Sibelium

Sibelium

flunarizine

Nhà sản xuất:

Janssen-Cilag

Nhà phân phối:

DKSH
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Contents
Flunarizine hydrochloride.
Description
Each SIBELIUM tablet contains flunarizine hydrochloride 5.89 mg equivalent to 5 mg flunarizine base.
Excipients/Inactive Ingredients: Lactose monohydrate, maize starch, hypromellose 2910 15mPa.s, polysorbate 20, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, and magnesium stearate.
Action
Pharmacotherapeutic Group: OTHER ANTIMIGRAINE DRUGS. ATC Code: N02CX.
Pharmacology: Pharmacodynamics: Flunarizine has an H1 antihistamine, an antidopaminergic, and anticholinergic action.
Flunarizine is a selective calcium antagonist. In addition, its use in the maintenance therapy of migraine is based on selectively opposing the entry of the cell's calcium ions.
Flunarizine has no effect on contractility or cardiac conduction.
Pharmacokinetics: Flunarizine is well absorbed, reaching peak plasma concentrations in 2-4 hours and steady state in 5-6 weeks.
Absorption: Flunarizine is well absorbed (>80%) from the gastrointestinal tract, reaching peak plasma concentrations 2-4 hours after oral administration. Under conditions of reduced gastric acidity (higher gastric pH), bioavailability may be lower.
Distribution: The plasma protein binding of flunarizine is >99%. It has a large volume of distribution of approximately 78 L/kg in healthy subjects and approximately 207 L/kg in epileptic patients indicating extensive distribution in the extravascular compartment. It quickly crosses the blood-brain barrier, and the intracerebral concentrations are around 10 times higher than the plasma concentrations.
Metabolism: Flunarizine is metabolized by the liver into at least 15 metabolites. La principle metabolic pathway is CYP2D6.
Elimination: Flunarizine is primarily excreted as unchanged product and metabolites in the feces via the bile. Within 24 to 48 hours after administration, about 3% to 5% of the dose of flunarizine administered is eliminated in the feces in unchanged form and as metabolites and less than 1% is excreted in the urine in unchanged form. Its terminal elimination half-life is very variable, ranging from 5-15 hours in most individuals after a single administration. Some subjects show measurable plasma concentrations of flunarizine (>0.5 ng/mL) for an extended period of time (up to 30 days), perhaps due to a redistribution of the product from other tissues.
Repeated administration: Plasma concentrations of flunarizine reach steady-state after approximately 8 weeks of once-daily multiple dosing and are about 3-fold higher than those observed after a single dose. Steady-state flunarizine concentrations are proportional over a dose range of 5 mg to 30 mg.
Toxicology: Preclinical Safety Data: In preclinical studies, effects on the central nervous system were observed only for exposures considered sufficiently high compared with the maximum human exposure indicating little clinical significance.
In a single dose toxicity study, the LD50 was 960-1896 mg/kg and 343-1935 mg/kg in mice and rats, respectively. Repeated dose toxicity studies in rats and dogs demonstrated clinical effects on the central nervous system (including: sedation in rats and salivation, miosis, relaxed nictitating membrane, ataxia, trembling of the body, muscle tension, prostration, myoclonus, and oscillating movements of the head in dogs) which may be due to an increase of the pharmacological effect; however, these effects are observed generally at doses well above (approximately 400 times) the maximum therapeutic doses for humans on a mg/kg basis.
In reproduction studies, no effects were seen on fertility and there were no teratogenic effects. However, at high doses (approximately 150-400 times the maximum therapeutic dose in humans on a mg/kg basis), a secondary fetal toxicity with maternal toxicity was observed.
Flunarizine is not mutagenic or carcinogenic. Slight effects on the development of the mammary gland and the occurrence of tumors linked to prolactin, but only at toxic doses (approximately 50-100 times the maximum therapeutic dose in humans on a mg/kg basis) were observed in mice.
Indications/Uses
Maintenance treatment of migraine, when other treatments are ineffective or poorly tolerated.
Dosage/Direction for Use
Dosage: Adults up to 65 years of age: 5 mg per day in the evening, for 4 to 8 weeks.
If depression, extrapyramidal symptoms, or other serious adverse effects occur, treatment should be discontinued (see Precautions).
If there is no response after 8 weeks the patient will be considered a non-responder and treatment will be stopped.
In case of inadequate clinical response, increasing the dose to 10 mg per day could be considered, depending on tolerance.
Do not exceed a treatment period of more than 6 months.
Patients over 65 years of age: 5 mg per day, in the evening, for 4 to 8 weeks.
If depression, extrapyramidal symptoms, or other serious adverse effects occur, treatment should be discontinued (see Precautions).
If there is no response after 8 weeks the patient will be considered a non-responder and treatment will be stopped.
Do not exceed a treatment period of more than 6 months.
Paediatric population: Children 12 years and older: as an exception when migraines are debilitating: 5 mg/day in the evening. Duration of treatment should not exceed 6 months.
Children less than 12 years old: the safety and efficacy of flunarizine have not been established. The use of flunarizine is not recommended in children under 12 years of age.
Method of administration: As a result of drowsiness and sedation, it is preferable to take the medication in the evening when going to bed.
Overdosage
A few cases of acute overdosage (doses higher than 600 mg per intake) have been reported.
The main symptoms observed are sedation, agitation, tachycardia.
Treatment consists of: charcoal administration, symptomatic treatment.
There is no specific antidote.
Contraindications
This medication MUST NEVER BE USED in the following cases: Hypersensitivity to the active substance or one of its excipients listed in Description; Pre-existing symptoms of Parkinson's disease (see Precautions and Adverse Reactions); History extrapyramidal symptoms (see Precautions and Adverse Reactions); Depression or recurrent history of depressive syndrome (see Precautions and Adverse Reactions).
Special Precautions
Flunarizine can induce depressive symptoms and extrapyramidal symptoms and reveal a Parkinsonian syndrome, especially in the elderly. Patients should therefore use it with caution.
The recommended dose must not be exceeded. Patients should be monitored at regular intervals, especially during maintenance treatment, so that any extrapyramidal or depressive symptoms may be detected early and if so, treatment discontinued.
The time before appearance of an extrapyramidal syndrome may be long (around 1 year). In general, they are not serious but may last for several months after the end of treatment (average regression time of 3 months). The improvement may be incomplete and it may be necessary to start anti-Parkinson treatment. In some cases, symptoms may persist in spite of treatment.
Cases of depressive syndrome have commonly been reported. They occur 5 to 8 months after the beginning of treatment. In general, they are not serious, however, in certain cases, the prescription of antidepressants and/or hospitalization may prove necessary.
Possibility of weight gain during treatment with flunarizine.
In rare cases, fatigue that increases progressively in intensity was reported during treatment with flunarizine: in this case, the treatment must be discontinued.
This medication contains lactose. Its use is not recommended for patients exhibiting an intolerance to galactose, Lapp lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary diseases).
Effects on Ability to Drive and Use Machines: Attention is drawn, notably for drivers of vehicles and users of certain machines, to the possible risks attached to the use of this medication.
Use In Pregnancy & Lactation
Pregnancy: There are no adequate data available on the use of flunarizine in pregnant women. Studies in animals have shown no evidence of direct or indirect harmful effects on pregnancy, embryo/fetal development, birth, or postnatal development.
In the absence of teratogenic effects in animals, a malformative effect in the human species is not expected. In fact, to date, substances responsible for malformations in the human species have proved to be teratogenic in animals during studies conducted on the two species.
As a result, as a precaution, it is preferable not to use flunarizine during pregnancy.
Breast-feeding: It is not known whether flunarizine passes into breast milk. Animal studies have shown excretion of flunarizine in breast milk.
The decision to interrupt breast-feeding or to continue/interrupt treatment with flunarizine must be made by taking into account the benefit of breast-feeding for the child and the benefit of the treatment for the mother.
Adverse Reactions
The safety of SIBELIUM was evaluated in 247 patients treated with flunarizine who participated in two controlled trials versus placebo, one in the treatment of migraine, the other in the treatment of dizziness, and among 476 patients treated with flunarizine participating in two controlled trials versus an active comparator in the treatment of vertigo and/or migraine (indication in the treatment of vertigo has been removed, the risk/benefit ratio being unfavorable). Based on the pooled safety data from these clinical studies, the most frequently reported undesirable effects (incidence ≥4%) were: weight gain (11%), drowsiness (9%), depression (5%), increased appetite (4%), and rhinitis (4%).
Undesirable effects reported with the use of SIBELIUM in clinical trials (including the previously-mentioned effects) and in the post-marketing period are summarized in the table as follows. The frequencies are presented according to the following convention: Very common: ≥1/10, Common: ≥1/100 to <1/10, Uncommon: ≥1/1000, Rare: ≥1/10000 to 1/1000, Very rare: <1/10000, Not known: the frequency cannot be estimated from the available data. (See table.)


