Sabril (Vigabatrin)

SABRIL®

Hoechst Marion Roussel

Vigabatrin

Antiepileptic

Action And Clinical Pharmacology: Vigabatrin is an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the catabolism of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain. The mechanism of action of vigabatrin is attributed to irreversible enzyme inhibition of GABA-T, and consequent increased levels of the inhibitory neurotransmitter, GABA.

Decreased serum levels of ALT and AST have been observed during treatment with vigabatrin and may be the result of inhibition of these transaminases by vigabatrin. The clinical significance of these findings is unknown.

The duration of effect of vigabatrin is thought to be dependent on the rate of GABA-T resynthesis rather than on the plasma concentration of vigabatrin.

Clinical Trials: In clinical trials, including double-blind, placebo-controlled studies involving 354 patients with drug-resistant complex partial seizures, vigabatrin reduced seizure frequency by 50% or more in approximately half of the patients studied. The efficacy of vigabatrin in children with refractory partial seizures was similar to that seen in adult patients.

A multicentre, double-blind, placebo-controlled, parallel group study was performed to evaluate the safety and efficacy of vigabatrin versus placebo as first line monotherapy in the treatment of newly diagnosed infantile spasms. The study involved a 2- to 3-day baseline period, a 5-day double-blind treatment phase, and a 6-month open-label follow-up. Complete cessation of spasms on the final day of double-blind treatment was achieved by 45% of vigabatrin patients (N=20) and by 15% of placebo patients (N=20). According to the Clinical Global Impression of Improvement, 80% of vigabatrin patients and 15% of placebo patients were considered to be moderately or markedly improved. These differences between the treatment groups were statistically significant. In the 6-month open-label extension of this study, 51% of patients (N=35) could be maintained on vigabatrin monotherapy, while 49% required the addition of other antiepileptic drugs.

In a retrospective analysis of 192 infants diagnosed with infantile spasms who had been treated with vigabatrin as first-line monotherapy (mean steady-state dose of 99 mg/kg/day), 162 patients (84%) experienced an initial decrease in spasm frequency of at least 50% with 131 patients (68%) experiencing a complete resolution of spasms. Demographic factors which seemed to be predictive of a positive response to vigabatrin included an etiology of tuberous sclerosis and an age of onset of illness of less than 3 months. According to long-term (mean 9.2 months) follow-up data for this retrospective study, 42% of the 192 patients could be successfully maintained on vigabatrin monotherapy, while the remainder required additional antiepileptic treatments. Of the 131 patients who were considered to be complete responders, 85 (65%) experienced neither relapse of infantile spasms nor onset of other seizure types during long-term follow-up.

Pharmacokinetics: Vigabatrin is rapidly absorbed following oral administration and peak plasma concentrations are reached within 2 hours. Vigabatrin is widely distributed with an apparent volume of distribution slightly greater than total body water. The primary route of elimination is via the kidney, with little metabolic transformation occurring. Following a single dose, approximately 70% is excreted in the urine as unchanged drug within the first 24 hours post-dose. The plasma elimination half-life is approximately 5 to 8 hours in young adults and 12 to 13 hours in the elderly. In renal impairment the elimination is prolonged and the rate of renal clearance is directly related to creatinine clearance (see Precautions and Dosage). Vigabatrin does not induce the hepatic cytochrome P450 system nor is it extensively metabolized or plasma-protein bound. Administration of vigabatrin with food slightly reduces the rate, but not the extent of absorption.

Indications And Clinical Uses: For the adjunctive management of epilepsy which is not satisfactorily controlled by conventional therapy.

Vigabatrin is indicated as initial monotherapy for the management of infantile spasms (West syndrome). Clinical experience indicates that at least 50% of patients may require the addition of other antiepileptic drugs owing to relapse or emergence of other seizure types following an initial response to the treatment of infantile spasms with vigabatrin.

Vigabatrin should be used under close monitoring by a neurologist.

Contra-Indications: In pregnancy and lactation (see Warnings) and in patients with a known hypersensitivity to vigabatrin or to any components of the product. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Ophthalmological Abnormalities: In the course of international postmarketing surveillance, a number of ophthalmological abnormalities, including visual field constriction, bilateral optic disc pallor, subtle peripheral retinal atrophy, optic atrophy, and optic neuritis have been reported in patients receiving vigabatrin often in combination with other antiepileptic agents.

According to these reports, the time to onset of symptomatic visual field constriction, when specified, has ranged from less than one month to over 6 years. Preliminary data suggest that the onset of symptoms tends to be reported most frequently within the first year of treatment.

Initial and periodic (approximately every 3 months) ophthalmological examinations are recommended during vigabatrin treatment including expert mydriatic peripheral fundus examination and visual field perimetry.

Patients should be questioned at frequent intervals during treatment for narrowing of the field of vision or loss of visual acuity and should be advised to report any emerging visual problems promptly to their physicians.

The use of vigabatrin should be discontinued in patients exhibiting any of the above ophthalmological abnormalities, unless the benefits of continued treatment in terms of seizure control are considered to outweigh the risk of visual impairment.

