INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo HISMANAL® 10 mg tablets
SCHEDULING STATUS
Schedule 4

PROPRIETARY NAME
(and dosage form)

HISMANAL® 10 mg tablets

COMPOSITION
Each tablet contains astemizole 10 mg.

PHARMACOLOGICAL CLASSIFICATION
A.5.7.1 Antihistaminics.

PHARMACOLOGICAL ACTION
HISMANAL is a long-acting and selective oral histamine H1-antagonist.
Pharmacokinetic studies in man demonstrated that astemizole is rapidly absorbed, peak plasma concentrations being attained within 1 to 4 hours. The drug is extensively metabolised, and excreted as metabolites chiefly in the faeces. The half-life of the parent substance is approximately 1 day and the elimination half-life of the active metabolites is 10 to 14 days.
Receptor binding studies have shown that HISMANAL at pharmacological doses provides occupancy of peripheral H1-receptors.

INDICATIONS
HISMANAL is indicated for the treatment of allergic rhinitis, allergic conjunctivitis and chronic urticaria.

CONTRA-INDICATIONS
HISMANAL is contra-indicated in patients with known intolerance to the drug or to any of the inactive ingredients.
Since HISMANAL is extensively metabolised by the liver, the use of HISMANAL in patients with a serious hepatic dysfunction is contra-indicated.
Concomitant administration of any of the following:
* any oral or parenteral formulation of azole antifungals;
* macrolide antibiotics except azithromycin;
* selective serotonin re-uptake inhibitors (SSRIs);
* HIV protease inhibitors;
* mibefradil;
* therapeutic doses of quinine
(see “Interactions”)
The recommended daily dosage should not be exceeded.
The safety of HISMANAL in pregnant or lactating women has not been established.

DOSAGE AND DIRECTIONS FOR USE
The recommended daily dosage should not be exceeded. HISMANAL tablets are not suited for children below 6 years of age.
Adults and children older than 12 years: 1 tablet (10 mg) once a day.
Children from 6 to 12 years: ½ tablet (5 mg) once a day.
Optimal absorption is achieved when HISMANAL is taken on an empty stomach.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Mass gain may occur during prolonged treatment.
Headache, dizziness and nausea may occur.
Cases of hypersensitivity reactions such as angio-oedema, bronchospasm, photosensitivity, pruritus, rash and anaphylactoid reactions have been reported. There have also been isolated cases of convulsions, benign paraesthesias, myalgia/arthralgia, oedema, mood disturbances, insomnia, nightmares, transaminase elevations and hepatitis. In most cases, a causal relationship with HISMANAL is unclear.
Drug interactions:
HISMANAL lacks significant sedative effects. Patients should, however, be warned that a small number of individuals may experience sedation. It is therefore advisable to determine individual response before driving or performing complicated tasks. This effect may be compounded by the simultaneous intake of alcohol or other central nervous system depressants.
The main metabolic pathway of astemizole is through CYP3A4. The concomitant use of drugs that significantly inhibit these enzymes may result in increased plasma levels of astemizole, which could increase the risk of QT prolongation. Therefore the use of such drugs is contra-indicated. Examples include the following:
* any oral or parenteral formulation of azole antifungals;
* macrolide antibiotics except azithromycin, which, in an in vivo study, was shown to have a negligible effect on the bioavailability of astemizole;
* serotonin re-uptake inhibitors, such as nefazodone, fluoxetine, fluroxamine, paroxetine, sertraline and others.
* HIV protease inhibitors, such as ritonavir, indinavir - saquinavir and others.
* mibefradil;
An interaction with therapeutic doses of quinine has also been established.
In vitro studies further suggest that an interaction with azithromycin and clarithromycin is unlikely. The clinical relevance of this in vitro finding is not known as the possibility of an interaction with clarithromycin or azithromycin in the clinical situation has not been studied.
Patients known to have conditions leading to QT-prolongation may experience QT-prolongation and/or ventricular arrhythmias with astemizole. Therefore it is advisable to avoid its use in patients with a congenital QT-syndrome; in patients who are taking medications which are reported to prolong the QT-interval (including anti-arrhythmics, terfenadine and erythromycin); or in patients with uncorrected hypokalaemia.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Although overdoses have been reported with no ill effects, rare cases of serious life-threatening cardiovascular adverse events including QT-prolongation, torsades de pointes, and other ventricular arrhythmias have been observed in patients exceeding recommended doses of astemizole. While the majority of such events have occurred following substantial overdoses of astemizole, torsades de pointes (arrhythmias) have very rarely occurred at reported doses of 20 - 30 mg daily (2 - 3 times the recommended daily dose).
In some cases, severe arrhythmias have been preceded by or associated with one or more episodes of syncope. Therefore, syncope in patients receiving astemizole should lead to immediate discontinuation of treatment and appropriate clinical evaluation, including electrocardiographic testing.
Supportive measures including gastric lavage and emesis should be employed, followed by the administration of activated charcoal. In these patients the ECG should be carefully monitored. If the QT-interval is prolonged, the monitoring should continue as long as it remains prolonged.
Appropriate anti-arrhythmic treatment may be needed, but treatment with anti-arrhythmics known to prolong QT-interval should be avoided.
Studies in patients with renal insufficiency suggest that haemodialysis does not increase clearance of the drug.

IDENTIFICATION
A white circular, biconvex scored tablet with “Ast”above “10”inscription on one side and “JANSSEN”on the other side.

PRESENTATION
Cartons containing one or more blister packs of 6 or 10 tablets each.

STORAGE INSTRUCTIONS
Store below 25°C, in a dry place. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
R/5.7.1/226

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN-CILAG
Janssen Pharmaceutica (Pty) Ltd
(Reg. No. 80/11122/07)
15th Road
HALFWAY HOUSE, 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
13 March 1998.

® = Trademark                Code: 023483
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