Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Aventis Pharma Limited, 410 Thames Valley Park Drive, Reading, Berkshire. RG6 1PT, UK Trading as: Sanofi, 410 Thames Valley Park Drive, Reading, Berkshire. RG6 1PT, UK
Hypersensitivity to vigabatrin or to any of the excipients listed in section 6.1.
Except for the treatment of infantile spasms, Sabril should not be initiated as monotherapy.
Visual field defects (VFD) have been reported in patients receiving vigabatrin with a high prevalence (about ⅓ of patients). Frequencies found in an open clinical study are present in section 5.1. The onset is usually after months to years of vigabatrin therapy. The degree of visual field restriction may be severe. Most of the patients with perimetry-confirmed defects have been asymptomatic. Hence, this undesirable effect can only be reliably detected by systematic perimetry which is usually possible only in patients with a developmental age of more than 9 years. 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. Electroretinography may be useful but should be used only in adults who are unable to cooperate with perimetry or in the very young (see Visual Field Defects).
Available data suggests that visual field defects are irreversible even after discontinuation of vigabatrin. A deterioration of VFD after the treatment is discontinued cannot be excluded.
Therefore, vigabatrin should only be used after a careful assessment of the balance of benefits and risk compared with alternatives.
Vigabatrin is not recommended for use in patients with any pre-existing clinically significant visual field defect.
Patients should undergo systematic screening examination when starting vigabatrin and at regular intervals for detection of visual field defects and reduced visual acuity. Visual field testing and assessment of visual acuity should continue at 6 month intervals for the whole duration of treatment (see Visual Field Defects and Visual Acuity).
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 ⅓ 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.
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.
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.
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 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 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 MRIs 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.
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, consideration should be given to dose reduction or a gradual discontinuation of treatment.
As with other antiepileptic medicinal products 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 medicinal products, 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 have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of antiepileptic medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this effect is not known (see Section 4.8 Undesirable effects.
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.
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).
The concomitant use of vigabatrin and clonazepam may exacerbate the sedative effect (see section 4.5). Need for concomitant use must be carefully assessed.
As vigabatrin is neither metabolised, nor protein bound and is not an inducer of hepatic cytochrome P450 drug metabolising-enzymes, interactions with other medicinal products are unlikely. However, during controlled clinical studies, a gradual reduction of 16-33% in the plasma concentration of phenytoin has been observed. The exact nature of this interaction is presently not understood, however, in the majority of cases it is unlikely to be of therapeutic significance.
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 a decrease in measured plasma activity of alanine aminotransferase (ALT) and to a lesser extent, aspartate aminotransferase (AST). The magnitude of suppression for ALT has been reported to vary between 30% and 100%. Therefore, these liver tests may be quantitatively unreliable in patients taking vigabatrin. (see section 4.8)
Vigabatrin may increase the amount of amino acids in the urine possibly leading to a false positive test for certain rare genetic metabolic disorders (e.g., alpha aminoadipic aciduria).
The concomitant use of vigabatrin and clonazepam may exacerbate the sedative effect (see Section 4.4).
In the offspring of women treated with antiepileptic medication, the prevalence of malformations is two to three times greater than in the general population. Most frequently reported are cleft lip, cardiovascular malformations and neural tube defects. Polytherapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is important that monotherapy is practiced whenever possible.
Specialist advice should be provided to all patients who could begin a pregnancy or who are in the fertile age. The need of antiepileptic treatment must be re-evaluated when a patient plans a pregnancy.
If a patient becomes pregnant, effective antiepileptic therapy should not be suddenly interrupted, since the aggravation of the illness may be detrimental to both the mother and the foetus.
Based on data on pregnancies exposed to vigabatrin, available from spontaneous reports, abnormal outcomes (congenital anomalies or spontaneous abortion) were reported in the offspring of mothers taking vigabatrin. No definite conclusion can be drawn as to whether vigabatrin produces an increased risk of malformation when taken during pregnancy because of limited data and the presence of concomitant antiepileptics.
Studies in animals have shown reproductive toxicity (see section 5.3).
Sabril should not be used during pregnancy unless the clinical condition of the woman requires treatment with vigabatrin.
There is limited amount of information on the possible occurrence of visual field defect in children who have been exposed to vigabatrin in utero.
Vigabatrin is excreted into human milk. There is insufficient information on the effects of vigabatrin in newborns/infants. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Sabril therapy taking into account the benefit to breast-feeding for the child and the benefit therapy for the woman.
Fertility studies in rats have shown no effect on male and female fertility (see section 5.3).
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 Sabril, 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 Sabril. 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.
Visual field defects ranging from mild to severe have been reported frequently in patients receiving vigabatrin. Severe cases are potentially disabling. The onset is usually after months to years of vigabatrin therapy. Pooled data from prevalence surveys suggest that as many as ⅓ of patients receiving vigabatrin therapy develop visual field defects (see also section 4.4).
Approximately 50% of patients in controlled clinical studies have 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 may experience an increase in seizure frequency, including status epilepticus with vigabatrin. Patients with myoclonic seizures may be particularly liable to this effect. New onset myoclonus and exacerbation of existing myoclonus may occur in rare cases.
Undesirable effects ranked under headings of frequency are listed below, using the following convention:
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); not known (cannot be estimated from the available data).
Common: anaemia
Common: agitation, aggression, nervousness, depression, paranoid reaction, insomnia
Uncommon: hypomania, mania, psychotic disorder
Rare: suicide attempt
Very rare: hallucination
Very common: somnolence
Common: speech disorder, headache, dizziness, paraesthesia, disturbance in attention and memory impairment, mental impairment (thought disturbance), tremor
Uncommon: coordination abnormal (ataxia)
Rare: encephalopathy**
Very rare: optic neuritis
Not known: Cases of brain MRI abnormalities have been reported (see section 4.4). Movement disorder, including dystonia, dyskinesia and hypertonia have been reported, either alone or in association with abnormalities in MRI (see section 4.4).
Very common: visual field defect
Common: vision blurred, diplopia, nystagmus
Rare: retinal disorder (mainly peripheral)
Very rare: optic atrophy
Not known: Reduced visual acuity
Common: nausea, vomiting, abdominal pain
Very rare: hepatitis
Common: alopecia
Uncommon: rash
Rare: angioedema, urticaria
Very common: arthralgia
Very common: fatigue
Common: oedema, irritability
Common: weight increased
* Psychiatric reactions have been reported during vigabatrin therapy. These reactions occurred in patients with and without a psychiatric history and were usually reversible when vigabatrin doses were reduced or gradually discontinued (see section 4.4). Depression was a common psychiatric reaction in clinical trials but seldom required discontinuation of vigabatrin.
** Rare reports of encephalopathic symptoms such as marked sedation, stupor and confusion in association with non-specific slow wave activity on electroencephalogram have been described soon after the initiation of vigabatrin treatment. Such reactions have been 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. Chronic treatment with vigabatrin may be associated with a slight decrease in haemoglobin which rarely attains clinical significance.
Very common: excitation, agitation
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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