Astemizole

(BAN, USAN, rINN)
Astemizole Chemical formula
Synonyms: Astemitsoli; Astemizol; Astemizolas; Astémizole; Astemizolum; Asztemizol; MJD-30. 1-(4-Fluorobenzyl)-2-{[1-(4-methoxyphenethyl)-4-piperidyl]amino}benzimidazole.
Cyrillic synonym: Астемизол.

💊 Chemical information

Chemical formula: C28H31FN4O = 458.6.
CAS — 68844-77-9.
ATC — R06AX11.
ATC Vet — QR06AX11.

Pharmacopoeias.

In Eur. and US.

Ph. Eur. 6.2

(Astemizole). A white or almost white powder. Practically insoluble in water; soluble in alcohol; freely soluble in dichloromethane and in methyl alcohol. Protect from light.

USP 31

(Astemizole). Store in airtight containers.

💊 Adverse Effects and Precautions

Increased appetite and weight gain have been reported with astemizole. Ventricular arrhythmias, including torsade de pointes, have occurred rarely with astemizole, particularly in association with raised blood concentrations (see Arrhythmias below) and as a result the drug has been withdrawn from the market in most countries. To reduce the risk of developing such arrhythmias recommendations were that licensed doses should not be exceeded, and that it should be avoided in patients with cardiac or significant hepatic disease, with hypokalaemia or other electrolyte imbalance, or with known or suspected prolonged QT interval. Use with drugs liable to interfere with the hepatic metabolism of astemizole, other potentially arrhythmogenic drugs including those that prolong the QT interval, and drugs likely to cause electrolyte imbalance, is contra-indicated (see Interactions below).

Arrhythmias.

Although severe life-threatening cardiovascular effects including torsade de pointes and other ventricular arrhythmias were initially reported mainly after substantial overdoses of astemizole, such reactions have also occurred rarely with doses as low as 20 to 30 mg daily and even as low as 10 mg daily in those with possible predisposing factors. There has been a report1 of astemizole-induced torsade de pointes in a 15-yearold girl who claimed to have taken 10 mg daily for 10 weeks but pharmacokinetic data were more consistent with acute ingestion of higher doses. There have also been several reports of cardiotoxicity after accidental overdosage with astemizole in children.2-4 Although the drug is now withdrawn in the UK, recommendations were made by the UK CSM to reduce the risk of developing serious arrhythmias5-7 (see Adverse Effects above for details). It was considered that astemizole should be stopped immediately in patients who experience syncope, and appropriate clinical evaluation including ECG monitoring instituted, because syncope has preceded or accompanied severe arrhythmias in some cases. Convulsions in patients taking astemizole may also be related to cardiovascular effects.8 Studies have suggested that astemizole induces ventricular arrhythmias by inhibiting cardiac potassium channels which results in prolongation of the QT interval, a risk factor for developing arrhythmias.9 For further discussion.
1. Simons FER, et al. Astemizole-induced torsade de pointes. Lancet 1988; ii: 624
2. Hoppu K, et al. Accidental astemizole overdose in young children. Lancet 1991; 338: 538–40
3. Tobin JR, et al. Astemizole-induced cardiac conduction disturbances in a child. JAMA 1991; 266: 2737–40
4. Wiley JF, et al. Cardiotoxic effects of astemizole overdose in children. J Pediatr 1992; 120: 799–802
5. CSM. Ventricular arrhythmias due to terfenadine and astemizole. Current Problems 35 1992. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2024453&RevisionSelectionMethod= LatestReleased (accessed 14/07/08
6. CSM/MCA. Drug-induced prolongation of the QT interval. Current Problems 1996; 22: 2. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2024458&RevisionSelectionMethod= LatestReleased (accessed 14/07/08
7. CSM/MCA. Astemizole (Hismanal): only available on prescription. Current Problems 1999; 25: 2. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2023233&RevisionSelectionMethod= LatestReleased (accessed 19/05/06
8. Clark A, Love H. Astemizole-induced ventricular arrhythmias: an unexpected cause of convulsions. Int J Cardiol 1991; 33: 165–7
9. Rankin AC. Non-sedating antihistamines and cardiac arrhythmia. Lancet 1997; 350: 1115–16.

Overdosage.

