Summary of medicine characteristics - PIZOTIFEN TABLETS BP 0.5 MG
PIZOTIFEN TABLETS BP 0.5mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
2 QUALITATIVE AND QUANTITATIVE COMPOSITIONEach tablet contains 0.725mg of Pizotifen hydrogen malate equivalent to 0.500mg of Pizotifen base.
Also contains Lactose.
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
3 PHARMACEUTICAL FORMFilm-coated tablet.
Cream film-coated, round, biconvex tablets embossed “0.5” on one side.
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.
Pizotifen is not effective in relieving a migraine attack once in progress.
4.2 Posology and method of administration
Posology
Adults: 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.
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
For oral use.
4.3 Contraindications
Known hypersensitivity to pizotifen or 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 (eg 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.
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 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, 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 lactationWomen of childbearing potential
There is no data for recommendations in women of child-bearing potential.
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.
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.
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 ( 11/10); common ( 11/100, < 1/10); uncommon ( 11/1000, < 1/100); rare ( 11/10,000, < 1/1000); very rare ( < 10,000), unknown (frequency cannot be estimated from available data).
| Nervous system disorders Common Rare Very rare | Drowsiness (including somnolence), dizziness. Paraesthesia. Seizures. |
| Gastrointestinal disorders Common Uncommon | Dry mouth, nausea. Constipation. |
| Hepatobiliary disorders Unknown | Hepatic enzyme increased, jaundice, hepatitis*1 |
| Skin and subcutaneous tissue disorders Rare | Urticaria, rash. |
| Musculoskeletal and connective tissue disorders Rare Unknown | Myalgia, arthralgia. Muscle cramps*1 |
| Metabolism and nutrition disorders Very common | Appetite stimulating effect and increase in body weight. |
| General disorders and administration site conditions Common | Fatigue. |
| Immune system disorders Rare | Hypersensitivity reactions, face oedema. |
| Psychiatric disorders | |
| Rare | Depression, CNS stimulation (e.g. aggression, agitation ), anxiety, hallucination, insomnia, rare cases of sleep disorders. |
*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; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdoseSymptoms: 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.
5 PHARMACOLOGICAL PROPERTIES
5 PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
| Pharmacotherapeutic group: antimigraine drug, ATC code: N02C X01 Pizotifen is a tricyclic (Benzocycloheptathiophene) compound possessing structural similarities to cyproheptadine and the 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. | |
| 5.2 | Pharmacokinetic properties Absorption Following oral administration, the drug is rapidly and almost completely absorbed from the gastrointestinal tract. The mean absolute bioavailablility 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 twocompartment 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 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 dataRepeat-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.
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.
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
Tablet core contains:
Povidone
Lactose monohydrate
Maize starch
Magnesium stearate
Microcrystalline cellulose (E460)
Film-coat contains:
Hypromellose
Medium Chain Triglycerides Titanium Dioxide (E171)
Yellow Iron Oxide (E172)
Black Iron Oxide (E172)
6.2. Incompatibilities
None known
6.3. Shelf Life
Shelf-life
Two years from date of manufacture.
Shelf-life after dilution/reconstitution Not applicable.
Shelf-life after first opening
Not applicable.
6.4 Special precautions for storage
Do not store above 25°C.
6.5. Nature and Contents of Container
6.5. Nature and Contents of ContainerThe product containers are rigid injection moulded polypropylene tablet containers with snap-on polyethylene lids.
The product may also be supplied in blister packs in cartons:
a) Carton: Printed carton manufactured from white folding box board.
b) Blister pack: (i) 250^m white rigid PVC. (ii) Surface printed 20^m
hard temper aluminium foil with 5–7g/M2 PVC compatible heat seal lacquer on the reverse side.
Pack sizes: 28, 30, 56, 60, 84, 90, 100, 112, 120, 168, 180.
6.6. Instruction for Use, Handling and Disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Accord-UK Ltd
(Trading style: Accord)
Whiddon Valley
Barnstaple
Devon
EX32 8NS
8. MARKETING AUTHORISATION NUMBER
PL 00142/0446
9. DATE OF FIRST AUTHORISATION/RENEWAL
OF
AUTHORISATION
December 1998