KIGABEQ Soluble tablet Ref.[9297] Active ingredients: Vigabatrin

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 presented in section 4.8. The onset is usually after months to years of vigabatrin therapy. The degree of visual field constriction may be severe and this may have practical consequences for the patient. Vigabatrin can cause permanent vision loss.

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. For younger patients electroretinography should be used (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 careful benefit/ risk assessment 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. Visual field testing should continue at 6 month intervals for the whole duration of treatment. The assessment must be continued 6 to 12 months after the discontinuation of therapy (see Visual Field Defects).

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 are potentially disabling.

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 4.8. 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 before or shortly after the initiation of vigabatrin treatment.

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. Frequency and severity have only been indirectly characterised in this population on the presence of electroretinogram or visual evoked potential anomalies.

Electroretinography is recommended in infants and children 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 parents and/or caregivers must be given a thorough description of the frequency and implications of the development of VFD during vigabatrin treatment. VFD may not be detected until it is severe and undetected moderate defects may affect child integrity. Therefore, vision assessment is required at baseline (no later than 4 weeks after starting treatment) and at least every 6 months while on therapy. The assessment must be continued 6 to 12 months after the discontinuation of therapy.

Available data suggests that visual field defects are irreversible.

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 medicinal products.

Neurologic 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 reactions 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).

Abnormal Magnetic Resonance Imaging signals

Abnormal Magnetic Resonance Imaging (MRI) signal changes characterised 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 with vigabatrin for infantile spasms. In a retrospective epidemiologic study in infants with infantile spasms (N=205), the prevalence of these changes was 22% in vigabatrin treated patients versus 4% 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.

Movement disorders including dystonia, dyskinesia and hypertonia, have been reported in patients treated with vigabatrin for infantile spasms. The benefit/risk ratio 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.

Some patients may experience an increase in seizure frequency or the onset of new types of seizures with vigabatrin (see section 4.8). Patients with myoclonic seizures may be particularly susceptible to this effect. New onset myoclonus and exacerbation of existing myoclonus may occur in rare cases. These phenomena may also be the consequence of an overdose, a decrease in plasma concentrations of concomitant antiepileptic treatment, or a paradoxical effect.

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 medicinal products 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 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.

Renal impairment

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

Interference with serological testing

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).

Risk of medication error

Because both tablet strengths (100 mg and 500 mg) can be used concomitantly there may be confusion between the tablets or tablet halves administered with a risk of incorrect dosing. Special attention should be paid to the tablet size to correctly identify the strength.

Interaction studies have only been performed in adults.

As vigabatrin is neither metabolised, nor protein bound and is not an inducer of hepatic cytochrome P450 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.

Pregnancy

This medicinal product is not intended for use in women of child-bearing potential.

Breastfeeding

This medicinal product is not intended for use in women who are breastfeeding.

Fertility

Fertility studies in rats have shown no effect on male and female fertility (see section 5.3).

Kigabeq has major influence on the ability to perform hazardous activities.

In view of the fact that drowsiness has been observed in clinical trials with vigabatrin, patients should be warned of this possibility at the start of treatment. Visual field defects which can significantly affect the ability to perform hazardous activities have been frequently reported in association with vigabatrin. Patients should be evaluated for the presence of visual field defects (see also section 4.4). Special care should be taken with young patients cycling, climbing or performing any other hazardous activity.

Summary of the safety profile

The most commonly reported adverse reaction related to vigabatrin are visual field defects (ranging from mild to severe and occurring usually after months to years of vigabatrin therapy), psychiatric disorders such as agitation, excitation, aggression, nervousness, depression, paranoid reaction, nervous system disorders such as marked sedation, stupor and confusion. Rarely seen events include suicide attempts, encephalopathy and retinal disorders.

Some patients may experience an increase in seizure frequency, including status epilepticus with vigabatrin. Patients with myoclonic seizures may be particularly susceptible to this effect. New onset myoclonus and exacerbation of existing myoclonus may occur in rare cases.

Tabulated list of adverse reactions

The adverse reactions listed below have been reported during pre- or post-approval use of vigabatrin worldwide. They are not specific to the paediatric population.

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).

Blood and lymphatic system disorders

Common: anaemia

Psychiatric disorders*

Common: agitation, aggression, nervousness, depression, paranoid reaction

Uncommon: hypomania, mania, psychotic disorder

Rare: suicide attempt

Very rare: hallucination

Nervous system disorders

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: brain MRI abnormalities. movement disorders, including dystonia, dyskinesia and hypertonia, either alone or in association with abnormalities in MRI

Eye disorders

Very common: visual field defect

Common: vision blurred, diplopia, nystagmus

Rare: retinal disorder (such as peripheral retinal atrophy)

Very rare: optic atrophy

Gastrointestinal disorders

Common: nausea, vomiting, abdominal pain

Hepato-biliary disorders

Very rare: hepatitis

Skin and subcutaneous tissue disorders

Uncommon: rash

Rare: angioedema, urticaria

Musculoskeletal and connective tissue disorders

Very common: arthralgia

General Disorders and administration site conditions

Very common: fatigue

Common: oedema, irritability

Investigations

Common: weight increased

Visual field defects

Epidemiology of VFD in patients with refractory partial epilepsy was observed in an observational, open-label, multicentre, 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 split in 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 the first and last conclusive evaluations in the evaluable population (n=524):

¹ Median treatment duration: 44.4 months, mean daily dose 1.48 g
² Median treatment duration: 20.6 months, mean daily dose 1.39 g
³ Median treatment duration: 48.8 months, mean daily dose 2.10 g
⁴ Median treatment duration: 23.0 months, mean daily dose 2.18 g

Description of selected adverse reactions

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 significance.

Asymptomatic and transient Magnetic Resonance Imaging (MRI) abnormalities in the brain have been observed in some infants treated with vigabatrin for infantile spasms. The clinical significance of these MRI abnormalities is unknown. As routine MRI surveillance of this paediatric population is not recommended, the frequency of MRI abnormalities cannot be reliably estimated from the available data. Movement disorders either alone or in association with abnormalities in MRI have been reported in patients treated with vigabatrin for infantile spasms but their frequency is not known.

Paediatric population

Psychiatric disorders

Very common: excitation, agitation

Reporting of suspected adverse reactions

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 the national reporting system listed in Appendix V.

Not applicable.