Severe cardiac events have been associated with astemizole overdosage (see Arrhythmias, above); management is mainly supportive. The absorption of astemizole from the gastrointestinal tract can be prevented by giving activated charcoal1but because astemizole is rapidly absorbed it would need to be given as soon as possible after poisoning. Haemodialysis does not appear to increase the clearance of astemizole.
1. Laine K, et al. The effect of activated charcoal on the absorption and elimination of astemizole. Hum Exp Toxicol 1994; 13: 502–5.

Porphyria.

Astemizole is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in in-vitro systems.

Sedation.

For discussion of the sedative effects of antihistamines.

💊 Interactions

Astemizole should not be given with drugs that inhibit its hepatic metabolism because of the increased risk of serious ventricular arrhythmias. These drugs include the imidazole and triazole antifungals such as ketoconazole and itraconazole, and the macrolide antibacterials clarithromycin, erythromycin, troleandomycin, and possibly other macrolides. Others, similarly to terfenadine, may include serotonin reuptake inhibitors, HIV-protease inhibitors, NNRTIs, and zileuton. The metabolism of astemizole may also be inhibited by grapefruit juice and use together should be avoided. Use with other potentially arrhythmogenic drugs (including those that prolong the QT interval) such as antiarrhythmics, tricyclic antidepressants, the antimalarials halofantrine and quinine, antipsychotics, cisapride, and the beta blocker sotalol should be avoided, as should diuretics that cause electrolyte imbalances such as hypokalaemia. The use of terfenadine and astemizole together is not recommended.

💊 Pharmacokinetics

Absorption of astemizole from the gastrointestinal tract is rapid and is reduced by food. First-pass metabolism is extensive, therefore plasma concentrations of unchanged drug are very low. The plasma concentration of astemizole plus metabolites takes about 4 to 8 weeks to reach steady state. The metabolism of astemizole is mediated through the cytochrome P450 enzyme system by the isoenzymes CYP3A4, CYP2D6, and CYP2A6. The elimination half-life of astemizole and its metabolites at steady state is about 19 days. Unchanged astemizole is highly bound to plasma proteins and does not appear to cross the blood-brain barrier to a significant extent. Desmethylastemizole, the major metabolite of astemizole, has histamine H1-receptor-blocking activity; tecastemizole (norastemizole) is another active metabolite. The metabolites of astemizole are excreted slowly in the urine and faeces, and undergo enterohepatic recycling. Virtually none of an oral dose is excreted as unchanged drug.

💊 Uses and Administration

Astemizole, a piperidine derivative, is a non-sedating antihistamine with a very long duration of action. It does not have significant sedative or antimuscarinic actions. Astemizole has been used for the symptomatic relief of allergic conditions including rhinitis and conjunctivitis, and skin disorders such as urticaria. Preparations of astemizole have now been withdrawn from the market in most countries because of the risk of adverse effects. Astemizole has been given in an oral dose of 10 mg once daily, or 5 mg daily in children aged 6 to 12 years. These doses must not be exceeded because of the risk of cardiac arrhythmias with higher doses. The active metabolite of astemizole, tecastemizole (norastemizole) has been investigated for the treatment of allergic rhinitis.

💊 Preparations

USP 31: Astemizole Tablets.

Proprietary Preparations

Arg.: Alermizol†; Astezol†; Cezane†; Mudantil†; Cz.: Hismanal†; Gr.: Mibiron†; Tulipe-R†; Tyrenol†; Waruzol†; India: Astizole; Stemiz†; Mex.: Adistan†; Alerfur; Alerken; Alermi; Aleztem; Anerzol; Antagon 1; Astemina; Astesen; Aztemin; Aztil; Aztrolen; Biostan; Dexodin; Emdar; Emizol; Farmidal S; Fustermizol; Ginomizol†; Histalino; Histaser; Novasten; Practizol; Ulcoid-Zol†; Urtigen; Port.: Perifer H1†; Spain: Alermizol†; Esmacen†; Hubermizol†; Narvizol†; Rifedot†; Simprox†; Urdrim†; Venez.: Asemin†; Corexan†; Histalong†; Prevan†. Multi-ingredient: Arg.: Bio Cabal†; Bronco Biotaer†; Dallamizol-D†; Gentiabron†; Muco Cortos†; Predual Descongestivo†; Wilpan C†.
Published October 20, 2018.