Sabril film-coated tablets 500 mg blister No. 100

Instructions for Sabril film-coated tablets 500 mg blister No. 100

Composition

active ingredient: vigabatrin;

1 tablet contains vigabatrin 500 mg;

Excipients: tablet core: povidone K30 (E1201), microcrystalline cellulose (E460), sodium carboxymethyl starch (type A), magnesium stearate; film coating: Opadry white OY-S-7298 (hypromellose 15 mPas (E464), titanium dioxide (E171), macrogol 8000).

Dosage form

Film-coated tablets.

Main physicochemical properties: white or almost white oval biconvex tablets, film-coated, with a breakline on one side and engraving “SABRIL” or “SABRILEX” on the other.

The dividing line is intended only to facilitate dividing the tablet for ease of swallowing, and not to divide into equal doses.

Pharmacotherapeutic group

Antiepileptic drugs.

ATX code N03A G04.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Vigabatrin is an antiepileptic drug with a well-defined mechanism of action. Treatment with vigabatrin increases the concentration of GABA (gamma-aminobutyric acid), an important inhibitory neurotransmitter in the brain. This is because 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, long-term clinical trials have shown that vigabatrin is an effective anticonvulsant when used as adjunctive therapy in patients with epilepsy inadequately controlled by standard therapy. This efficacy is particularly noted in patients with partial seizures.

The epidemiology of visual field defects (VFDs) in patients with refractory partial epilepsy was observed in an observational, open-label, multicenter, parallel-group, phase IV comparative study that 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 never treated with vigabatrin (group III). The table below presents the main results at the time of inclusion, as well as the first and last summary assessments in the evaluable 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 absorption of vigabatrin. The time to reach maximum plasma concentrations (tmax) is approximately 1 hour.

Distribution

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

Biotransformation

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

Excretion from the body

Vigabatrin is eliminated by renal excretion with a terminal half-life of 5–8 hours. The 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 as unchanged drug in the urine within the first 24 hours after administration.

Pharmacokinetic/pharmacodynamic relationships

There is no direct correlation between plasma concentration and efficacy. The duration of action of the drug 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. Following a single dose of 37–50 mg/kg of vigabatrin oral solution, tmax was approximately 2.5 hours in neonates, 5.7 hours in infants, and 5.5 hours in children. The mean Cl/F of the active S-enantiomer of vigabatrin in infants and children was 0.591 L/h/kg and 0.446 L/h/kg, respectively.

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

Microvacuolation of white matter was observed in the brains of rats, mice, and dogs at doses of 30 to 50 mg/kg/day. In monkeys, these pathological changes were minimal or equivocal. This phenomenon is caused by the detachment of the outer lamellar sheath of myelinated fibers, a characteristic change of intramyelinic edema. In both rats and dogs, intramyelinic edema was reversible after cessation of vigabatrin treatment, and even with continued treatment, histological regression was observed.

However, in rodents, minor residual changes such as axonal swelling (eosinophilic spheroids) or peroxisome mineralization were observed. Electrophysiological studies in dogs indicate that intramyelinic swelling is associated with an increase in the latency of evoked sensory potentials, which is reversible upon discontinuation of treatment.

Vigabatrin-associated retinotoxicity 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 cone and rod cell zones. Other retinal layers were not affected. These lesions occurred in 80–100% of animals at an oral dose of 300 mg/kg/day.

The histological appearance of these lesions was found to be comparable to those seen in albino rats after excessive light exposure. However, the retinal changes may also be a direct consequence of the drug.

Animal studies have shown that vigabatrin does not have any harmful effects on fertility or development of the offspring. No teratogenic effects were observed in rats given doses up to 150 mg/kg (3 times the human dose) and in rabbits given doses up to 100 mg/kg. However, a slight increase in the incidence of cleft palate was observed in rabbits at doses of 150 to 200 mg/kg.

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

Indication

Use in combination with other antiepileptic drugs for the treatment of patients with resistant partial epilepsy, with or without secondary generalization, in case of ineffectiveness or poor tolerance of appropriate drug combinations.

Use as monotherapy for infantile spasms (West syndrome).

Contraindication

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

Interaction with other medicinal products and other types of interactions

Since vigabatrin is not metabolized, is not protein bound, and is not a cytochrome P450 inducer, interactions with other drugs are unlikely. However, in controlled clinical trials, a gradual decrease in phenytoin plasma concentrations of 16–33% was observed. The exact nature 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 in controlled clinical trials, and no clinically significant interactions were identified.

