This information is intended for use by health professionals

1. Name of the medicinal product

Pizotifen 0.5 mg Tablets

2. Qualitative and quantitative composition

Each tablet contains 0.725 mg pizotifen hydrogen malate BP, equivalent to 0.5 mg of pizotifen base. Each film-coated tablet contains lactose monohydrate 32.14 mg, as excipient

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Film coated tablet.

The tablets are white, marked P on one side and plain on the reverse.

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

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 according to individual patient requirements, up to a maximum of 4.5 mg daily. Up to 3 mg can be given as a single dose.

Children (aged over 2 years): Up to 1.5 mg daily, usually as a divided dose, although up to 1 mg has been given as a single dose at night.

Elderly: As for adults.

Method of administration: oral

4.3 Contraindications

Hypersensitivity to the drug or to any of the other tablet ingredients.

Pizotifen should not be given to children under 2 years of age

4.4 Special warnings 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 required in patients with renal insufficiency.

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

Pizotifen tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-glactose malabsorption should not take Pizotifen tablets.

4.5 Interaction with other medicinal products and other forms of interaction

The central effects of sedatives, hypnotics, antihistamines (including certain common cold preparations) and alcohol may be enhanced by pizotifen.

Pizotifen antagonises the hypotensive effect of adrenergic neurone blockers

4.6 Fertility, pregnancy and lactation

Pregnancy

As clinical data with pizotifen in pregnancy are very limited, it should only be administered under compelling circumstances.

Lactation

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 commonly reported side-effects are appetite stimulating effect, increase in body weight and drowsiness (including somnolence and fatigue).

Frequencies are defined as: 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), including isolated reports; 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), 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

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

Pharmacotherapeutic group: antimigraine drug, ATC code: N02C X01

Studies in experimental animals have indicated that pizotifen has strong anti-serotonin and anti- tryptaminic properties, marked antihistaminic effects and some antagonistic activity against kinins. It also possesses weak anti-cholinergic effects and sedative properties.

Pizotifen 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 re- uptake by the platelets, thus maintaining plasma serotonin and preventing the loss of tone and passive distension of the extracranial arteries.

5.2 Pharmacokinetic properties

Absorption

The absorption of pizotifen in man is fast (absorption half-life 0.5 to 0.8 hours) and nearly complete. The absolute bioavailablility 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 those in other sections of the SPC.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose monohydrate, cellulose microcrystalline, maize starch, Povidone K30, magnesium stearate, silicon dioxide, hypromellose, macrogol 6000, talc, titanium dioxide (E171).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

Do not store above 30° C. Store in the original package.

6.5 Nature and contents of container

White, opaque blister, 250 μ m PVC/40 gm2 PVDC sealed to 25 μm aluminium foil/PVDC.

The blistered product is available in cartons containing 28, 30, 56, 60, 84, 90, 112 and 120 tablets. (Please note that not all pack sizes may be marketed.)

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

Edmond Pharma Srl

Strada Statale dei Giovi 131

20037 Paderno Dugnano (MI)

Italy

8. Marketing authorisation number(s)

PL 14682/0001

9. Date of first authorisation/renewal of the authorisation

23 August 2001/ 13 March 2009

10. Date of revision of the text

October 2015

Legal category

POM