Sabril

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SABRIL SABRIL

Composition:

Active substance: vigabatrin;

1 sachet contains vigabatrin 500 mg

Excipients: povidone K30 (E1201).

Pharmaceutical form. Granules for oral solution.

Main physico-chemical characteristics:

A sachet containing a fine-dispersed granular powder of white or almost white color.

Pharmacotherapeutic group. Antiepileptic drugs.

ATC code N03AG04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Vigabatrin is an antiepileptic medicinal product with a clearly defined mechanism of action. Treatment with vigabatrin leads to an increase in the concentration of GABA (gamma-aminobutyric acid), an important inhibitory neurotransmitter in the brain. This is due to the fact that vigabatrin was specifically designed as a selective irreversible inhibitor of GABA transaminase, the enzyme responsible for the breakdown of GABA.

Clinical efficacy and safety

Controlled and long-term clinical studies have shown that vigabatrin is an effective anticonvulsant when used as adjunctive therapy in patients with epilepsy that is not adequately controlled with standard therapy. This efficacy has been particularly noted in patients with partial seizures.

The epidemiology of visual field defects (VFD) in patients with refractory partial epilepsy was evaluated in an observational, open-label, multicenter, comparative Phase IV study with parallel groups, which included 734 patients aged at least 8 years with refractory partial epilepsy for at least one year.

Patients were divided into three treatment groups: patients currently treated with vigabatrin (Group I), patients previously treated with vigabatrin (Group II), and patients who had never received vigabatrin (Group III). The table below presents the main results at inclusion, as well as the first and last follow-up assessments in the evaluated population (n = 524):

1 Average duration of treatment: 44.4 months, average daily dose 1.48 g.

2 Average duration of treatment: 20.6 months, average daily dose 1.39 g.

3 Average duration of treatment: 48.8 months, average daily dose 2.10 g.

4 Average duration of treatment: 23.0 months, average daily dose 2.18 g.

Pharmacokinetics.

Absorption

Vigabatrin is a water-soluble drug that is rapidly and completely absorbed from the gastrointestinal tract. Food intake does not affect the extent of vigabatrin absorption. Time to reach maximum plasma concentration (tmax) is approximately 1 hour.

Distribution

Vigabatrin is widely distributed, with a theoretical volume of distribution slightly greater than the total body water volume. Plasma and cerebrospinal fluid concentrations are linearly related to dose within the recommended dosage range.

Biotransformation

Vigabatrin is not significantly metabolized. No metabolites have been detected in plasma.

Elimination

Vigabatrin is eliminated from the body by renal excretion, with a terminal half-life of 5–8 hours. Oral clearance of vigabatrin (CI/F) is approximately 7 L/h (i.e., 0.1 L/h/kg). Approximately 70% of a single oral dose was recovered unchanged in urine within the first 24 hours after administration.

Pharmacokinetic/pharmacodynamic relationships

There is no direct correlation between plasma concentration and efficacy. The duration of drug action depends on the rate of GABA-transaminase resynthesis.

Children

The pharmacokinetic properties of vigabatrin were studied in groups of six neonates (aged 15–26 days), six infants (aged 5–22 months), and six children (aged 4.6–14.2 years) with refractory epilepsy. After administration of a single oral dose of 37–50 mg/kg of vigabatrin solution, tmax values were approximately 2.5 hours in neonates, 5.7 hours in infants, and 5.5 hours in children. Mean Cl/F values of the active S-enantiomer of vigabatrin in infants and children were 0.591 L/h/kg and 0.446 L/h/kg, respectively.

Preclinical safety data.

Safety studies conducted in rats, mice, dogs, and monkeys showed that vigabatrin has no significant adverse effects on the liver, kidneys, lungs, heart, or gastrointestinal tract.

Microvacuolization of white matter in the brain was observed in rats, mice, and dogs at doses ranging from 30 to 50 mg/kg/day. In monkeys, these pathological changes were minimal or questionable. This phenomenon is caused by detachment of the outer lamellar sheath of myelinated fibers, which is characteristic of intramyelinic edema. In both rats and dogs, intramyelinic edema was reversible after discontinuation of vigabatrin treatment, and histological regression was even observed during continued treatment.

However, minor residual changes such as axonal swelling (eosinophilic spheroids) or peroxisomal mineralization were observed in rodents. Electrophysiological studies in dogs indicated that intramyelinic edema is associated with increased latency of evoked sensory potentials, which is reversible upon discontinuation of vigabatrin treatment.

