Consumer medicine information

Sabril

Vigabatrin

BRAND INFORMATION

Brand name

Sabril

Active ingredient

Vigabatrin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sabril.

What is in this leaflet

This leaflet answers some common questions about Sabril.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits.

Your doctor has weighed the risks of you taking Sabril against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Sabril is used for

Sabril is a medicine used to help control epilepsy, a condition where you have repeated fits or convulsions. Sabril is used in addition to other medicines to treat epilepsy.

Sabril is an anticonvulsant. It works by stopping the breakdown of an important chemical transmitter ("messenger") in the brain and this helps reduce seizure activity.

Your doctor, however, may have prescribed Sabril for another reason.

Ask your doctor if you have any questions about why it has been prescribed for you.

This medicine is available only with a doctor's prescription.

Before you take it

When you must not take it

Do not take Sabril if you are allergic to it or any of the ingredients listed at the end of this leaflet.

Some symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.

Do not take it if you are pregnant or intend to become pregnant. It may affect your developing baby if you take it during pregnancy.

Do not take it if you are breast-feeding or planning to breast-feed. Sabril passes into breast milk and there is a possibility your baby may be affected.

Do not take it after the expiry date (EXP) printed on the pack. If you take this medicine after the expiry date has passed, it may not work as well.

Do not take it if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if you have allergies to:

  • any of the ingredients listed at the end of this leaflet
  • any other medicines
  • any other substances, such as foods, preservatives or dyes

Tell your doctor if you have or have had any medical conditions, especially the following:

  • kidney problems
  • nervous or mental illness
  • depression
  • psychosis, a severe mental condition in which the person is unable to think and judge clearly.

Tell your doctor if you are pregnant or intend to become pregnant. Like most medicines for epilepsy, Sabril may affect your unborn baby. However, it is very important to control your epilepsy while you are pregnant, since seizures may also affect your baby. Your doctor will help you decide whether or not you should take Sabril during pregnancy.

Tell your doctor if you are breast-feeding or plan to breast-feed. Sabril passes into breast milk. Your doctor will discuss the risks and benefits of using it if you are breast-feeding or planning to breast-feed.

Tell your doctor or pharmacist if you plan to have surgery.

If you have not told your doctor about any of the above, tell them before you take Sabril.

Your doctor may want to test your eyesight before you start taking Sabril and during the course of your treatment so that any changes in your sight can be detected. Some anti-epilepsy medicines may affect eyesight. In rare cases, patients treated with Sabril have experienced changes to their peripheral vision (i.e., they had trouble seeing things that were not directly in front of them).

Please ask your doctor if you want more information about this.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with the absorption of Sabril. These include phenytoin, a medicine used to treat seizures.

Other medicines can increase the drowsiness that Sabril causes. These include clonazepam, a medicine used as a sedative or to treat anxiety.

These medicines may be affected by Sabril. You may need to use different amounts of your medicine, or take different medicines.

Your doctor will advise you.

Your doctor or pharmacist has more information about medicines to be careful with or avoid while taking Sabril.

How to take it

Follow all directions given to you by your doctor and pharmacist carefully.

These directions may differ from the information contained in this leaflet.

How much to take

Sabril tablets and sachets are taken by mouth either once or twice a day.

The dose of Sabril varies between patients. Your doctor may have prescribed a different dose.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you how much to take.

Follow the instructions they give you. If you take the wrong dose, Sabril may not work as well and your problem may not improve.

How to take it

Tablets
Swallow your tablet(s) whole with plenty of water. Do not crush or chew the tablet(s).

Sachets
The contents of the sachets should be dissolved in half a glass of water, juice or soft drink just before you plan to take it. Once dissolved, the solution should be taken immediately. It will dissolve easily and has no taste or smell.

Once mixed, any remaining solution should be discarded within 24 hours.

When to take it

You can take Sabril with or without food.

Take Sabril at about the same time each day. Taking Sabril at the same time each day will have the best effect. It will also help you remember when to take it.

