1. Name Of The Medicinal Product
SANOMIGRAN Elixir 0.25mg/5ml
2. Qualitative And Quantitative Composition
The active ingredient is : 4-(1-methyl-4-piperidylidene)-9,10-dihydro-4H-benzo-[4,5]cyclohepta [1,2-b] thiophene hydrogen maleate (= pizotifen hydrogen malate).
The syrup contains 0.365mg of pizotifen hydrogen malate B.P. in every 5mls.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Syrup
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 1.5mg 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 4.5mg daily. Up to 3mg may be given as a single dose.
Children and adolescents from 2 years of age
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 SANOMIGRAN 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 any of the excipients (see section 6.1 List of excipients).
4.4 Special Warnings And Precautions For Use
SANOMIGRAN Elixir does not contain sucrose nor tartrazine. The sweetening agent in SANOMIGRAN Elixir is maltitol liquid at a concentration of 4g in 5ml. Maltitol liquid contains 45% readily absorbable carbohydrate. This should be considered if prescribing the drug for diabetic patients.
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 SANOMIGRAN 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 with caution in patients with epilepsy (see section 4.8 Undesirable effects).
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 N-glucuronidation. Increased plasma concentration of pizotifen upon concomitant administration of drugs which exclusively undergo glucuronidation can not be excluded.
Central nervous system agents
The central effects of sedatives, hypnotics, antihistamines (including certain common cold preparations) and alcohol may be enhanced by SANOMIGRAN.
SANOMIGRAN antagonises the hypotensive effect of adrenergic neurone blockers.
4.6 Pregnancy And Lactation
Pregnancy
As clinical data with SANOMIGRAN in pregnancy are very limited it should only be administered during pregnancy under compelling circumstances.
Breast-feeding
Although the concentrations of SANOMIGRAN measured in the milk of treated mothers are not likely to affect the infant, its use in nursing mothers is not recommended.
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 and/or somnolence episodes 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 ( (
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*1 These adverse events were reported in patients treated with pizotifen based on post-marketing spontaneous reports.
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.
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 symptoms. 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
Pharmacodynamic studies demonstrate pizotifen to have powerful anti-serotonin and anti-tryptaminic properties, marked anti-histaminic 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 SANOMIGRAN 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
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 2mg 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 (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 pre-clinical data of relevance to the prescriber, which are additional to that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
The syrup contains raspberry flavour 50969, maraschino flavour, methyl hydroxybenzoate, propyl hydroxybenzoate, citric acid (anhydrous), disodium phosphate (anhydrous), maltitol liquid, ethanol 96% and purified water.
6.2 Incompatibilities
None.
6.3 Shelf Life
60 months.
6.4 Special Precautions For Storage
None.
6.5 Nature And Contents Of Container
The syrup is clear, colourless liquid, with a fruity odour and taste and comes in amber glass bottles with a polypropylene closure or polypropylene child resistant, tamper evident cap (polythene wad faced with PP, PVDC or PET lining) in a 300ml pack size.
6.6 Special Precautions For Disposal And Other Handling
None.
7. Marketing Authorisation Holder
Novartis Pharmaceuticals UK Limited
(trading as Sandoz Pharmaceuticals)
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
8. Marketing Authorisation Number(S)
PL 00101/0163
9. Date Of First Authorisation/Renewal Of The Authorisation
06 June 1983 / 11 March 2009
10. Date Of Revision Of The Text
11 October 2011
LEGAL CATEGORY
POM
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