Vigabatrin-related retinal toxicity was observed only in albino rats, but not in pigmented rats, dogs, or monkeys. Retinal changes in albino rats were characterized by focal or multifocal lesions of the outer nuclear layer with displacement of nuclei in the region of cone and rod cells. Other retinal layers were unaffected. These lesions were observed in 80–100% of animals receiving an oral dose of 300 mg/kg/day.

The histological appearance of these lesions has been shown to be comparable to those observed in albino rats after excessive light exposure. However, retinal changes may also result from the direct effect of the drug.

Animal studies have shown that vigabatrin does not adversely affect fertility or offspring development. In rats receiving doses up to 150 mg/kg (three times the human dose) and in rabbits receiving doses up to 100 mg/kg, no teratogenic effects were observed. However, in rabbits, a slight increase in the incidence of cleft palate was observed at doses of 150–200 mg/kg.

Studies with vigabatrin have not revealed any evidence of mutagenic or carcinogenic potential.

Clinical characteristics.

Indications.

Use in combination with other antiepileptic medicinal products for the treatment of patients with refractory partial epilepsy, with or without secondary generalization, when adequate combinations of other medicinal products have been ineffective or poorly tolerated.

Use as monotherapy in infantile spasms (West syndrome).

Contraindications.

Hypersensitivity to vigabatrin or to any of the excipients listed in the section "Composition".

Interaction with other medicinal products and other forms of interaction.

Since vigabatrin is not metabolized, does not bind to proteins, and is not a cytochrome P450 inducer, interaction with other medicinal products is unlikely. However, during controlled clinical trials, a gradual reduction in plasma phenytoin concentrations by 16–33% was observed. The exact mechanism of this interaction is currently unclear, but in most cases, its therapeutic significance is unlikely.

Plasma concentrations of carbamazepine, phenobarbital, and sodium valproate were also monitored during controlled clinical trials, and no clinically significant interactions were identified.

Vigabatrin may cause a reduction in measured alanine aminotransferase (ALT) activity in plasma, and to a lesser extent, aspartate aminotransferase (AST). The reported degree of ALT suppression ranged from 30% to 100%. Therefore, such liver parameters in patients taking vigabatrin may yield falsely low results (see section "Adverse reactions").

Vigabatrin may increase the amount of amino acids in urine, which may lead to false-positive results in tests for certain rare genetic metabolic disorders (e.g., alpha-aminoadipic aciduria).

Concomitant use of vigabatrin and clonazepam may enhance the sedative effect (see section "Special precautions").

Special precautions for use.

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

Visual field defects (VFDs)

Available data indicate that visual field defects are typically manifested as bilateral concentric constriction of the visual field, which is usually more pronounced on the nasal side than on the temporal side. A ring-shaped defect is often observed in the central visual field (within 30 degrees of eccentricity). VFDs in patients receiving vigabatrin have varied in severity—from mild to severe. Severe cases may be characterized by tunnel vision. Cases of blindness have also been reported in severe instances.

Most patients with abnormalities confirmed by perimetry previously had not noticed any symptoms, including in cases where significant abnormalities were detected by perimetry. Available data suggest that VFDs are irreversible, including after discontinuation of vigabatrin therapy. Worsening of visual field defects after stopping treatment cannot be ruled out.

Summary data indicate that one-third of patients receiving vigabatrin suffer from VFDs. Men are more susceptible to developing VFDs than women. The incidence of VFDs determined in an open clinical study is specified in the section "Pharmacodynamics". This study demonstrated a possible association between the risk of VFDs and vigabatrin exposure depending on daily dose (from 1 g to over 3 g) and duration of treatment (up to a maximum of the first 3 years).

Before initiating vigabatrin therapy, all patients should consult an ophthalmologist for visual field examination.

Prior to starting treatment, appropriate visual field testing (perimetry) should be performed using standard static (Humphrey or Octopus) or kinetic (Goldmann standard) perimetry, followed by testing every six months throughout the entire treatment period. Static perimetry is the method of choice for detecting visual field abnormalities associated with vigabatrin use.

Electroretinography may be a useful method but should only be performed in adults who are unable to cooperate during perimetry. Available data show that the first oscillatory potential and the 30 Hz flicker response on electroretinogram correlate with VFDs caused by vigabatrin. These responses are delayed and have lower amplitude than normal. Such changes have not been observed in patients receiving vigabatrin who do not have VFDs.