If you are not sure when to take it, ask your doctor or pharmacist.

How long to take it

Do not stop taking Sabril until your doctor tells you to.

Ask your doctor or pharmacist if you are not sure how long to take the medicine for.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

If there is still a long time to go before your next dose, take it as soon as you remember, and then go back to taking your dose as you would normally.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766) for advice, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much Sabril. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking it

Things you must do

Tell all the doctors, dentists and pharmacists that are treating you that you are taking Sabril.

If you are about to start taking any new medicine, tell your doctor and pharmacist that you are taking Sabril.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking this medicine.

If you become pregnant while you are taking Sabril, tell your doctor immediately.

Things you must not do

Do not stop taking Sabril until your doctor tells you to.

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not take more than the recommended dose unless your doctor or pharmacist tells you to.

Do not use this medicine to treat any other complaints unless your doctor tells you to.

Things to be careful of

Be careful driving or operating machinery until you know how Sabril affects you. Sabril may cause dizziness or light-headedness in some people. Make sure you know how you react to Sabril before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or light-headed. This effect decreases with time.

Side Effects

All medicines can cause side effects and this may occur with the normal use of Sabril. Sometimes they are serious, most of the time they are not.

Your doctor or pharmacist has weighed the risks of using this medicine against the benefits they expect it will have for you.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Sabril.

It helps most people with epilepsy, but it may have unwanted side effects in a few people.

You may need medical treatment if you get some of the side-effects.

Tell your doctor if you notice any of the following and they worry you:

  • drowsiness
  • nervousness, irritability, depression
  • dizziness
  • confusion
  • headache
  • tiredness
  • difficulty sleeping
  • joints pain
  • impaired concentration
  • weight gain
  • difficulty in speaking or slurred speech
  • lack of coordination
  • agitation, excitation
  • aggression
  • tremors
  • nausea
  • vomiting
  • abdominal pain
  • unusual hair loss or thinning

These are the most common side effects of this medicine.

Tell your doctor immediately if you notice any of the following:

  • an increase in the number of seizures
  • changes in your usual behaviour or mood
  • severe sedation or confusion
  • suicidal thoughts (thoughts of self-harm)
  • suicide attempts
  • changes in your eyesight (eg:blurred vision, tunnel vision)

Tell your Doctor immediately or go to the Accident and Emergency department of your nearest hospital if you have any thoughts of harming yourself or committing suicide.

Do not stop taking Sabril without consulting your doctor first.

If any of the following happen, stop taking this medicine and tell your doctor immediately, or go to Accident and Emergency at your nearest hospital:

  • swelling of the face, lips, mouth or throat, which may cause difficultly in swallowing or breathing
  • hives

These are very serious side effects. If you have them, you may have had a serious allergic reaction to Sabril. You may need urgent medical attention or hospitalisation.

Other side effects not listed above may occur in some patients.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell.

Ask your doctor or pharmacist to answer any questions you may have.

After taking it

If you have any queries about any aspect of your medicine, or any questions regarding the information in this leaflet, discuss them with your doctor or pharmacist.

Storage

Keep your tablets or sachets in the container until it is time to take them.

Keep Sabril in a cool dry place where the temperature stays below 30°C.

Do not store Sabril or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep Sabril where children cannot reach it.

Disposal

If your doctor tells you to stop taking Sabril tablets or sachets or the expiry date has passed, ask your pharmacist what to do with any tablets or sachets that are left over.

Return any unused medicine to your pharmacist.

Product description

What it looks like

Tablets
Sabril 500 mg are white to off-white, biconvex oval shaped tablets with a single breakline on one face and Sabril inscribed in the other. They come in a blister pack of 100 tablets.

Sachets
Sabril sachets contain 500 mg of vigabatrin. They come in a pack of 60 sachets.

Ingredients

Sabril does not contain gluten, sucrose, tartrazine or any other azo dyes.