In view of the difficulties of assessing visual field in infants and young pediatric patients, vigabatrin should be used in these patient groups only if clearly indicated. The need for continued use of vigabatrin should be reassessed periodically. Frequent examination by a pediatric ophthalmologist are recommended for all infants and young children receiving vigabatrin.

Neurotoxicity in Animals: Rat, Mouse and Dog: Safety studies carried out in the rat, mouse and dog at doses of 30 to 50 mg/kg/day and higher, caused dose- and time-dependent microvacuolation within certain white matter tracts of the brain (the cerebellum, reticular formation and thalamus in rodents and the columns of the fornix and optic tracts in dogs were most affected). The microvacuolation was caused by the separation of the outer lamellar sheath of myelinated fibres, a change characteristic of noninflammatory intramyelinic edema.

In both the rat and dog (mouse was not tested), the intramyelinic edema was reversible after stopping the administration of vigabatrin; however, in the mouse and rat, residual changes consisting of swollen axons and mineralized microbodies were observed.

Monkey: In monkeys, the oral administration of 300 mg/kg/day for 16 months produced minimal microvacuolation with equivocal differences between treated and control animals. Low oral absorption of vigabatrin in the monkey resulted in an actual absorbed dose of 75 mg/kg/day. In spite of the poor absorption, cerebrospinal fluid (CSF) levels of vigabatrin in the monkeys were comparable to those seen in rats treated with 300 mg/kg/day; however, GABA levels in the CSF and the brain cortex in treated monkeys were not significantly different from untreated monkeys. This finding may explain the reason for the equivocal effects, since the intramyelinic edema associated with vigabatrin treatment appears to be related to increased brain GABA levels.

Evoked Potentials: Evoked Potentials in Animals: In the dog, studies indicate that intramyelinic edema is associated with increased latencies in somatosensory and visually evoked potentials. Magnetic resonance imaging (MRI) changes also correlated with intramyelinic edema in the fornix, thalamus and hypothalamus.

Evoked Potentials in Man: No increased evoked potential latencies have been observed in man. Two hundred and twenty-one patients treated for 4 to 5 months showed no significant evoked potential latency changes at the end of treatment as compared to baseline. MRI results in man did not show the changes observed in dogs who had intramyelinic edema.

Postmortem neuropathological changes seen in 11 patients who were treated with vigabatrin (mean duration of treatment was 28 months, and the longest treatment was 6 years) showed no myelin vacuolation in the white matter that was considered to be outside of the control range.

Although clinical trials have not revealed the type of neurotoxicity seen in animal studies, increased CSF GABA levels have been observed in humans. It is recommended that patients treated with vigabatrin be closely observed for adverse effects on neurological function, with special attention to visual disturbance.

Pregnancy and Lactation: In a teratology study in the rabbit a dose-related incidence, 2% and 9%, of cleft palate was observed at doses of 150 and 200 mg/kg/day, respectively.

In animal reproductive studies neurohistopathology was not performed on the fetuses; therefore, it is not known whether microvacuolation occurred in utero. The possibility that microvacuolation or other neurotoxicity may occur in human fetuses cannot be disregarded.

Precautions: Patients with a History of Psychosis: Behavioral disturbances such as aggression and psychotic episodes have been reported following initiation of vigabatrin therapy. A history of abnormal behavior or psychosis appears to be a predisposing factor for such reactions, therefore treatment in such patients should be initiated cautiously at low doses and with frequent monitoring.

Geriatrics and Patients with Renal Impairment: Vigabatrin is eliminated via the kidney and caution should be exercised when administering the drug to elderly patients and to patients with renal impairment (see Dosage).

Patients with Myoclonic Seizures: As with other antiepileptic drugs, some patients may experience an increase in seizure frequency with vigabatrin. Patients with myoclonic seizures may be particularly liable to this effect.

Discontinuation of Therapy: As with other antiepileptic drugs, abrupt discontinuation may lead to rebound seizures. If a patient is to be withdrawn from vigabatrin treatment, it is recommended that this be done gradually by reducing the dose over a 2- to 4-week period if possible.

Drug Interactions: During concurrent vigabatrin administration, mean decreases of 16 to 33% in phenytoin levels have been reported. A 9 to 21% reduction in phenobarbital levels has also been seen in patients receiving concomitant vigabatrin treatment. The clinical relevance of these decreases is not known.

Occupational Hazards: Patients with uncontrolled epilepsy should not drive or handle potentially dangerous machinery. During clinical trials, the most common adverse reactions observed were drowsiness and fatigue. Patients should be advised to refrain from activities requiring mental alertness or physical coordination until they are sure that vigabatrin does not affect them adversely.

Adverse Reactions: Vigabatrin is generally well tolerated in epileptic patients. Adverse events are mainly CNS-related and probably a secondary consequence of increased GABA levels caused by vigabatrin. The safety of vigabatrin was evaluated in 438 epileptic patients treated in double-blind, placebo-controlled clinical trials. The relationship of adverse events to vigabatrin therapy was not clearly established as patients were taking other antiepileptic drugs concomitantly.

