SANDOMIGRAN®

(pizotifen malate)

S
COOH

CH OH
. CH2
Pizotifen
COOH
N

MALATE
CH3

DESCRIPTION

Pizotifen is a cycloheptathiophene derivative structurally related to cyproheptadine and the

tricyclic antidepressants. The malate salt is a white to yellow-tinged crystalline powder. MW =
429.54, pKa 6.95 in water.

Excipients: silica colloidal anhydrous, lactose, magnesium stearate, starch-maize, talc-

purified, povidone, acacia, sucrose, titanium dioxide, cetyl palmitate.

PHARMACOLOGY

Pharmacodynamics
Sandomigran (pizotifen) is a competitive serotonin antagonist. It also possesses antihistamine,
antibradykinin and weak anticholinergic properties. It is suitable for the prophylactic treatment
of migraine, reducing the frequency of attacks, but is without effect in the migraine attack.

The migraine attack is thought to consist of a prodromal phase of constriction followed by

dilatation of the extracranial vessels. The mode of action of pizotifen in preventing migraine is
not fully understood but it is known to inhibit the reuptake of serotonin by blood platelets,
preventing loss of tone of extracranial vessels. It also possesses appetite-stimulating and
antidepressant properties.

Pharmacokinetics
The absorption of pizotifen is rapid (absorption half-life 0.5 - 0.8 hours) and nearly complete
(estimated 80%). Peak plasma levels are achieved 4 - 6 hours following a single oral dose.
Metabolism is extensive and the drug is widely distributed. Volume of distribution is at least 7
litres/kg. Protein binding amounts to 91%. The main metabolite (N-glucuronide) is eliminated
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with a half-life of about 23 hours. Less than 1% of the drug is excreted in the urine unchanged
although as much as 55% of a dose has been detected in the urine as metabolites. In patients
with kidney insufficiency dosage adjustment may therefore be necessary.

INDICATIONS

 Prophylactic (interval) treatment of vascular headaches.

- typical and atypical migraine
- vasomotor headache
- cluster headache (Horton's syndrome)

Sandomigran is without effect in the migraine attack. For this purpose preparations containing
ergotamine are recommended.

CONTRAINDICATIONS

Hypersensitivity to pizotifen or any of the excipients in the formulation.

PRECAUTIONS

Renal impairment
Caution is required in patients with renal impairment. Dosage adjustment may be necessary.

Hepatic impairment
Caution is required in patients with hepatic impairment. Dosage adjustment may be
necessary.

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.

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

Effects on the ability to drive and use machines:

Patients should be warned that Sandomigran may cause sedation, somnolence and dizziness.
Therefore, caution should be exercised when driving or using machines.

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Patients being treated with Sandomigran and presenting with sedation 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.

Anticholinergic effects:
In view of the very slight anticholinergic effect of pizotifen, caution is required in patients with
narrow angle glaucoma (except those successfully treated by surgery) or urinary retention (e.g.
prostatic enlargement). Up to now no untoward reactions have been reported in such patients
given the recommended dosage.

Use in Pregnancy (Category B1)

No embryotoxic or teratogenic effects were observed in animal studies and fertility was
unimpaired.

Clinical data with pizotifen in pregnancy are very limited; it should be administered in
pregnancy only if the expected benefits outweigh any potential risks.

Use in Lactation
Animal studies show that pizotifen enters the milk.

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.

Use in Children
Experience in children is still limited.

Interactions with other medicines

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: Central effects of sedatives, hypnotics, antihistamines, including
certain common cold preparations, and alcohol may be enhanced.

Monoamine oxidase inhibitors: MAOIs can prolong and intensify the anticholinergic effects of
antihistaminic substances. Concomitant use with MAOIs should therefore be avoided.

Cisapride: Concomitant administration of pizotifen with cisapride may lead to reduced efficacy
of cisapride.

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Epilepsy
Seizures as undesirable effects have been observed more frequently in patients with epilepsy.
Pizotifen should be used with caution in patients with epilepsy.

Sandomigran coated tablets contain lactose. Patients with rare hereditary problems of
galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should
not take Sandomigran.

ADVERSE REACTIONS
The most common reactions are appetite-stimulating effect, increase in body weight and
sedation (including somnolence and fatigue). It can usually be avoided by increasing the
dosage gradually or reversed by a progressive reduction in dosage.

The appetite-stimulating effect of pizotifen may lead to an increase in body weight.

The following 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),
including isolated reports.

Immune system disorders

Rare: Hypersensitivity reactions, face oedema
Metabolism and nutrition disorders
Very common: Increased appetite and body weight increased
Psychiatric disorders
Rare: Depression, CNS stimulation (e.g. aggression, agitation),
hallucination, insomnia, anxiety
Nervous system disorders
Common: Sedation (including somnolence), dizziness
Rare: Paraesthesia
Very rare: Seizures
Gastrointestinal disorders
Common: Nausea, dry mouth
Uncommon Constipation
Skin and subcutaneous tissue disorders
Rare: Urticaria, rash
Musculoskeletal and connective tissue disorders
Rare: Myalgia
General disorders and administration site conditions
Common Fatigue

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Headache, hypotension and impotence have also been reported during treatment with
Sandomigran, but a causal relationship was not established.

Adverse drug reactions from post-marketing spontaneous reports

The following additional adverse drug reactions have been identified with pizotifen based on
post-marketing spontaneous reports. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency.

Hepatobiliary disorders
Unknown: Hepatic enzyme increased, jaundice, hepatitis

Musculoskeletal and connective tissue disorders

Unknown: Muscle cramps

Withdrawal symptoms
Withdrawal reactions have been reported following abrupt cessation of pizotifen, therefore
gradual withdrawal is recommended (see PRECAUTIONS). Withdrawal symptoms may
include: depression, tremor, nausea, anxiety, malaise, dizziness, sleep disorder and weight
decreased.

DOSAGE AND ADMINISTRATION

The dosage should be progressively increased, starting with 0.5 mg daily. The average
maintenance dosage is 1.5 mg daily in single or divided doses. Recent studies have shown a
single daily dose of 3 tablets (1.5 mg) taken at night to be effective. In refractory cases the
dosage may be gradually raised to 3 - 4.5 mg daily in two or three divided doses.

OVERDOSAGE

Symptoms
Symptoms which may be expected are: drowsiness, nausea, dry mouth, tachycardia, pyrexia,
hypotension, dizziness, excitatory states (in children), respiratory depression, convulsions
(particularly in children), coma.

Treatment
Treatment is gastric lavage followed by administration of activated charcoal. If necessary,
symptomatic treatment should be given including monitoring of the cardiovascular and
respiratory symptoms; for excitatory states or convulsions: benzodiazepines.

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PRESENTATION

Tablets containing 0.5 mg pizotifen present as 0.725 mg pizotifen malate (off-white,

sugar-coated); 100's.

Store below 30°C. Protect from light.

SPONSOR

NOVARTIS Pharmaceuticals Australia Pty. Ltd.

ABN 18 004 244 160
54 Waterloo Road,
NORTH RYDE, NSW 2113

Approved by the Therapeutic Goods Administration: 05.12.86

Date of most recent amendment: 5 May 2011

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