Special Warning : אזהרת שימוש

4.4      Special Warnings and precautions for use

Sabrilan should not be instituted as monotherapy.
Visual Field Defects (VFD)
Based on available data, the usual pattern is a concentric constriction of the visual field of both eyes, which is generally more marked nasally than temporally. In the central visual field (within 30 degree 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 may be characterized by tunnel vision. Blindness was also reported in severe cases.

Most patients with perimetry confirmed defects had not previously spontaneously noticed any symptoms, even in cases where a severe defect was observed in perimetry.
Available evidence suggests that the VFD is irreversible even after discontinuation of vigabatrin. A deterioration of VFD after the treatment is discontinued cannot be excluded.

Pooled data from prevalence surveys suggest that as many as 1/3 of patients receiving vigabatrin therapy have VFDs. Males may be at greater risk than females. Frequencies found in an open clinical study are presented in section 5.1. A possible association between the risk of visual field defects and the extent of vigabatrin exposure,both in terms of daily dose (from 1 gram to more than 3 grams) and in terms of duration of treatment (maximum during the first three years) has been shown in this study.

All patients should have ophthalmological consultation with visual field examination before the initiation of vigabatrin treatment.

Appropriate visual field testing (perimetry) by using a standardised static perimetry (Humphrey or Octopus) or kinetic perimetry (Goldmann) must be performed before treatment initiation and at six month intervals for the whole duration of treatment. Static perimetry is the preferred method for detecting vigabatrin associated visual field defect.

Electroretinography may be useful but should 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 a vigabatrin associated VFD. These responses are delayed and reduced beyond the normal limits. Such changes have not been seen in vigabatrin treated patients without a VFD. The patient and/or caregiver must be given a thorough description of the frequency and implications of the development of VFD during vigabatrin treatment. Patients should be instructed to report any new visual problems and symptoms which may be associated with visual field constriction. If visual symptoms develop, the patient should be referred to an ophthalmologist.

If a visual field constriction is observed during follow-up, consideration should be given to gradual discontinuation of vigabatrin. If the decision to continue treatment is made, consideration should be given to more frequent follow-up (perimetry) in order to detect progression or sight threatening defects.

Vigabatrin should not be used concomitantly with other retinotoxic drugs.

Paediatric population
Perimetry is seldom possible in children less than 9 years of developmental age. The risks of treatment must be very carefully weighed against possible benefit in children. Currently, there is no established method to diagnose or exclude visual field defects in children in whom a standardised perimetry cannot be performed. A specifically developed method based on field specific Visual Evoked Potentials (VEP) is available from the company on request to test the presence of peripheral vision in children aged 3 years and above. At present this method has not been validated in the detection of vigabatrin-attributed visual field defects. If the method reveals normal central visual field response but an absent peripheral response, benefit-risk of vigabatrin must be reviewed and consideration given to gradual discontinuation. The presence of peripheral vision does not exclude the possibility of developing VFD. Electroretinography may be useful but should be used only in children less than 3 years of age.


Visual acuity
The prevalence of reduced visual acuity in vigabatrin treated patients is unknown.
Retinal disorder, blurred vision, optic atrophy or optic neuritis may lead to decrease in visual acuity (see section 4.8). Visual acuity should be assessed during ophthalmological consultations, before initiation of vigabatrin treatment and at six-month intervals during treatment.

Neurological and psychiatric conditions
In view of the results of the animal safety studies (see section 5.3), it is recommended that patients treated with vigabatrin are closely observed for adverse effects on neurological function.

Rare reports of encephalopathic symptoms such as marked sedation, stupor and confusion in association with nonspecific slow wave activity on electroencephalogram have been described soon after the initiation of vigabatrin treatment. Risk factors for the development of these reactions include higher than recommended starting dose, faster dose escalation at higher steps than recommended, and renal failure. These events have been 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 infants treated for infantile spasms with high doses of vigabatrin. The clinical significance of these findings is currently unknown.
Additionally, cases of intramyelinic oedema (IME) have been reported, particularly in infants treated for infantile spasms (see section 4.8 and 5.3). IME has been reported to be reversible following drug discontinuation, and it is therefore recommended to progressively discontinue vigabatrin when IME is observed.

As with other antiepileptic drugs, some patients may experience an increase in seizure frequency or the onset of new types of seizures with vigabatrin (see section 4.8). These phenomena may also be the consequence 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 a patient is to be withdrawn from vigabatrin treatment, it is recommended that this is done by gradual dose reduction over a 2 to 4-week period.

Vigabatrin should be used with caution in patients with a history of psychosis, depression or behavioural problems. Psychiatric events (e.g., agitation, depression, abnormal thinking, paranoid reactions) have been reported during vigabatrin treatment. These events occurred in patients with and without a psychiatric history, and were usually reversible when vigabatrin doses were reduced or gradually discontinued.
Suicidal ideation and behaviour

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised, placebo-controlled trials of antiepileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this effect is not known and the available data do not exclude the possibility of an increased risk for vigabatrin.
Therefore, patients should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice immediately should signs of suicidal ideation or behaviour emerge.

Older people and patients with renal impairment

Since vigabatrin is eliminated via the kidney, caution should be exercised in patients with a creatinine clearance of less than 60 ml/min and in older people. These patients should be monitored closely for undesirable effects such as sedation and confusion. (see section 4.2).

Interactions to be taken into account
The concomitant use of vigabatrin and clonazepam may exacerbate the sedative effect (see section 4.5). Need for concomitant use must be carefully assessed.

Effects on Driving

4.7      Effects on ability to drive and use machines
As a general rule, patients with uncontrolled epilepsy are not allowed to drive or handle potentially dangerous machinery. In view of the fact that drowsiness has been observed in clinical trials with Sabrilan, patients should be warned of this possibility at the start of treatment.

Visual field defects which can significantly affect the ability to drive and use machines have been frequently reported in association with Sabrilan. Patients should be evaluated for the presence of visual field defect (see also section 4.4). Special care should be taken by patients driving, operating machinery or performing any hazardous task.