Most Frequent Adverse Events (incidence higher than placebo): fatigue, headache, drowsiness, dizziness, depression, weight increase, agitation, tremor, abnormal vision, amnesia.

Postmarketing Ophthalmological Adverse Events: cases of peripheral visual field constriction, bilateral optic disc pallor, subtle peripheral retinal atrophy, and optic atrophy have been reported. There are also rare reports of optic neuritis (see Warnings).

The sedative effect of vigabatrin decreases with continuing treatment.

Other adverse events that have been reported less frequently include hypomania, mania, psychosis and suicide attempt.

Rare instances of marked sedation, stupor and confusion associated with nonspecific slow wave activity on EEG have been described soon after the introduction of vigabatrin therapy. These events have been reversible following dose reduction or discontinuation of vigabatrin.

Rare reports of hypersensitivity reactions (including angioedema and urticaria) have been received.

As with other antiepileptic drugs, some patients may experience an increase in seizure frequency with vigabatrin treatment (see Precautions).

Laboratory data indicate that vigabatrin treatment does not lead to renal or hepatic toxicity. Chronic treatment with vigabatrin may be associated with a slight decrease in hemoglobin, which rarely attains clinical significance.

Pediatric Safety: Safety data are available in 299 children, aged 2 months to 16 years (1 patient was 18 years of age), participating in clinical trials with vigabatrin. Relationship of adverse events to vigabatrin therapy was not clearly established as children were taking other antiepileptic drugs concomitantly.

The most frequent adverse event observed in children was “hyperactivity” (reported as hyperkinesia 7.7%, agitation 2.3%, excitation 0.3% or restlessness 0.7%), which was observed in 11% of children, an incidence higher than that seen in adults. There have been postmarketing reports of visual field constriction, optic disc pallor, optic atrophy, and optic neuritis in pediatric patients receiving vigabatrin treatment (see Warnings). Other commonly reported adverse events were somnolence (8%) and weight gain (3%).

Symptoms And Treatment Of Overdose: Symptoms and 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 adsorb vigabatrin in an in vitro study. The effectiveness of hemodialysis in the treatment of vigabatrin overdose is unknown. In isolated case reports in renal failure patients receiving therapeutic doses of vigabatrin, hemodialysis reduced vigabatrin plasma concentrations by 40 to 60%

Cases of vigabatrin overdose have been reported. The doses of vigabatrin taken were usually between 7.5 and 30 g; however, ingestions of up to 65 g have been reported. When reported, the most common symptoms included drowsiness, loss of consciousness and coma. Other less frequently reported symptoms included vertigo, headache, psychosis, respiratory depression or apnea, bradycardia, hypotension, agitation, irritability, confusion, abnormal behavior or speech disorder.

Dosage And Administration: Vigabatrin is intended for oral administration once or twice daily and may be taken with or without food. Vigabatrin should be added to the patient’s current antiepileptic therapy.

The recommended doses may be taken as tablets or sachets. The entire contents of the sachet(s) should be dissolved in a glass of cold or room temperature water, juice or milk immediately before oral administration. Instructions to the patient on the use of vigabatrin are provided in the Information for the Patient section.

Adults: The recommended starting dose is 1 g/day, although patients with severe seizure manifestations may require a starting dose of up to 2 g/day. The daily dose may be increased or decreased in increments of 0.5 g depending on clinical response and tolerability. The optimal dose range is between 2 to 4 g/day. Increasing the dose beyond 4 g/day does not usually result in improved efficacy and may increase the occurrence of adverse reactions.

Children: The recommended starting dose in children is 40 mg/kg/day, increasing to 80 to 100 mg/kg/day depending on response. Therapy may be started at 0.5 g/day, and raised by increments of 0.5 g/day weekly depending on clinical response and tolerability.

Infants (Treatment of Infantile Spasms): The recommended dose for the management of infantile spasms (West Syndrome) is between 50 to 100 mg/kg/day, depending on the severity of the spasms. This dose may be titrated over a period of 1 week if necessary. Doses of up to 150 mg/kg/day have been used with good tolerability.

The total daily dose should be divided and administered on a b.i.d. basis. The entire contents of the vigabatrin sachet(s) should be dissolved in a 10 mL volume of water, fruit juice, milk or infant formula, and the appropriate aliquot of this volume administered using an oral syringe.

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

Information for the Patient: See Blue Section – Information for the Patient “Sabril”.

Availability And Storage: Sachets: Each sachet of white to off-white granular powder contains: vigabatrin 0.5 g. Lactose-free. Cartons of 50.

Tablets: Each white to off-white, film-coated, oval, biconvex tablet, imprinted “SABRIL” on one side, contains: vigabatrin 500 mg. Nonmedicinal ingredients: cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, povidone, sodium starch glycolate and titanium dioxide. Lactose-free. HDPE bottles of 100.

Store at controlled room temperature (15 to 30°C). Protect from moisture.

SABRIL® Hoechst Marion Roussel Vigabatrin Antiepileptic

Connected Diseases :

Epilepsy

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