Click on icon to see table/diagram/image


Reporting of suspected adverse reactions: Reporting suspected undesirable effects after authorization of the medication is important. It allows continuous clinical monitoring of the benefit/risk ratio of the medication. Healthcare professionals report any suspected undesirable effect via the national reporting system: National Centre and Regional Centre for Drug Information and Adverse Drug Reactions Monitoring.
Please inform the doctor or pharmacist immediately of all adverse reactions upon drug administration.
Drug Interactions
Combinations not recommended: Alcohol: Increase of sedative effect with alcohol. Impairment of alertness may make driving vehicles and the use of machines dangerous.
Avoid consuming alcoholic drinks and medications containing alcohol.
Combinations to take into account: Atropinic medications: Take into account that atropine-like substances can add to undesirable effects and more easily cause urinary retention, acute onset glaucoma, constipation, dry mouth, etc.
Various atropine medicinal products are represented by tricyclic antidepressants, most atropinic H1-antihistamines, anti-parkinsonian anticholinergics, atropinic antispasmodic agents, disopyramide, phenothiazine neuroleptics, as well as clozapine.
Sedative drugs: It is necessary to take into account the fact that numerous medications or substances may add to their depressive effects on the central nervous system and contribute to reducing vigilance. This refers to morphinic derivatives, (analgesics, antitussives and replacement therapies), neuroleptics, barbiturates, benzodiazepines, anxiolytics other than benzodiazepines (for example, meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedative H1 antihistamines, central antihypertensives, baclofen and thalidomide.
Others: Topiramate: Topiramate did not affect the pharmacokinetics of flunarizine. During the administration of flunarizine with 50 mg of topiramate every 12 hours, a 16% increase in systemic exposure to flunarizine was observed in migraine patients compared with a 14% increase observed in patients treated by flunarizine alone. The pharmacokinetics of the steady state of topiramate is not modified by the concomitant administration of flunarizine.
Caution For Usage
Incompatibilities: Not applicable.
Storage
Do not store above 30°C. Store in the original package. 
Shelf-Life: 2 years from manufacturing date.
ATC Classification
N07CA03 - flunarizine ; Belongs to the class of antivertigo preparations.
Presentation/Packing
Tab 5 mg x 5 x 20's.
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