The patient and/or caregiver should be fully informed about the frequency and consequences of developing VFDs during vigabatrin therapy. Patients should be instructed to report any new visual problems or symptoms that may be related to visual field constriction. If visual symptoms occur, the patient should be referred to an ophthalmologist.

If visual field constriction is detected during monitoring, consideration should be given to gradually discontinuing vigabatrin therapy. If continued treatment is necessary, more frequent examinations (perimetry) may be required to detect progression of constriction or emergence of visual defects.

Vigabatrin should not be used concomitantly with other retinotoxic drugs.

Children

Perimetry is not recommended for children under 9 years of age. The risk of treatment in children should be carefully weighed against the expected benefit. Currently, there is no validated method for diagnosing or excluding visual field defects in children who are unable to undergo standard perimetry.

However, the presence of peripheral vision does not exclude the possibility of developing VFDs.

Electroretinography may be a useful method but should only be performed in children under 3 years of age.

Visual acuity

The prevalence of reduced visual acuity in patients receiving vigabatrin is unknown.

Retinal disorders, blurred vision, optic nerve atrophy, or optic neuritis may lead to reduced visual acuity (see section "Adverse reactions").

Visual acuity should be assessed during ophthalmological consultations before starting vigabatrin therapy and then every 6 months during treatment.

Neurological and psychiatric disorders

Based on safety studies conducted in animals, possible neurological adverse reactions in patients receiving vigabatrin should be carefully monitored.

Rare cases of encephalopathy symptoms, such as marked sedation, stupor, or confusion, associated with non-specific presence of slow waves on electroencephalogram, have been observed shortly after initiation of vigabatrin therapy. Risk factors for these reactions include, in particular, an initial dose exceeding the recommended dose, more rapid dose escalation and/or dose increments larger than recommended, or presence of renal impairment. These reactions were reversible after dose reduction or discontinuation of vigabatrin (see section "Adverse reactions").

Cases of brain abnormalities on MRI have been reported, particularly in infants/young children receiving high-dose vigabatrin for infantile spasms. The clinical significance of these abnormalities is currently unknown. Additionally, cases of intramyelinic edema (IME), particularly in infants/young children treated for infantile spasms, have been reported (see sections "Adverse reactions" and "Non-clinical safety data"). IME was reversible upon discontinuation of treatment; therefore, gradual discontinuation of vigabatrin is recommended if IME is detected.

Abnormal movements, including dystonia, dyskinesia, and hypertonia, have been reported in patients receiving treatment for infantile spasms. The benefit-risk balance of vigabatrin use should be evaluated individually for each patient. If new abnormal movements occur during vigabatrin therapy, dose reduction or gradual discontinuation of treatment should be considered.

In some patients receiving vigabatrin, increased seizure frequency or development of new types of seizures may occur (see section "Adverse reactions"). These phenomena may also arise due to overdose, decreased plasma concentration of concomitantly administered antiepileptic drugs, or paradoxical effect.

As with any antiepileptic drug, abrupt discontinuation of vigabatrin therapy may lead to seizure occurrence. If discontinuation of vigabatrin is required, a gradual dose reduction over 2–4 weeks is recommended.

Vigabatrin should be used with caution in patients with a history of psychosis, depression, or behavioral disorders. Psychiatric adverse events (e.g., agitation, depression, thought disturbances, paranoid reactions) have been reported during vigabatrin therapy. These events occurred both in patients with and without psychiatric history. They were generally reversible upon dose reduction or gradual discontinuation of vigabatrin.

Suicidal ideation and behavior

Suicidal ideation and behavior have been reported in patients receiving antiepileptic drugs for various indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a slightly increased risk of suicidal ideation and behavior. The underlying causes of this risk are unknown, and available data do not exclude an increased risk with vigabatrin use. Therefore, patients should be closely monitored for signs of suicidal ideation and behavior, and appropriate treatment should be initiated. Patients (and their caregivers) should be advised to contact their physician if signs of suicidal ideation or behavior occur.

Elderly patients and patients with renal impairment

Since vigabatrin is eliminated by the kidneys, particular caution is required when treating patients with creatinine clearance below 60 mL/min and elderly patients. These patients should be closely monitored for adverse effects such as sedation or confusion (see section "Dosage and administration").

