Janssen-Cilag Ltd

Sibelium 5 mg Tablets

Each tablet contains 5 mg of flunarizine as flunarizine dihydrochloride.

Also contains lactose.

For a full list of excipients see section 6.1.

Tablet.

White, oblong tablet.

In the prophylaxis of migraine. The limited information available for periods longer than 12 months has shown flunarizine to continue to be effective. Patients should be regularly reviewed to assess their response to treatment, and if a sustained attack-free period is established, interrupted flunarizine treatment should be considered.

Adults only:

Starting Dose

Treatment is started at 10 mg daily (at night) in patients less than 65 years of age and at 5 mg daily (at night) in patients over 65 years. If, during this treatment, depressive, extrapyramidal or other unacceptable adverse experiences occur, administration should be discontinued. If, after 2 months of this initial treatment, no significant improvement is observed, the patient should be considered a non-responder and administration should be discontinued.

Maintenance Treatment

If the patient is responding satisfactorily and a maintenance treatment is needed, the same daily dose should be used, but this time interrupted by two successive drug-free days every week, eg Saturday and Sunday.

Even if the prophylactic maintenance treatment is successful and well tolerated, it should be interrupted after 6 months and it should be re-initiated only if the patient relapses.

Elderly: As above.

Children, Infants and Neonates: Not recommended.

Use in patients with current depressive illness or with a history of recurrent depression (see Sections 4.4 and 4.8).

Use in patients with pre-existing symptoms of Parkinson's Disease or other extrapyramidal disorders (see Sections 4.4 and 4.8).

Sibelium Tablets are contra-indicated in patients with a known hypersensitivity to flunarizine, or to any excipients contained in the formulation.

Flunarizine may give rise to extrapyramidal and depressive symptoms and reveal Parkinsonism, especially in elderly patients. Therefore, it should be used with caution in such patients.

The recommended dose should not be exceeded. Patients should be seen at regular intervals, especially during maintenance treatment, so that extrapyramidal or depressive symptoms may be detected early and if so, treatment discontinued.

Female patients with a history of depressive illness may be at particular risk of depression during chronic treatment with this medicine.

Accumulation may occur if given at dose levels higher than recommended, with an increased incidence of side effects.

In rare cases fatigue may increase progressively during flunarizine therapy. In this event, the therapy should be discontinued and possibly initiated again at a lower dosage.

Lactose

Flunarizine tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

When used in conjunction with anti-hypertensive drugs, dosage of the latter may need adjustment.

Galactorrhoea has been reported in some female patients on oral contraceptives within the first two months of flunarizine treatment.

Excessive sedation can occur when alcohol, hypnotics or tranquillisers are taken simultaneously with flunarizine.

The pharmacokinetics of flunarizine were unaffected by topiramate. After repeated dosing in migraine patients, systemic exposure to flunarizine increased by 14%. When flunarizine was co-administered with topiramate 50 mg every 12 hours, repeated dosing resulted in a 16% increase in systemic exposure to flunarizine. . The steady-state pharmacokinetics of topiramate were unaffected by flunarizine. Chronic administration of flunarizine did not affect the disposition of phenytoin, carbamazepine, valproate or phenobarbital. Plasma concentrations of flunarizine were generally lower in patients with epilepsy taking these anti-epileptic drugs (AEDs) compared to healthy subjects given similar doses. The plasma protein binding of carbamazepine, valproate, and phenytoin is not affected by co-administration with flunarizine.

4.6.1 Use during pregnancy

There are no data from the use of flunarizine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/ foetal development, parturition or postnatal development. As a precautionary measure, it is preferable to avoid the use of flunarizine during pregnancy.

4.6.2 Use during lactation

It is unknown whether flunarizine is excreted in human milk. Animal studies have shown excretion of flunarizine in breast milk. A decision on whether to discontinue breast-feeding or to continue/discontinue therapy with flunarizine should be made taking into account the benefit of breast-feeding to the child and the benefit of therapy to the woman..

Since somnolence may occur, especially at the start of the treatment, caution should be exercised during activities such as driving or operating dangerous machinery.

The safety of Sibelium (5 to 10mg/day) was evaluated in 247 flunarizine-treated subjects who participated in two placebo-controlled clinical trials in the treatment of vertigo and migraine, and in 476 flunarizine-treated subjects who participated in two comparator-controlled clinical trials in the treatment of vertigo and/or migraine. Based on pooled safety data from these clinical trials, the most commonly reported (≥ 4% incidence) Adverse Drug Reactions (ADRs) were: Weight Increased (11%), Somnolence (9%), Depression (5%), Increased Appetite (4%); and Rhinitis (4%).

Including the above-mentioned ADRs, the following table displays ADRs that have been reported with the use of Sibelium from both clinical trial and post-marketing experiences. The displayed frequency categories use the following convention:

Very common (≥1/10); common (≥1/100 to 1/10); uncommon (≥1/1,00 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data)

On the basis of the pharmacological properties of the drug, sedation and asthenia may be expected to occur.Cases of acute overdosage (up to 600 mg in one intake) have been reported and the observed symptoms were sedation, agitation and tachycardia. Treatment of acute overdosage consists of charcoal administration, induction of emesis or gastric lavage and supportive measures. No specific antidote is known.

ATC Code, N2C: Anti-Migraine Preparations

Class IV selective calcium entry blocker, which reduces arterial and arteriolar smooth muscle spasm.

The drug is well absorbed reaching peak plasma concentrations within 2-4 hours, and reaching steady state at 5-6 weeks.

Absorption

Flunarizine is well absorbed (>80%) from the gastrointestinal tract, reaching peak plasma concentrations within 2 to 4 hours after oral dosing. Under conditions of reduced gastric acidity (higher gastric pH), bioavailability may be moderately lower.

Distribution

Flunarizine is >99% bound to plasma proteins. 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 into extravascular tissue. The drug quickly crosses the blood brain barrier; concentrations in the brain are approximately 10 times higher than those in plasma.

Metabolism

Flunarizine is metabolised in the liver into at least 15 metabolites. The primary metabolic pathway is CYP2D6.

Elimination

Flunarizine is primarily eliminated as parent drug and metabolites through the faeces via bile. Within 24 to 48 hours after administration, approximately 3% to 5% of the administered dose of flunarizine is eliminated in the faeces as parent drug and metabolites and <1% is excreted as unchanged drug in urine. Its terminal elimination half-life is highly variable, ranging from 5 to 15 hours in most individual subjects after a single dose. Some subjects show measurable plasma concentrations of flunarizine (>0.5 ng/mL) for a prolonged time period (up to 30 days), possibly due to redistribution of the drug from other tissues.

Multiple-Dose

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.

Preclinical effects of a CNS nature (e.g. sedation, salivation, ataxia) were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Lactose monohydrate

Maize starch

Magnesium stearate

Colloidal anhydrous silica

Hypromellose

Polysorbate 20

Microcrystalline cellulose

Croscarmellose sodium

Not applicable.

2 years.

Do not store above 25°C.

The tablets are supplied in PVC/Aluminium blister packs in a carton containing 20 tablets.

No special requirements.

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Bucks

HP12 4EG

United Kingdom

PA 748/31/2

Date of First Authorisation: 30^th January 2009

March 2011