Tablets
Active ingredient:

Each tablet contains 500 mg of vigabatrin.

Inactive ingredients:

Each tablet also contains povidone, microcrystalline cellulose, sodium starch glycollate, magnesium stearate, hypromellose, titanium dioxide, macrogol 8000, and Opadry White OY-S-7298

Sachets
Active ingredient:

Each sachet contains 500 mg of vigabatrin.

Inactive ingredients:

Each sachet also contains povidone.

Manufacturer

Sabril is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113

Sabril is supplied in New Zealand by:

sanofi-aventis new zealand limited
Level 8, 56 Cawley Street
Ellerslie
Auckland 1051

This leaflet was prepared in August 2019

Australian Register Numbers

Sabril tablets: AUST R 150021

Sabril sachets: AUST R 52985

sabril-ccdsv13-cmiv8-19aug19

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Sabril

Active ingredient

Vigabatrin

Schedule

S4

 

1 Name of Medicine

Vigabatrin.

2 Qualitative and Quantitative Composition

Each tablet contains 500 mg vigabatrin.
Each oral powder sachet contains 500 mg vigabatrin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets.

White to off-white, biconvex oval shaped tablets with a single breakline on one face and Sabril inscribed on the other.

Oral powder.

White to off-white granular powder.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of epilepsy which is not satisfactorily controlled by other antiepileptic drugs.

4.2 Dose and Method of Administration

Vigabatrin is intended for oral administration once or twice daily. Initiation of treatment should be as add-on therapy in epilepsy which is not satisfactorily controlled by other drugs. Thus, the starting daily dose of 2 g (4 tablets) should be added on to the patient's current antiepileptic drug regimen. If necessary, the daily dose may be increased or decreased in 0.5 g or 1.0 g increments at weekly or greater intervals depending on clinical response and tolerability. Increasing the dose beyond 4 g/day does not usually result in greater efficacy.
Use of vigabatrin should be under the general direction of a specialist practitioner who is experienced in the treatment of epilepsy (see Section 4.4 Special Warnings and Precautions for Use).

Therapeutic dose.

Adults.

Starting dose is 2 g daily, which should be added on to the patient's current antiepileptic drug regimen. If necessary, the dose may be increased or decreased in 1.0 g increments as clinically warranted, up to 4 g/day.

Children.

3-9 years old.

Starting dose: 1 g daily.

> 10 years old.

Starting dose: 2 g daily.
When administering the sachet, the contents of the sachet should be dissolved in water or a soft drink immediately prior to oral administration.

4.3 Contraindications

Contraindicated for patients who have a history of hypersensitivity to vigabatrin or any of the components.

4.4 Special Warnings and Precautions for Use

Animal safety studies indicate that vigabatrin causes intramyelinic oedema in the brain of some species. Currently, there is no evidence to suggest that this effect occurs in man. However, it is recommended that patients treated with vigabatrin are closely observed for adverse effects on neurological functions.
Drowsiness has been observed in clinical trials and patients should be warned of this possibility at the start of treatment.
Vigabatrin should be used with caution in patients with a history of psychosis, depression or behavioural problems. Psychiatric events (agitation, depression, abnormal thinking, paranoid reactions) have been reported during vigabatrin therapy. These events occurred in patients with and without a psychiatric history and were usually reversible when vigabatrin doses were reduced or gradually discontinued. It is advisable that in patients who may be susceptible to such reactions (e.g. patients with a previous history), vigabatrin be introduced cautiously at low dose with frequent monitoring. In clinical trials, depression occurred in less than 10% of patients and seldom required discontinuation of vigabatrin. Less common events included psychotic symptoms.
Cases of abnormal brain magnetic resonance imaging (MRI) findings have been reported, particularly 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 Adverse Effects (Undesirable Effects)).
Movement disorders including dystonia, dyskinaesia 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 drugs, some patients may experience an increase in seizure frequency, including status epilepticus with vigabatrin, or the onset of new types of seizures with vigabatrin. New onset myoclonus and exacerbation of existing myoclonus may occur in rare cases.
As with other antiepileptic drugs, abrupt withdrawal may lead to rebound seizures; therefore, it is recommended that withdrawal from vigabatrin treatment occurs by gradual dose reduction over a 2 to 4 week period.
Vigabatrin is eliminated via the kidney and, therefore, caution should be exercised when administering the product to elderly patients and more particularly to patients with a creatinine clearance of less than 60 mL/min. Reduced doses should be used and patients monitored closely for adverse events such as sedation and confusion.
Rare reports of encephalopathic symptoms such as marked sedation, stupor and confusion in association with nonspecific slow wave activity on electroencephalogram (EEG) 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.

