Pizotifen

Pizotifen 0.5mg Tablets.

Each tablet contains Pizotifen Malate equivalent to Pizotifen 0.5mg.

Excipients with known effect: Each tablet contains 66.87 mg of lactose (as lactose monohydrate)

For the full list of excipients, see section 6.1.

Tablet.

Pale cream to yellow circular biconvex film-coated tablets with an approximate diameter of 6mm, marked “PZT 0.5” on one face.

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

Pizotifen is not effective in relieving a migraine attack once in progress.

Posology

Adults including the elderly:

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

Children (aged 2 years and over):

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

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

For oral use.

Known hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 (e.g. prostate hypertrophy). Dosage adjustment may be necessary in patients with kidney insufficiency.

Seizures as adverse effects have been observed more frequently in patients with epilepsy. Pizotifen should be used with caution in patients with a history of epilepsy.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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.

The following drugs may exhibit drug interactions with pizotifen upon concomitant administration.

Anticipated drug interactions to be considered

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

Central nervous system agents

The central effects of sedatives, hypnotics, anti-histamines (including certain common cold preparations) and alcohol may be enhanced by Pizotifen.

Pizotifen antagonises the hypotensive effect of adrenergic neurone blockers.

Women of childbearing potential

There is no data for recommendations in women of child-bearing potential.

Pregnancy

As clinical data with pizotifen in pregnancy are very limited, it should only be administered during pregnancy if the expected benefits outweigh the potential risks.

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.

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.

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).

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

In children CNS stimulation may occur.

Withdrawal symptoms

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

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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 (epinephrine) may produce paradoxical effects).

If necessary, symptomatic treatment should be given including monitoring of the cardiovascular and respiratory symptoms.

Excitatory states or convulsions may be treated with short-acting barbiturates or benzodiazepines. General surveillance measures are indicated.

Pharmacotherapeutic group: antimigraine drug, ATC Code: N02C X01

Pizotifen is a tricyclic (benzocycloheptathiophene) compound possessing structural similarities to cyproheptadine and tricyclic antidepressant drugs.

Pharmacodynamic studies demonstrate pizotifen to have powerful antiserotonin and antitryptaminic properties, marked antihistaminic effects and some antagonistic activity against kinins. It also possesses weak anticholinergic 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 the 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.

Absorption

Following oral administration, the drug is rapidly and almost completely absorbed from the gastrointestinal tract. The mean absolute bioavailability after oral administration is about 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).

Distribution

Pizotifen is extensively and rapidly distributed throughout the body with the mean distribution volume of 833 L and 70 L for the parent drug and its metabolite N-glucuronide, respectively. Approximately, 91% of the drug is bound to plasma proteins. The distribution and elimination kinetics have generally been described as a bi-exponential decay function using two compartment model.

Metabolism

Pizotifen is extensively metabolised in the liver primarily by glucuronidation. The main metabolite is the N-glucuronide-conjugate and accounts for at least 50% of the plasma exposure.

Elimination

About one-third of an orally applied dose is excreted via the biliary route. A significant proportion of the parent drug, corresponding to about 18% of the administered dose, is found in the faeces. The remaining fraction of the administered dose (about 55%) is primarily eliminated in the forms of metabolites in the urine. Less than 1% of the administered dose of pizotifen is excreted unchanged through the kidneys. Pizotifen and its major metabolite the N-glucuronide conjugate is eliminated with a half-life of approximately 23 hours.

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 cannot be ruled out. Caution is required in patients with renal impairment and dosage adjustment may be necessary.

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.

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 fetal 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.

Tablet Core:

Lactose Monohydrate Microcrystalline Cellulose Magnesium Stearate

Tablet Coating:

Purified Water

Opadry OY-32935 containing:

Hypromellose (E464)

Titanium Dioxide (El71)

Macrogol

Iron Oxide Yellow (El72)

Quinoline Yellow Aluminium Lake (E104)

Iron Oxide Black (El72)

None known

2 years

Store below 25^°C. Keep in the original package.

Pizotifen Tablets 0.5mg will be packed into either of the following presentations:

Blister strips constructed of 250μm PVC with a 60g/m² PVdC coating and 20μm aluminium foil with a heat sealing lacquer. The blister strips are packed into a cardboard carton. Each carton contains 28 or 84 tablets.

Polypropylene containers fitted with a polyethylene cap and a tamper-evident tear strip. Each container holds 28 or 84 tablets.

Not all pack sizes or types may be marketed.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Tillomed Laboratories Limited

220 Butterfield

Great Marlings

Luton

LU2 8DL

UK

PL 11311/0379

Date of first authorization: 17/03/2006

Date of latest renewal: 07/05/2009

20/07/2021