Concomitant use of vigabatrin and clonazepam

Concomitant use of vigabatrin and clonazepam may enhance sedative effects (see section "Interaction with other medicinal products and other forms of interaction"). The necessity of such concomitant use should be evaluated considering all risks.

Use during pregnancy or breastfeeding.

Pregnancy

Risk associated with epilepsy and antiepileptic drugs in general

In children born to women treated with antiepileptic drugs, the prevalence of congenital malformations is 2–3 times higher than in the general population. Most frequently reported malformations include cleft lip, cardiovascular defects, and neural tube defects. Polytherapy may be associated with a higher risk of congenital malformations than monotherapy; therefore, monotherapy should be used whenever possible.

All female patients of reproductive age should be advised to consult a specialist. The need for antiepileptic treatment should be reviewed when a patient plans pregnancy.

In women with epilepsy, abrupt discontinuation of antiepileptic therapy during pregnancy should be avoided, as this may lead to increased seizures and may adversely affect both mother and fetus.

Risk associated with vigabatrin

From spontaneous reports on vigabatrin use during pregnancy, cases of congenital anomalies in children and spontaneous abortions are known. Due to limited data and concomitant use of other antiepileptic drugs during these pregnancies, a definitive conclusion cannot be drawn regarding whether vigabatrin causes an increased risk of developmental abnormalities when used during pregnancy.

Animal studies have shown reproductive toxicity (see section "Non-clinical safety data").

Sabril should not be used during pregnancy unless the clinical condition of the woman necessitates treatment with vigabatrin.

The amount of information regarding possible occurrence of visual field defects in children exposed to vigabatrin in utero is limited.

Breastfeeding

Vigabatrin is excreted in human breast milk. Information on the effects of vigabatrin on newborns and infants is insufficient. A decision whether to discontinue breastfeeding or to discontinue therapy with Sabril should be made, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Reproductive function

Studies on reproductive function in rats did not reveal effects on male and female reproductive function (see section "Non-clinical safety data").

Ability to affect reaction speed when driving or operating machinery.

Generally, patients with uncontrolled epilepsy are not permitted to drive or operate potentially dangerous machinery. Given that somnolence was observed during clinical trials with Sabril, patients should be warned about this possibility at the beginning of treatment.

Visual field defects, which may significantly impair the ability to drive or operate machinery, have frequently been reported in connection with Sabril use. Patients should be evaluated for visual field defects, with particular attention to patients who drive, operate machinery, or perform any hazardous tasks (see also section "Special precautions for use").

Method of Administration and Dosage

Treatment with the medicinal product Sabril may be initiated only by a specialist in epileptology, neurology, or pediatric neurology. Further treatment must be coordinated and conducted under the supervision of a specialist in epileptology, neurology, or pediatric neurology.

Sabril is intended for oral administration, once or twice daily, and may be taken with or without food.

The contents of the sachet should be dissolved in a beverage (water, fruit juice, or milk) immediately before administration.

If, after a trial period, treatment with vigabatrin does not provide clinically significant improvement in symptoms of epilepsy, such treatment should not be continued. Vigabatrin therapy should be gradually discontinued under continuous medical supervision.

Adults

Maximum efficacy is usually observed with doses in the range of 2–3 g/day. The initial dose of 1 g/day should be added to the patient’s current regimen of antiepileptic medicinal products. The daily dose should then be titrated in increments of 0.5 g at weekly intervals, depending on clinical response and tolerability. The maximum recommended dose is 3 g/day.

There is no direct correlation between plasma concentration and efficacy. The duration of action of the medicinal product depends on the rate of GABA-transaminase resynthesis, not on the drug concentration in plasma (see also sections "Pharmacodynamics" and "Pharmacokinetics").

Children

Refractory Partial Epilepsy

The recommended initial dose of vigabatrin for children is 40 mg/kg/day.

Recommended maintenance doses according to body weight:

Do not exceed the maximum recommended dose in each of these categories.

Monotherapy of infantile spasms (West syndrome)

The recommended initial dose is 50 mg/kg/day. If necessary, the dose may be titrated over a one-week period. Doses up to 150 mg/kg/day have demonstrated acceptable tolerability.

If the required doses of Sabril cannot be achieved according to body weight, alternative medications for monotherapy of infantile spasms (West syndrome) should be used.

