Summary of Product Characteristics (SmPC) - Pizotifen 0.5 mg tablets

1 NAME OF THE MEDICINAL PRODUCT

Pizotifen 0.5 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 0.725mg of Pizotifen hydrogen malate 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

White round tablet marked MP84 on one side and plain on reverse.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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

The International Classification of Headache Disorders 2nd edition (ICHD-II) are standard classifications of headache used by health professionals and describe the above-mentioned disorders as follows: prophylactic treatment of recurrent migraine headache with or without aura and of cluster headache. 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 3 divided doses. Dosage should be adjusted 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 and adolescents from 2 years of age

Up to 1.5 mg daily, usually a divided dose, although up to 1 mg has been given as a single dose at night.

Use in the elderly

Clinical work with Pizotifen has not shown elderly patients to require

different dosages from younger patients.

Special populations

Renal and hepatic impairment

Caution is required in patients with renal or hepatic impairment and dosage adjustment may be necessary (see section 5.2).

Method of Administration:

Oral

4.3 Contraindications

Known hypersensitivity to Pizotifen or to any of the excipients (see section 6.1. List of excipients).

4.4 Special warnings and precautions for use

Hepatic injury has been reported, ranging from transaminase elevations to severe hepatitis. Pizotifen treatment should be discontinued if there is any clinical evidence of hepatic dysfunction during treatment and until the cause of the liver abnormality is determined.

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. Withdrawal symptoms like depression, tremor, nausea, anxiety, malaise, dizziness, sleep disorder and weight decrease have been reported following abrupt cessation of pizotifen, therefore gradual withdrawal is recommended.

Pizotifen tablets contain lactose

Patients with rare hereditary problems of galactose intolerance, total 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), antidepressants. Pizotifen should not be used in patients receiving monoamine oxidase inhibitors (MAOIs). Pizotifen antagonises the hypotensive effect of adrenergic neurone blockers (antihypertensives).

Anticipated drug interactions to be considered

Pizotifen is extensively metabolized in the liver, primarily by N-glucuronidation. Increased plasma concentration of pizotifen upon concomitant administration of drugs which exclusively undergo glucuronidation can not be excluded.

4.6 Fertility, Pregnancy and lactation

Pregnancy

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

Breast-feeding

Although the concentrations of Pizotifen measured in the milk of treated mothers are not likely to affect the infant, its use in nursing mothers is not recommended.

Fertility

There were no fertility effects in a rat study with pizotifen hydrogen maleate.

4.7 Effects on ability to drive and use machines

Pizotifen may cause drowsiness, somnolence dizziness and other CNS effects. 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 effect, increase 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), unknown (frequency cannot be estimated from available data).

Immune system disorders:

Rare: Hypersensitivity reaction, face oedema

Metabolism and nutrition disorders:

Very common: Appetite stimulating effect and increase in body weight

Psychiatric disorders:

Rare: Depression, Central Nervous System 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

Hepatobiliary disorders

Unknown: Hepatic enzyme increased, jaundice, hepatitis^*1

Skin and subcutaneous tissue disorders

Rare: Urticaria, rash

Musculoskeletal and connective tissue disorders:

Rare: Myalgia, arthralgia

Unknown: Muscle cramps^*1

General disorders and administration site conditions:

Common: Fatigue

^*1These adverse events were reported in patients treated with pizotifen based on post- marketing spontaneous reports.

Withdrawal symptoms

Acute withdrawal reactions have been reported following abrupt cessation of Pizotifen therefore gradual withdrawal is recommended (see section 4.4 Special warnings and precautions for use). Withdrawal symptoms may include depression, tremor, nausea, anxiety, malaise, dizziness, sleep disorder and weight decrease.

Reporting of suspected adverse reactions

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow card scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card Google play or Apple App Store.

By reporting side effects you can help provide more information on the safety of this medicine.

4.9 Overdose

Symptoms: Drowsiness, dizziness, pyrexia, 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 should be given including monitoring of the cardiovascular and respiratory systems. Excitatory states or convulsions may be treated with short acting benzodiazepines.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antimigraine drug, ATC code: N02C X01 Pizotifen is a tricyclic (benzocycloheptathiopene) compound possessing structural similarities to cycloheptadine and the tricyclic antidepressants. It possesses strong antiserotoninergic, anti-tryptaminic properties, antihistaminergic effects and some antagonistic activity against kinins. Pizotifen also possesses appetite-stimulating properties.

The prophylactic effect of pizotifen in migraine is associated with its ability to modify the humoral mechanism 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

Absorption of pizotifen in man is fast (absorption half life 0.5 to 0.8 hours) and nearly complete. The absolute bioavailability is 78%. Following a single 1mg oral administration of pizotifen the mean maximum plasma concentration (Cmax) of pizotifen and its metabolite measured together were about 5 ng/mL (Tmax: 5.5 hr). Following repeated administration of 1mg three times a day for six days, the mean maximum plasma concentration at steady state was observed at 4 hr post dose (Cmax,ss: 14 ng/mL) and the mean trough plasma concentration was about 11 ng/mL Cmin,ss).

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 of 833 L and 70 L or pizotifen and its Nglucuronide, 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 administered 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 Nglucuronide have, as estimated from the excretion in the urine, a comparable elimination half-life.

Special population

Renal impairment

No specific pharmacokinetic studies were conducted in patients with renal impairment. Although pizotifen is primarily eliminated in the form of metabolites in the urine, the possibility of accumulation of inactive metabolites subsequently leading to the accumulation of the parent drug can not be ruled out. Caution is required in patients with renal impairment and dosage adjustment may be necessary. Hepatic impairment

Hepatic impairment

Although no specific pharmacokinetic studies were conducted in patients with hepatic impairment, pizotifen is extensively metabolized in liver and primarily eliminated in the form of glucuronides in the urine. Caution is required in patients with hepatic impairment and dosage adjustment may be necessary.

5.3 Preclinical safety data

Repeat-dose toxicity

Repeat-dose toxicity studies were performed in rats and dogs of up to 2 years duration. Target organs, based on histopathological findings, were liver, kidney and possibly thyroid in rats and liver, thyroid and spleen in dogs. The no-observed-effect level (NOEL) in both rats and dogs was 3 mg/kg (corresponding to 18 mg/m2 in rats and to 60 mg/m2 in dogs) which is, respectively, 5- and 18-times the maximum recommended human daily dose of 3.33 mg/m2 based on body surface area comparisons.

Reproductive toxicity

Pizotifen hydrogen malate was evaluated in reproductive and developmental toxicity studies in mice, rats and rabbits. There were no effects on fertility or teratologic effects noted at all doses up to 30 mg/kg/day. At 10 and 30 mg/kg/day in mice there was a small decrease in foetal body weight in the presence of increased maternal mortality and in rats at the highest dose there was evidence of fetotoxicity.

Mutagenicity and Carcinogenicity

Pizotifen hydrogen malate was not genotoxic in standard in vitro and in vivo tests. Conventional rodent carcinogenicity studies have not been conducted.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Cellulose microcrystalline

Maize starch,

Povidone K30

Magnesium stearate

Colloidal anhydrous silica

Hypromellose

Macrogol 6000

Talc

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable

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

Blister packs:

1. White opaque blister, 250 μm PVC/40 gm²PVDC sealed to 25 μm aluminium foil /PVDC.
2. White opaque blister, 250 μm PVC/40 gm²PVDC sealed to 25 μm aluminium foil.

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