Visual disorders.

Visual field defects (VFDs) have been reported in patients receiving vigabatrin. Based on currently available data, the VFDs may result from increased levels of GABA in the retina. Males may be at greater risk than females. Asymptomatic VFDs appear to be frequent (about 30%) whereas symptomatic visual field constriction of various degrees is uncommon. Most patients were receiving other antiepilepsy drugs and baseline examinations were generally not provided. In case of symptomatic defects, where the information was available, the condition was diagnosed between 1 month and over 6 years of treatment, but most frequently during the first year. In most reported cases, VFDs persisted even after discontinuation of treatment.
Based on currently 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 degrees of eccentricity), a nasal annular defect is frequently seen. Severe cases may be characterised by tunnel vision.
Vigabatrin should not be used concomitantly with retinotoxic drugs.
Most patients with perimetry confirmed defects had not previously spontaneously noticed any symptoms (i.e. were asymptomatic), even in cases where a severe defect was observed in perimetry. Therefore, VFDs may only be reliably detected by systematic perimetry. This is only usually possible in patients with a developmental age of more than 9 years. Currently there is no established method available to diagnose and establish or exclude visual field defects in children in whom a standardised perimetry cannot be performed.
Available evidence suggests that VFDs are irreversible even after discontinuation of vigabatrin. A deterioration of VFD after the treatment is discontinued cannot be excluded.
The onset is months to years of vigabatrin therapy. A possible association between the risk of VFDs and the extent of vigabatrin exposure, both in terms of daily dose (from 1 g to more than 3 g) and in terms of duration of treatment has been shown in an open clinical study.
Vigabatrin is not recommended for use in patients with any pre-existing clinically significant VFD.
Appropriate visual field testing should be performed at baseline and during routine follow-up of the patient (initially and at about six month intervals). Static perimetry (such as Humphrey or Octopus) is the preferred method for detecting a vigabatrin associated VFD. The patient and/or caregiver must be given a thorough description of the frequency and implications of the development of VFDs during vigabatrin treatment. Patients should be instructed to report any new vision problems and symptoms which may be associated with visual field constriction. If visual symptoms develop, then the patient should be referred to an ophthalmologist for further evaluation.
If VFDs are identified, the decision to continue or discontinue vigabatrin should be based on an individual benefit-risk assessment. 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.
In patients where visual field testing cannot be adequately performed (e.g. commonly in young children), the decision to start vigabatrin should similarly be based on an individual benefit/ risk judgment.

Visual acuity.

Retinal disorder, blurred vision, optic atrophy or optic neuritis may lead to decrease in visual acuity. Visual acuity should be assessed during ophthalmological consultations.

Suicidal behaviour and ideation.

Antiepileptic drugs (AEDs), including vigabatrin increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour. Pooled analyses of 199 placebo controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomised to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behaviour compared to patients randomised to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behaviour for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behaviour with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behaviour beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behaviour was generally consistent among drugs in the data analysed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analysed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
The relative risk for suicidal thoughts or behaviour was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing vigabatrin or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviour. Should suicidal thoughts and behaviour emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behaviour and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behaviour, or the emergence of suicidal thoughts, behaviour, or thoughts about self harm. Behaviours of concern should be reported immediately to the treating doctor.

