SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Pizotifen 1.5mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains pizotifen 1.5 mg (as hydrogen malate).

For excipients see section 6.1

3    PHARMACEUTICAL FORM

Coated tablet.

White, film-coated tablets.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Prophylactic treatment of recurrent vascular headaches, including classical migraine, common migraine and cluster headache (periodic migrainous neuralgia).

It is not effective in relieving migraine attacks once in progress.

4.2. Posology and method of administration

Dose:

Adults:

Usually 1.5 mg daily. This may be taken as a single dose at night or in three divided doses. Dosage should be adjusted to individual patient requirements up to a maximum of 4.5 mg daily. Up to 3 mg may be given as a single dose.

Children (aged over 7years):

Use of 1.5 mg Pizotifen Tablets is not recommended. The appropriate paediatric doses may be given using the 0.5 mg Pizotifen Tablets.

The elderly :

Clinical work with pizotifen has not shown that elderly patients require different dosages from younger patients.

Method of Administration

For oral use.

4.3. Contraindications

Hypersensitivity to pizotifen or to any of the excipients. Pizotifen should not be given to children under 7 years of age.

4.4. Special warning and precautions for use

Although the anticholinergic activity of pizotifen is relatively weak, caution is required in the presence of closed angle glaucoma and in patients with a predisposition to urinary retention. Dosage adjustment may be necessary in patients with kidney insufficiency.

Pizotifen should be used in caution in patients with a history of epilepsy.

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

4.5. Interaction with other medicinal products and other forms of interaction

The effect of alcohol may be enhanced. Pizotifen may increase and prolong drowsiness that occurs as an adverse effect of commonly used tranquillizers, hypnotics, antihistamines (including certain common cold preparations) and antidepressants. Pizotifen should not be used in patients receiving monoamine oxidase inhibitors (MAOIs). The hypotensive effect of adrenergic neurone blockers (antihypertensives) are antagonised by pizotifen.

Pregnancy and lactation

Clinical data with pizotifen in pregnancy are very limited and should therefore only be prescribed or administered under compelling circumstances.

Although the concentration of pizotifen measured in the milk of treated mothers are not likely to affect breast-fed infants, its use in nursing mothers is not recommended.

4.7. Effects on ability to drive and use machines

Pizotifen may cause drowsiness, somnolence and dizziness. Therefore, caution should be exercised when driving or using machines.

Patients being treated with pizotifen and presenting with drowsiness (including somnolence and fatigue) must be instructed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk.

4.8. Undesirable effects

The most common side-effects are appetite stimulating effects, increases in body weight and drowsiness (including somnolence and fatigue).

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (>1/10); common (>1/100, < 1/10); uncommon (>1/1000, < 1/100); rare (>1/10,000, < 1/1000); very rare (< 1/10,000)and not known (cannot be estimated from the available data).

Immune system disorders:

Rare: Hypersensitivity reactions, face oedema, urticaria and rash.

Metabolism and nutrition disorders:

Very common: Appetite stimulating effect and increase in body weight. Psychiatric disorders:

Rare: Depression, CNS stimulation (e.g. aggression, agitation, restlessness and excitability), hallucination, insomnia, anxiety.

Nervous system disorders:

Common: Drowsiness (including somnolence), dizziness.

Rare: Paraesthesia.

Very rare: Seizures.

Gastrointestinal disorders:

Common: Nausea, dry mouth.

Uncommon: Constipation.

Musculoskeletal and connective tissue disorders:

Rare: Myalgia, arthralgia.

General disorders and administration site conditions:

Common: Fatigue.

Acute withdrawal reactions have been reported following abrupt cessation of Pizotifen therefore gradual withdrawal is recommended. Withdrawal symptoms include anxiety, tremors, insomnia, nausea and loss of consciousness.

4.9. Overdose Symptoms

Drowsiness, dizziness, hypotension, dryness of the mouth, confusion, excitatory states (in children), ataxia, nausea, vomiting, dyspnoea, cyanosis, tachycardia, convulsions (particularly in children), coma and respiratory paralysis.

Treatment

Administration of activated charcoal is recommended; in case of very recent uptake, gastric lavage may be considered. Severe hypotension must be corrected (CAVE: adrenaline may produce paradoxical effects). If necessary, symptomatic treatment including monitoring of the cardiovascular and respiratory systems. Excitatory states or convulsions may be treated with short acting benzodiazepines.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pizotifen is a tricyclic (benzocycloheptathiopene) compound possessing structural similarities to cycloheptadine and the tricyclic antidepressants. It possesses strong antiserotoninergic and antihistaminergic effects, together with a weak anticholinergic action. It also possesses appetite-stimulating properties.

The prophylactic effect of pizotifen in migraine is associated with its ability to modify the humoral mechanisms of headache. It inhibits the permeability-increasing effect of serotonin and histamine on the affected cranial vessels, thereby checking the transudation of plasmakinin so that the pain threshold of the receptors is maintained at ‘normal’ levels. In the sequence of events leading to migraine attack, depletion of plasma serotonin contributes to loss of tone in the extracranial vessels. Pizotifen inhibits serotonin-reuptake by the platelets, maintaining plasma serotonin and preventing the loss of tone and passive distension of the extracranial arteries.

5.2. Pharmacokinetic properties Absorption

Absorption of pizotifen in man is fast (absorption half life 0.5 to 0.8 hours) and nearly complete. The absolute bioavailability is 78%. Maximum blood levels are reached 5 hours after a single 2 mg oral administration of pizotifen (parent compound and N-glucuronide-conjugate measured together).

Biotransformation

Pizotifen is extensively metabolised. Glucuronidation is the main route of biotransformation and the main metabolite is the N-glucuronide-conjugate, accounting for at least 50% of the plasma and 60-70% of urinary excreted radioactivity.

Distribution

Protein binding of pizotifen in human plasma in vitro amounts to 91%. The distribution volume in man is 833 L and 70 L for pizotifen and its N-glucuronide, respectively.

Elimination

About one-third of an orally applied dose is excreted via the biliary route into the faeces, a significant proportion, corresponding to about 18% of the applied dose, representing parent drug, likely produced in the intestine after biliary excretion of the N-glucuronide-conjugate. Less than 1% of the administered dose of pizotifen is excreted unchanged in the urine, whereas up to 55% is excreted as metabolites. Pizotifen is eliminated with a half life of approximately 23 hours (total radioactivity). Unchanged pizotifen and the N-glucuronide have, as estimated from the excretion in the urine, a comparable elimination half-life.

Special patient groups

In patients with kidney insufficiency dosage adjustment may be necessary.

5.3. Preclinical safety data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Cores

Lactose

Microcrystalline cellulose Maize starch Povidone

Magnesium stearate Silicon dioxide

Coating

Hydroxypropylmethylcellulose

Polyethylene glycol

Talc

Titanium dioxide

6.2. Incompatibilities

None stated

6.3. Shelf life

48 Months

6.4. Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5. Nature and contents of container

Blisters containing 28, 56 and 60 tablets.

6.6. Instructions for use and handling

None stated

MARKETING AUTHORISATION HOLDER

Waymade Plc

t/a Sovereign Medical

Sovereign House

Miles Gray Road

Basildon

Essex, SS14 3FR

United Kingdom

8.    MARKETING AUTHORISATION NUMBER

PL 06464/1003

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/12/2008

10    DATE OF REVISION OF THE TEXT

07/07/2010