Pizotifen 1.5mg Tablets

Tablet (film-coated tablet). White, round, film-coated tablet, embossed with 'PZ 1.5' on one side. Approximately 9 mm in diameter.

4.1 Therapeutic indications 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. 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 and adolescents from 2 years of age:* 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. *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.4.3 Contraindications 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 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, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. 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.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. **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 Clinical data with pizotifen in pregnancy are very limited and should therefore only be prescribed or administered under compelling circumstances. Breast-feeding 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. 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 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. 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. 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. \*1 These adverse events were reported in patients treated with pizotifen based on post-marketing spontaneous reports. 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 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, website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.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 including monitoring of the cardiovascular and respiratory systems. Excitatory states or convulsions may be treated with short acting benzodiazepines.

5.1 Pharmacodynamic properties ATC CODE: N02CX Other migraine preparations Pizotifen is a tricyclic (benzocycloheptathiopene) compound possessing structural similarities to cycloheptadine and the tricyclic antidepressants. It possesses strong antiserotoninergic, antitryptaminic properties, antihistaminergic effects and some antagonistic activity against kinins, 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%. 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: 5.5hr). 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 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** **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** 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 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.

6.1 List of excipients Lactose monohydrate Microcrystalline cellulose Maize starch Povidone Magnesium stearate Colloidal anhydrous silica ***Coating*** Hypromellose Macrogol Talc Titanium dioxide6.2 Incompatibilities None stated6.3 Shelf life 48 Months6.4 Special precautions for storage Do not store above 25ºC. Store in the original package.6.5 Nature and contents of container Blisters containing 28, 56 or 60 tablets. Not all pack sizes may be marketed6.6 Special precautions for disposal and other handling None stated