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Drug Details

SABRIL

• Drug Class Description
  GABA analogues (anticonvulsants / anti-epileptics).
• Generic Name
  Vigabatrin
• Presentation
  Film-coated tablet: White to off-white, oval, biconvex, tablets with a break-line on one side and “Sabril” engraved on the other side. The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses. Granules for oral solution: White to off-white granular powder.
• Description
  Each sachet or tablet contains 500mg vigabatrin
• Indications
  Treatment in combination with other anti-epileptic drugs for patients with resistant partial epilepsy with or without secondary generalisation, that is where all other appropriate drug combinations have proved inadequate or have not been tolerated. Monotherapy in the treatment of infantile spasms (West's syndrome).
• Adult Dosage
  

  Sabril treatment may only be initiated by a specialist in epileptology, neurology or paediatric neurology. Follow-up should be arranged under supervision of a specialist in epileptology, neurology or paediatric neurology.

  Sabril is for oral administration once or twice daily and may be taken before or after meals. Sachet contents may be placed in beverage (e.g. water, fruit juice or milk) immediately before oral administration.

  If the control of epilepsy is not clinically significantly improved after an adequate trial, vigabatrin treatment should not be continued. Vigabatrin should be gradually withdrawn under close medical supervision.

  Adults

  Maximal efficacy is usually seen in the 2-3g/day range. A starting dose of 1g daily should be added to the patient's current anti-epileptic drug regimen. The daily dose should then be titrated in 0.5g increments at weekly intervals depending on clinical response and tolerability. The highest recommended dose is 3g/day.

  No direct correlation exists between the plasma concentration and the efficacy. The duration of the effect of the drug is dependent on the rate of GABA transaminase resynthesis rather than the concentration of the drug in the plasma.

• Child Dosage
  

  The recommended starting dose in children is 40mg/kg/day. Maintenance recommendations in relation to bodyweight are:

  Bodyweight:	10 to 15kg:	0.5-1g/day
  	15 to 30kg:	1-1.5g/day
  	30 to 50kg:	1.5-3g/day
  	>50kg:	2-3g/day

  The maximum recommended dose in each of these categories should not be exceeded.

  Infants - Monotherapy for infantile spasms (West's Syndrome). The recommended starting dose is 50mg/kg/day. This may be titrated over a period of one week if necessary. Doses of up to 150mg/kg/day have been used with good tolerability.

   

• Elderly Dosage
  

  Elderly and Patients with Renal Impairment

  Since vigabatrin is eliminated via the kidney, caution should be exercised when administering the drug to the elderly and more particularly in patients with creatinine clearance less than 60ml/min. Adjustment of dose or frequency of administration should be considered. Such patients may respond to a lower maintenance dose. Patients should be monitored for undesirable effects such as sedation or confusion.

• Contra Indications
  

  Hypersensitivity to vigabatrin or to any excipient in the medicinal product.

• Special Precautions
  

  Except for the treatment of infantile spasms, Sabril should not be initiated as monotherapy.

  Visual field defects have been reported in patients receiving vigabatrin with a high prevalence (about 1/3 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 and this may have practical consequences for the patient. 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. 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 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. Central visual acuity is not impaired. 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 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.

  Children

  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.

  Neurological and psychiatric conditions

  In view of the results of the animal safety studies, 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.

  As with other antiepileptic drugs some patients may experience an increase in seizure frequency or the onset of new types of seizures with vigabatrin. These phenomena may also be the consequence of an overdosage, 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 4week 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 anti-epileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk 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.

  Elderly 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 60ml/min and in elderly patients. These patients should be monitored closely for undesirable effects such as sedation and confusion. (See Section 4.2 Posology and method of administration).

• Interactions
  

  As vigabatrin is neither metabolised, nor protein bound and is not an inducer of hepatic cytochrome P450 drug metabolising-enzymes, interactions with other drugs 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, phenobarbitone, 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.

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

• Adverse Drug Reactions
  

  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 1/3 of patients receiving vigabatrin therapy develop visual field defects.

  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).

  Investigations*

  Common: weight increased

  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

  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, abdominal pain

  Skin and subcutaneous tissue disorders

  Uncommon: rash

  Rare: angioedema, urticaria

  General disorders and administration site conditions

  Very common: fatigue

  Common: oedema, irritability

  Hepato-biliary disorders

  Very rare: hepatitis

  Psychiatric disorders***

  Very common: excitation (children), agitation (children)

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

  Uncommon: hypomania, mania, psychotic disorder

  Rare: suicide attempt

  Very rare: hallucination

  *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.

  **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.

  ***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. Depression was a common psychiatric reaction in clinical trials but seldom required discontinuation of vigabatrin.