Vigabatrin may cause a decrease in measurable plasma alanine aminotransferase (ALT) and, to a lesser extent, aspartate aminotransferase (AST). The magnitude of ALT suppression has been reported to range from 30% to 100%. Therefore, these liver function tests may be misleading in patients taking vigabatrin (see section 4.8).

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

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

Application features

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

Visual field defects (VFD)

According to available data, visual field defects usually manifest as bilateral concentric narrowing of the visual field, which is usually more pronounced on the nasal side than on the temporal side. An annular defect is often observed in the central visual field (within 30 degrees of eccentricity). DVT in patients treated with vigabatrin varied in severity, ranging from mild to severe. Severe cases may be characterized by tunnel vision. In severe cases, blindness has also been reported.

Most patients with perimetry-confirmed abnormalities were previously asymptomatic, including those with severe perimetry abnormalities. Available data suggest that DVT is irreversible, including after discontinuation of vigabatrin treatment. Aggravation of visual field defects after discontinuation of treatment cannot be excluded.

The summary of these surveys shows that one third of patients treated with vigabatrin suffer from BPH. Men are more likely to develop BPH than women. The incidence of BPH determined in an open clinical trial is given in the Pharmacodynamics section. This study shows a possible relationship between the risk of BPH and the degree of exposure to vigabatrin depending on the daily dose (from 1 g to more than 3 g) and the duration of treatment (maximum during the first 3 years).

Before starting treatment with vigabatrin, all patients should consult an ophthalmologist for a visual field examination.

Appropriate visual field (perimetry) testing using standard static (Humphrey or Octopus) or kinetic (Goldmann standard) perimetry should be performed prior to initiation of treatment and every six months thereafter throughout the treatment period. Static perimetry is the method of choice for determining visual field abnormalities associated with vigabatrin.

Electroretinography may be useful but should be performed only in adults who are unable to cooperate during perimetry. The first oscillatory potential and 30 Hz blink response seen on electroretinograms have been reported to correlate with vigabatrin-induced DVT. These responses are delayed and have a smaller amplitude than normal. These changes have not been observed in patients receiving vigabatrin who do not have DVT.

The patient and/or caregiver should be fully informed about the frequency and consequences of developing DVT during vigabatrin treatment. Patients should be informed of any new visual problems or symptoms that may be related to visual field narrowing. If visual symptoms develop, the patient should be referred to an ophthalmologist.

If visual field narrowing is observed during follow-up, gradual discontinuation of vigabatrin treatment should be considered. If continued treatment is necessary, more frequent examinations (perimetry) may be necessary to detect progression of the narrowing or the appearance of visual defect.

Vigabatrin should not be used concomitantly with other retinotoxic drugs.

Children

Perimetry is not recommended for children under 9 years of age. The risks of treatment for children should be weighed very carefully against the expected benefits. There is currently no approved method for diagnosing or ruling out visual field defects in children who cannot undergo standard perimetry.

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

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

Visual acuity

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

Retinal disease, blurred vision, optic 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 treatment and then every 6 months during treatment.

Neurological and psychiatric disorders

Given the results of safety studies conducted in animals, patients receiving vigabatrin should be carefully monitored for possible neurological adverse reactions.

Cases of brain abnormalities on MRI have been reported, particularly in infants/young children treated with high doses of vigabatrin for infantile spasms. The clinical significance of these abnormalities is not yet known. In addition, cases of intramyelinating edema (IMO) have been reported, particularly in infants/young children treated with infantile spasms (see sections 4.8 and 5.3). IMO was reversible upon discontinuation of treatment, and it is therefore recommended that vigabatrin be gradually discontinued if IMO occurs.

Abnormal movements, including dystonia, dyskinesia and hypertonia, have been reported in patients treated for infantile spasms. The benefit/risk of vigabatrin should be assessed on an individual patient basis. If new abnormal movements develop during treatment with vigabatrin, consideration should be given to reducing the dose or gradually discontinuing treatment.

Some patients receiving vigabatrin may experience an increased frequency of seizures or the development of new types of seizures (see section 4.8). These events may also occur as a result of overdose, decreased plasma concentrations of concomitantly administered antiepileptic drugs, or paradoxical effects.

As with any antiepileptic drug, abrupt discontinuation of vigabatrin treatment may result in the recurrence of seizures. If a patient needs to discontinue vigabatrin treatment, gradual dose reduction over 2–4 weeks is recommended.