Geriatric patients and patients with renal impairment

Since vigabatrin is eliminated by the kidneys, caution should be exercised when prescribing the drug to elderly patients and, in particular, to patients with creatinine clearance less than 60 mL/min. Dose adjustment or modification of dosing frequency may be required. Such patients may respond to lower doses of the drug. Patients should be monitored for adverse effects such as sedation or confusion (see sections "Special precautions" and "Adverse reactions").

Children

The drug is administered to children according to indications, taking into account body weight, as described in the section "Dosage and administration".

Overdose

Symptoms

Cases of vigabatrin overdose have been reported. In the reported cases, doses were most commonly between 7.5 and 30 g; however, doses up to 90 g have also been reported. In approximately half of the cases, multiple drugs were ingested. The most common symptoms included somnolence or coma. Other symptoms reported less frequently included dizziness, headache, psychosis, respiratory depression or apnea, bradycardia, hypotension, agitation, irritability, confusion, abnormal behavior, and speech disturbances. No case of overdose resulted in death.

Treatment

There is no specific antidote. Standard supportive measures should be implemented. Measures to remove unabsorbed drug may be used. Activated charcoal has shown minimal ability to adsorb vigabatrin in an in vitro study. The effectiveness of hemodialysis in treating vigabatrin overdose is unknown. In individual cases of patients with renal insufficiency receiving therapeutic doses of vigabatrin, hemodialysis reduced plasma vigabatrin concentrations by 40–60%.

Adverse reactions.

Visual field defects, ranging from mild to severe, have been frequently observed in patients receiving vigabatrin. Severe visual disturbances may lead to loss of work capacity. These defects typically develop several months or even years after initiation of vigabatrin therapy. Pooled study data indicate that visual field defects occur in approximately one-third of patients treated with vigabatrin (see section "Special precautions").

In controlled clinical trials, approximately 50% of patients experienced adverse effects during treatment with vigabatrin. In adults, most adverse effects are related to the central nervous system and include sedation, somnolence, fatigue, and attention disturbances. In children, by contrast, agitation or hyperexcitability are more commonly observed. The frequency of these adverse effects is usually higher at the beginning of treatment and gradually decreases over time.

As with any antiepileptic drug, in some patients taking vigabatrin, an increased frequency of seizures or even epileptic status may occur. Patients experiencing myoclonic seizures are particularly susceptible to such effects. Rarely, new-onset myoclonus or worsening of pre-existing myoclonus has been observed.

The table below lists adverse reactions associated with the use of vigabatrin, classified by frequency: very common (≥ 1/10); common (≥ 1/100 — < 1/10); uncommon (≥ 1/1000 — < 1/100); rare (≥ 1/10000 — < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

*Psychiatric reactions have been reported during vigabatrin treatment. These reactions occurred both in patients with and without a history of psychiatric disorders. They were usually reversible upon dose reduction or gradual discontinuation of vigabatrin therapy (see section "Special precautions"). Depression was a commonly observed psychiatric reaction in clinical trials, but rarely required discontinuation of vigabatrin treatment.

** Rare cases of encephalopathy-like symptoms such as marked sedation, stupor, or confusion associated with non-specific presence of slow waves on electroencephalogram (EEG) have been observed shortly after initiation of vigabatrin treatment. These reactions are reversible after dose reduction or discontinuation of vigabatrin (see section "Special precautions").

*** Laboratory test results indicate that vigabatrin treatment does not cause nephrotoxicity. Decreases in ALT and AST levels have been observed, which are believed to result from inhibition of these aminotransferases by vigabatrin.

Adverse reactions observed in children

In children, psychiatric disorders such as agitation and hyperexcitability were very commonly observed during vigabatrin treatment.

Reporting suspected adverse reactions

Reporting suspected adverse reactions of medicinal products is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua/.

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Use immediately after reconstitution. Keep out of reach of children.

Packaging.

Oral granules, 50 sachets in a cardboard box.

Oral granules, 50 sachets in a cardboard box with a Ukrainian-language sticker.

Prescription status. Prescription only.

Manufacturer.

PATHEON FRANCE, France / PATHEON FRANCE, France

Manufacturer's address and location of operations:

40 boulevard de Champaret, BOURGOIN JALLIEU, 38300, France / 40 boulevard de Champaret, BOURGOIN JALLIEU, 38300, France.