Use in renal impairment.

70% of a single oral dose being recovered in the urine as unchanged drug in the first 24 hours post-dose and, therefore, caution should be exercised when administering the product to patients with a creatinine clearance of less than 60 mL/min. Adjustment of dose or frequency of administration should be considered. Such patients may respond to a lower maintenance dose. Such patients should be monitored for undesirable effects such as sedation or confusion. According to isolated case reports, haemodialysis reduces vigabatrin plasma concentrations by 40% to 60% in patients with renal failure receiving therapeutic doses of vigabatrin.

Use in the elderly.

Vigabatrin is eliminated via the kidney and, therefore, caution should be exercised when administering the drug to the elderly and, more particularly, in patients with creatinine clearance less than 60 mL/min. It is recommended that such patients are started on a lower dose of vigabatrin and observed closely for adverse events, such as sedation and confusion.

Paediatric use.

See Section 4.8 Adverse Effects (Undesirable Effects).

Effects on laboratory tests.

Vigabatrin may lead to a decrease in measured plasma activity of alanine transaminase (ALT) and, to a lesser extent, aspartate transaminase (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 diseases (e.g. alpha aminoadipic aciduria).

4.5 Interactions with Other Medicines and Other Forms of Interactions

As vigabatrin is neither extensively metabolised, nor plasma protein bound, and is not an inducer of hepatic cytochrome P450, interactions with other drugs are unlikely. However, during controlled clinical studies a gradual reduction of about 20% in the plasma concentration of phenytoin has been observed. The exact nature of this interaction is presently not understood and the therapeutic significance is not known.
The plasma concentrations of carbamazepine, phenobarbital (phenobarbitone) and sodium valproate have also been monitored during controlled clinical trials and no clinically significant interactions have been detected.
The concomitant use of vigabatrin and clonazepam may exacerbate the sedative effect or lead to coma. Need for concomitant use must be carefully assessed.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D)
No adequate and well controlled studies with vigabatrin have been conducted in pregnant women. The risk of congenital defects is increased from 2 to 3 fold in children born from mothers treated with an antiepileptic; those more frequently reported are cleft lip, cardiovascular defects and neural tube defects. Polytherapy with antiepileptic drugs may be associated with a higher risk of congenital malformation than monotherapy.
Based on data on a limited number of exposed pregnancies with 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 antiepileptic drugs during each reported pregnancy.
The risk of having an abnormal child as a result of antiepileptic medication is far outweighed by the dangers to the mother and foetus of uncontrolled epilepsy. It is recommended that women on antiepileptic drugs receive pre-pregnancy counselling with regard to foetal abnormalities. Specialised advice should be provided to all patients who could begin a pregnancy or who are in the fertile age. The need for antiepileptic treatment must be re-evaluated when a patient plans a pregnancy. Antiepileptic medication should be continued during pregnancy at the lowest effective dose. The need of antiepileptic treatment must be re-evaluated when a patient plans a pregnancy. Folic acid supplementation (5 mg) should be commenced four weeks prior to and continue for twelve weeks after conception. Specialist prenatal diagnosis including detailed mid-trimester ultrasound should also be offered during pregnancy.
Vigabatrin should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus.
If a patient falls pregnant, antiepileptic therapy should not be suddenly interrupted due to the hazard of epileptic attack relapse that might have serious outcomes both for the mother and the child.
Reproductive studies in rats have shown no evidence of embryotoxicity, foetotoxicity, or teratogenicity at doses up to 150 mg/kg/day. Studies in rabbits administered vigabatrin during the period of organogenesis at doses above 100 mg/kg/day have shown an increased incidence of cleft palate together with evidence of maternal toxicity.
There are no well controlled studies with vigabatrin in pregnant women or during lactation.
Vigabatrin is excreted into breast milk in low concentrations. Therefore, a decision should be made on whether to discontinue the drug, taking into account the importance of the drug to the mother.
Vigabatrin is not recommended for breastfeeding mothers, unless expected benefits clearly outweigh potential risks.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Pooled data from prevalence surveys suggest that as many as 1/3 of patients receiving vigabatrin therapy develop visual field defects.
Adverse events are mainly CNS related, such as sedation, somnolence, fatigue and impaired concentration and probably a secondary consequence of increased GABA levels caused by vigabatrin. The most commonly reported adverse effects in children are excitation and agitation. 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, or the onset of new types of seizures with vigabatrin treatment. 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 heading of frequency, are listed below in CIOMS format.
The following CIOMS frequency rating is used: Very common: ≥ 10%; common: ≥ 1 and < 10%; uncommon: ≥ 0.1 and < 1%; rare: ≥ 0.01 and < 1.0%; very rare: < 0.01%.