Vigabatrin should be used with caution in patients with a history of psychosis, depression, or conduct disorder. Psychiatric adverse events (e.g., agitation, depression, thought disorder, paranoid reactions) have been reported during vigabatrin treatment. These events have occurred in patients with and without a 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 small increased risk of suicidal ideation and behavior. The reasons for this risk are unknown, and the available data do not exclude an increased risk with vigabatrin. Therefore, patients should be closely monitored for signs of suicidal ideation and behavior and treated appropriately. Patients (and their caregivers) should be advised to seek medical advice if signs of suicidal ideation and behavior appear.

Elderly people and patients with renal insufficiency

Since vigabatrin is excreted by the kidneys, special caution is required when treating patients with creatinine clearance below 60 ml/min and the elderly. Such patients should be closely monitored for side effects such as sedation or confusion (see section 4.2).

Concomitant use of vigabatrin and clonazepam

Concomitant use of vigabatrin and clonazepam may increase the sedative effects (see section 4.5). The need for such concomitant use should be assessed taking into account all the risks.

Sabril film-coated tablets, 500 mg, contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.

Use during pregnancy or breastfeeding

Pregnancy

Risk associated with epilepsy and antiepileptic drugs in general

Children born to women treated with antiepileptic drugs have a 2–3-fold higher incidence of birth defects than the general population. The most commonly reported are cleft lip, cardiovascular malformations, and neural tube defects. Polytherapy may be associated with a higher risk of birth defects than monotherapy, so monotherapy should be used whenever possible.

All patients of reproductive age are advised to seek specialist advice. The need for antiepileptic treatment should be reviewed when the patient is planning pregnancy.

In the event of pregnancy in women being treated for epilepsy, abrupt discontinuation of antiepileptic therapy should be avoided, as this may lead to increased seizures and may have a detrimental effect on both the mother and the fetus.

Risk associated with vigabatrin

Spontaneous reports of birth defects and spontaneous abortions have been received from vigabatrin use during pregnancy. It is not possible to draw a definitive conclusion as to whether vigabatrin causes an increased risk of malformations when used during pregnancy due to the limited data and the concomitant use of other antiepileptic drugs during these pregnancies.

Studies in animals have shown reproductive toxicity (see section 5.3).

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

There is limited information on the possible occurrence of visual field defects in children exposed to vigabatrin in utero.

Vigabatrin is excreted in human milk. There is insufficient information on the effects of vigabatrin on newborns and infants. A decision must be made whether to discontinue breast-feeding or to discontinue Sabril therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Reproductive function

Reproductive studies in rats revealed no effects on male and female reproductive function (see section 5.3).

Ability to influence reaction speed when driving vehicles or other mechanisms

Patients with uncontrolled epilepsy are generally not allowed to drive or operate machinery. Given that drowsiness has been observed in clinical trials with Sabril, patients should be warned of this possibility at the start of treatment.

Visual field defects have been commonly reported with Sabril, which may significantly affect the ability to drive or use machines. Patients should be evaluated for visual field defects, with particular attention given to patients who drive or use machines, or perform any hazardous tasks (see also section 4.4).

Method of administration and doses

Sabril therapy should only be initiated by a specialist in epileptology, neurology or pediatric neurology. Further treatment should be coordinated and supervised by a specialist in epileptology, neurology or pediatric neurology.

Sabril is intended for oral administration once or twice daily and can be taken before or after meals.

If, after a trial of vigabatrin treatment, a clinically significant improvement in epilepsy is not achieved, treatment should not be continued. Vigabatrin should be gradually discontinued under close medical supervision.

The tablet dosage form is not used in children under 6 years of age due to the risk of inhalation.

Adults

Maximal efficacy is usually observed with doses in the range of 2–3 g/day. An initial dose of 1 g/day should be added to the patient's current antiepileptic drug regimen. The daily dose should then be titrated in 0.5 g increments at weekly intervals based 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 drug depends on the rate of resynthesis of GABA transaminase, and not on the plasma concentration of the drug (see also sections "Pharmacodynamics" and "Pharmacokinetics").

Children

Resistant partial epilepsy

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

Recommended doses for maintenance therapy depending on body weight:

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

Monotherapy of infantile spasms (West syndrome)

The recommended starting dose is 50 mg/kg/day, i.e. 1 tablet once daily. If necessary, it can be titrated over a one-week period. Doses up to 150 mg/kg/day have been well tolerated.

