days), six infants (5 to 22 months) and six children (4.6 to 14.2 years) with resistant epilepsy. After administration of a single
dose of 37-50 mg/kg of vigabatrin as an oral solution, the tmax was approximately 2.5 hours in the newborns,
5.7 hours in the infants and 5.5 hours in the children. The mean CL/F of the active S enatiomer in vigabatrin in infants and children was 0.591 L/h/kg and 0.446 L/h/kg, respectively. Vigabatrin is a water-soluble compound and it is rapidly and completely absorbed from the gastrointestinal tract.

Animal safety studies carried out in rats, mice, dogs and monkeys have indicated that vigabatrin has no significant adverse effects on the liver, kidney, lung, heart or gastrointestinal tract.
In the brain, microvacuolation has been observed in the white matter of rats, mice and dogs at doses of 30 to 50 mg/kg/day. In monkeys, these lesions are minimal or debatable. This effect is caused by detachment of the outer lamellar layer of myelinated fibers, a change characteristic of intramyelinic edema. In both rats and dogs, the intramyelinic edema was reversible on stopping vigabatrin treatment and even with continued treatment, histologic regression was observed. However, in rodents, minor residual changes consisting of swollen axons (eosinophilic spheroids) and mineralized microbodies have been observed. In dogs, the results of an electrophysiological study indicate that intramyelinic edema is associated with an increase in the latency of the sensory evoked potential which is reversible when the drug is discontinued.
Vigabatrin-associated retinotoxicity has been observed in albino rats, but not in pigmented rats, dogs or monkeys. The retinal changes in albino rats were characterized by focal or multifocal disorganization of the outer nuclear layer with displacement of nuclei into the layer of rods and cones. The other layers of retina were not affected. These lesions were observed in 80 to 100% of animals at the dose of 300 mg/kg/day orally. The histologic appearance of these lesions was similar to that found in albino rats following excessive exposure to light. However, the retinal changes may also be a direct drug-induced effect.
Animal experiments have shown that vigabatrin has no negative influence on fertility or development of the young. No teratogenicity was seen in rats treated with doses up to 150 mg/kg (3 times the dose in humans) or in rabbits treated with doses up to 100 mg/kg. However, in rabbits, a slight increase in the incidence of cleft palate was seen at doses of 150 to 200 mg/kg.
Studies with vigabatrin revealed no evidence of mutagenic or carcinogenic effects.

Tablet core: povidone K30 (E1201), microcrystalline cellulose (E460), sodium starch glycolate (Type A), magnesium stearate.
Film-coating: Opadry®, white, OY-S-7298 [hypromellose 15 mPa.s (E464), titanium dioxide (E171), macrogol 8000].

NA

Do not store above 30°C

Transparent, heat-formed (PVC/Aluminum) blister packs containing 10 film-coated tablets or opaque blue, heat- formed (PVC/Aluminum) blister packs containing 10 tablets, in boxes of 30, 50, 60, 100 or 200 tablets.
Some pack sizes may not be marketed.

No special requirements.