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 abnormality (ataxia); movement disorder, including dystonia, dyskinaesia and hypertonia, either alone or in association with abnormalities in nuclear magnetic resonance imaging. Cases of cytotoxic oedema or related abnormal magnetic resonance imaging findings/ increase in signal intensity have been reported.
Rare: encephalopathy**.
Very rare: optic neuritis.
Not known: Cases of brain MRI abnormalities have been reported. Intramyelinic oedema (particularly in infants) (see Section 4.4 Special Warnings and Precautions for Use).

Eye disorders.

Very common: visual field defects***.
Common: blurred vision, diplopia, nystagmus.
Rare: retinal disorder (mainly peripheral).
Very rare: optic atrophy.

Gastrointestinal disorders.

Common: nausea, vomiting, abdominal pain.

Skin and subcutaneous tissue disorders.

Common: alopecia.
Uncommon: rash.
Rare: angioedema, urticaria.

General disorders and administration site conditions.

Very common: fatigue.
Common: oedema, irritability.

Psychiatric disorders****.

Very common: excitation (children), agitation (children).
Common: agitation, aggression, nervousness, depression, paranoid reaction, insomnia.
Uncommon: hypomania, mania, psychotic disorder.
Rare: suicide attempt.
Very rare: hallucination.

Blood and lymphatic system disorders.

Common: anaemia.

Musculoskeletal and connective tissue disorders.

Very common: arthralgia.
*Decreases in ALT and AST, which are considered to be a result of inhibition of these aminotransferases by vigabatrin, have been observed.
**Rare reports of encephalopathic symptoms such as marked sedation, stupor and confusion in association with nonspecific slow wave activity on EEG have been described soon after the introduction of vigabatrin therapy. Such reactions have been fully reversible following dose reduction or discontinuation of vigabatrin.
***Visual field defects (VFDs) have been reported in patients receiving vigabatrin. Males may be at greater risk than females. Asymptomatic VFDs appear to be frequent (about 30%) whereas symptomatic visual field constriction of various degrees is uncommon. Rare cases of retinal disorders (such as peripheral retinal atrophy) and very rare cases of optic neuritis or atrophy have also been reported.
****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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

When reported, the most common symptoms included drowsiness or coma; other less frequently reported symptoms included vertigo, headache, psychosis, respiratory depression or apnoea, bradycardia, hypotension, agitation, irritability, confusion, abnormal behaviour or speech disorder. None of the overdoses resulted in death.

Treatment.

There is no specific antidote. The usual supportive measures should be employed.
Measures to remove unabsorbed drug should be considered. Activated charcoal has been shown to not significantly absorb vigabatrin in an in vitro study. The effectiveness of haemodialysis in the treatment of vigabatrin overdose is unknown. In isolated case reports in renal failure patients receiving therapeutic doses of vigabatrin, haemodialysis reduced vigabatrin plasma concentrations by 40% to 60%. Isolated cases of vigabatrin overdosage have been reported. In the first case, the patient accidentally took a dose of 14 g daily for 3 days and transient vertigo and tremor were reported. In the second case, an 18 year old female took 30 g of vigabatrin and 250 mg of dipotassium chlorazepate in a suicide attempt. The patient was admitted to hospital in a state of coma which lasted 4 days. However, the coma was considered to be due to the dipotassium chlorazepate rather than vigabatrin. The patient recovered without sequelae.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Actions: anticonvulsant.