If your child has difficulty swallowing a tablet, you can use Sabril in the form of granules for oral administration.

If it is not possible to obtain the required doses of Sabril according to body weight, alternative drugs for monotherapy of infantile spasms (West syndrome) should be used.

Elderly patients and patients with renal impairment

Since vigabatrin is excreted by the kidneys, caution should be exercised when prescribing the drug to the elderly and, in particular, to patients with creatinine clearance less than 60 ml/min. Adjustment of the dose or frequency of administration may be necessary. Such patients may respond to a lower dose of the drug. Patients should be monitored for side effects such as sedation or confusion (see sections "Special instructions for use" and "Adverse reactions").

Children.

The drug is used in children according to indications, taking into account body weight, according to the section "Method of administration and dosage".

The tablet dosage form of vigabatrin is not used in children under 6 years of age due to the risk of inhalation.

Overdose

Symptoms

Vigabatrin overdose has been reported. The most common doses reported were 7.5 to 30 g; however, doses up to 90 g have been reported. In approximately half of the cases, multiple drugs were taken. The most common symptoms included drowsiness or coma. Other symptoms reported rarely included dizziness, headache, psychosis, respiratory depression or apnea, bradycardia, hypotension, agitation, irritability, confusion, abnormal behavior, and speech disorders. No overdoses resulted in death.

There is no specific antidote. Usual supportive measures should be used. Measures to remove unabsorbed drug may be used. Activated charcoal has shown little ability to absorb vigabatrin in an in vitro study. The efficacy of hemodialysis in the treatment of vigabatrin overdose is unknown. In isolated cases, hemodialysis has reduced plasma concentrations of vigabatrin by 40–60% in patients with renal insufficiency receiving therapeutic doses of vigabatrin.

Adverse reactions

Both mild and severe visual field defects have been reported frequently in patients treated with vigabatrin. Severe defects may be disabling. These defects usually occur after several months or even years of treatment with vigabatrin. The results of these studies suggest that visual field defects occur in one third of patients treated with vigabatrin (see section 4.4).

In controlled clinical trials, approximately 50% of patients experienced side effects during treatment with vigabatrin. In adults, the majority of side effects are related to the central nervous system, including sedation, drowsiness, fatigue, and impaired concentration. In children, on the other hand, agitation or agitation has been reported frequently. The incidence of these side effects is usually higher at the beginning of treatment and then gradually decreases.

As with any antiepileptic drug, some patients taking vigabatrin may experience an increased frequency of seizures or even status epilepticus. Patients with a history of myoclonic seizures are particularly susceptible to these effects. New onset or worsening of pre-existing myoclonus has been reported rarely.

The table below lists adverse reactions 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 unknown (cannot be estimated from the available data).

*Psychiatric reactions have been reported during treatment with vigabatrin. These reactions have occurred in patients with and without a psychiatric history. They were generally reversible upon dose reduction or gradual discontinuation of treatment (see section 4.4). Depression is a psychiatric reaction that was commonly observed in clinical trials but rarely required discontinuation of vigabatrin.

** Rare cases of encephalopathy symptoms such as marked sedation, stupor or confusion associated with non-specific slow waves on the electroencephalogram have been observed shortly after initiation of vigabatrin treatment. These reactions are reversible upon dose reduction or discontinuation of vigabatrin (see section 4.4).

*** Laboratory results indicate that treatment with vigabatrin does not cause nephrotoxicity. Decreases in ALT and AST were observed, which are believed to be the result of inhibition of these aminotransferases by vigabatrin.

Adverse reactions observed in children

In children, mental disorders, namely: agitation, agitation, were very often observed when using vigabatrin.

Reporting adverse drug reactions is important. This allows for continued monitoring of the benefit/risk ratio of this medicinal product. Healthcare professionals, pharmacists, and patients or their legal representatives should report all suspected adverse drug reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Expiration date

3 years.

Storage conditions

Does not require any special storage conditions. Keep out of the reach of children.

Packaging

No. 100 (10 × 10): 10 film-coated tablets in a blister; 10 blisters in a cardboard box.

No. 100 (10 × 10): 10 film-coated tablets in a blister; 10 blisters in a cardboard box with a sticker in Ukrainian.

Vacation category

According to the recipe.

Producer

PATHEON FRANCE, France.

Location of the manufacturer and its business address.

Boulevard de Champaret 40, Bourgoin Jallieu, 38300, France / 40 boulevard de Champaret, BOURGOIN JALLIEU, 38300, France.