Mechanism of action.

The mechanism of action is attributed to dose dependent enzyme inhibition of GABA-transaminase (GABA-T) and consequent increased levels of the inhibitory neurotransmitter, GABA. In mice, decreased GABA-T levels in the brain persisted for 5 days following a single intraperitoneal dose (1500 mg/kg) and was accompanied by a marked rise in brain GABA concentration.

Clinical trials.

Short and long-term controlled clinical trials have shown that vigabatrin reduces seizure frequency when given as add-on therapy in patients with epilepsy not controlled satisfactorily by conventional therapy. Efficacy is particularly marked in patients with complex partial seizures.
During long-term clinical follow-up, tests done to confirm lack of significant adverse effect on neurological function include evoked potential studies, magnetic resonance imaging and, in a small number of cases, neuropathological examinations of human brain specimens. Therefore, clinical trials have revealed no evidence in humans of the type of neurotoxicity seen in animal studies. In man, no tendency towards increased evoked potential latency was observed even on prolonged treatment.

5.2 Pharmacokinetic Properties

Vigabatrin is a water soluble compound and is rapidly absorbed from the gastrointestinal tract; absorption is unaffected by the presence of food. The drug is widely distributed with an apparent volume of distribution slightly greater than total body water. Plasma and CSF concentrations are linearly related to dose over the recommended dose range.
There is no direct correlation between plasma concentration and efficacy. Duration of drug effect is thought to be dependent on the rate of enzyme resynthesis rather than the plasma concentration of drug.
Vigabatrin is eliminated from the plasma with a terminal half-life of 5-8 hours with approximately 70% of a single oral dose being recovered in the urine as unchanged drug in the first 24 hours postdose.
Vigabatrin does not induce the hepatic cytochrome P450 enzymes nor is it extensively metabolised or plasma protein bound, therefore, drug interactions are unlikely.

5.3 Preclinical Safety Data

Animal safety studies carried out in rat, mouse, dog and monkey 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 white matter tracts of rat, mouse and dog at doses of 30-50 mg/kg/day. This effect is caused by a separation of the outer lamellar sheath of myelinated fibres, a change characteristic of intramyelinic oedema.
In both rat and dog (mouse, not tested), the intramyelinic oedema was reversible on stopping vigabatrin treatment. However, in rodents, residual changes consisting of swollen axons and mineralised microbodies have been observed. In the monkey, no lesions were noted after 6 years of treatment at 50 and 100 mg/kg. In monkeys receiving 300 mg/kg for 16 months, minimal microvacuolation was noted with equivocal differences between treated and control animals. In the dog, results of an electrophysiological study indicate that intramyelinic oedema is associated with increased latency of the somatosensory evoked potential which is reversible when the drug is withdrawn.

Genotoxicity.

No data available.

Carcinogenicity.

Carcinogenicity studies indicate that vigabatrin is not a potential carcinogen nor did it adversely affect life expectancy in the two species studied (rat and mouse).
No evidence of carcinogenic potential was observed in rats during a 24 month study or in mice during an 18 month study at doses up to 150 mg/kg/day. In standard mutagenicity studies, vigabatrin did not induce gene mutations or cause chromosomal damage.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sabril tablets contain the following inactive ingredients: povidone, microcrystalline cellulose, sodium starch glycollate, magnesium stearate, hypromellose, titanium dioxide, macrogol 8000 and Opadry White OY-S-7298.
Sabril sachets contain the inactive ingredient povidone.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Tablets.

PVC/Al blister packs containing 100 tablets.

Oral powder.

Packs of 60 sachets containing 0.5 g oral powder.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

60643-86-9.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes