Johnson & Johnson Merck
Action And Clinical Pharmacology: Astemizole is a potent, long-acting, and selective histamine H1-antagonist. It produces a dose-related inhibition of skin reactions to intradermal histamine. Astemizole inhibits the nose reaction to nasal challenge with histamine and allergens. It inhibits the bronchial reaction to inhaled histamine and allergens in asthmatic patients. Astemizole has extremely weak serotonin antagonism, no anticholinergic properties, antagonism of dopamine and other catecholamines. In clinical studies, astemizole did not cause daytime sedation or evening somnolence.
Pharmacokinetics: Astemizole is rapidly absorbed after a single oral administration with peak plasma levels of approximately 0.5 ng/mL (0.3 to 1.0) being achieved within 1 hour. Astemizole undergoes extensive first pass metabolism in the liver; plasma levels of astemizole remain detectable (0.1 ng/mL) for 4 hours after administration due to rapid tissue distribution and the formation of metabolites. Peak plasma levels of the major active metabolite, desmethylastemizole, are similar to those of the unchanged drug and are reached at 2 hours. The terminal half-lives of astemizole and desmethylastemizole after a single oral administration were 1 to 3 and 11 to 16 days respectively.
Following chronic oral administration, steady-state plasma levels were reached in 7 to 10 days for astemizole (0.4 to 1.2 ng/mL) and within 4 to 5 weeks for desmethylastemizole (2 to 9 ng/mL). Peak plasma levels at steady-state were obtained within 1 hour for astemizole and after 4.2 hours (range 2 to 8) for desmethylastemizole. At steady-state, 90% of the plasma concentrations of astemizole plus its metabolite desmethylastemizole (considered together to represent the pharmacologically active fraction), fall within the range of 1 and 7 ng/mL. The terminal half-life is 1 to 2 days for astemizole and 8 to 18 days for desmethylastemizole. These elimination half-lives are similar to those after a single oral administration, which demonstrate that the pharmacokinetics of both astemizole and desmethylastemizole remain linear.
In human blood, only 2.3% was present as free drug in the plasma water, 61.5% was bound to plasma proteins and 36.2% was distributed to the blood cell fraction. Astemizole or its metabolites did not accumulate in erythrocytes.
Indications And Clinical Uses: For the treatment of seasonal allergic rhinitis, allergic conjunctivitis, chronic urticaria and other allergic conditions.
Contra-Indications: Concurrent therapy of astemizole with erythromycin is contraindicated because erythromycin is known to impair the cytochrome P450 enzyme system which also influences astemizole metabolism. Concomitant administration of astemizole with other macrolide antibiotics (e.g., clarithromycin) prone to the formation of inactive cytochrome P450-metabolite complexes is contraindicated. An open-label study of the effects of azithromycin on the steady-state pharmacokinetics and cardiovascular safety of astemizole was conducted in 21 healthy adult males. Azithromycin treatment led to a neglible decrease in the bioavailability of astemizole and did not cause any clinically meaningful further increase in QT or QTc intervals. More data in a wider population would be required to allow for the conclusion that coadministration of azithromycin and astemizole has no negative impact on the QTc.
Concurrent therapy of astemizole with oral ketoconazole is contraindicated because available human pharmacokinetic data indicate that oral ketoconazole significantly inhibits the metabolism of astemizole, resulting in elevated plasma levels of astemizole and desmethylastemizole. Serious cardiac effects and arrhythmias (prolongation of the QT interval, torsades de pointes) can occur when astemizole is used in the daily recommended dose in conjunction with erythromycin and/or ketoconazole.
Due to the chemical similarity of fluconazole, itraconazole and metronidazole to ketoconazole, concomitant use with an oral or parenteral formulation of these products with astemizole is also contraindicated.
Concurrent administration of astemizole with quinine is contraindicated. Therapeutic doses of quinine may decrease the metabolism of astemizole and result in elevated plasma levels.
Concomitant administration of astemizole with drugs known to prolong the QT interval is contraindicated. These include certain class IA and III antiarrhythmic drugs (quinidine, procainamide amiodarone, sotalol, bretylium), certain psychiatric drugs (thioridazine, pimozide, phenothiazines, haloperidol, tricyclic antidepressants, lithium, chloral hydrate), terfenadine, certain antimalarial drugs (quinine, chloroquine, halofantrine, mefloquine) and others such as amantidine, pentamidine, cisapride, probucol, TMP-SMX and tacrolimus.
Concomitant administration of astemizole is contraindicated with drugs or foods that inhibit the metabolism of astemizole at the cytochrome P450 level. This includes serotonin reuptake inhibitors (e.g., fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline), and HIV protease inhibitors (e.g., indinavir, ritonavir, saquinavir) and grapefruit juice. Certain calcium channel blocking agents that are primarily metabolized by the hepatic CYP 3A4 isoenzyme, such as the dihydropyridines, also have the potential to elevate plasma astemizole levels.
In patients with hepatic dysfunction such as hepatitis, jaundice, or chronic alcoholism, and in patients with electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia) or in patients taking certain diuretics, systemic corticosteroids or liquid protein diets with the potential for inducing electrolyte abnormalities.
In patients with congenital QT-syndrome or have conditions leading to QT-prolongation.
In patients with heart disease unless authorized by a physician.
In patients with a known hypersensitivity to the drug or to its excipients.
Manufacturers’ Warnings In Clinical States: Rare cases of serious cardiovascular adverse events, including death, cardiac arrest, QT prolongation, torsades de pointes and other ventricular arrhythmias have been reported in patients taking astemizole, particularly in overdosage. Torsades de pointes have rarely occurred at doses 2 to 3 times the recommended dose (20 to 30 mg). It is therefore very important that the recommended dose (10 mg) not be exceeded.
Episodes of syncope, dizziness, chest pain, dyspnea, and/or palpitations in association with the use of astemizole should be carefully investigated. The drug should be discontinued and a full electrocardiographic evaluation for QT prolongation and arrhythmias carried out.
Pregnancy: Experience with astemizole in pregnant women is inadequate to determine whether there exists a potential for harm to the fetus. Therefore, astemizole should be used in pregnant women only when, in the opinion of the physician, the potential benefits outweigh the possible hazards. In view of the prolonged half-life, women of childbearing potential should discontinue the use of astemizole for at least 4 weeks prior to contemplating pregnancy.
Lactation: In nursing dogs, astemizole and its metabolites are excreted in the maternal milk. Therefore, astemizole should not be administered to lactating women unless in the judgment of a physician, the potential benefits outweigh the possible risks.
Precautions: General: A negative skin prick test to allergens immediately following astemizole treatment should be viewed with caution since astemizole can affect skin test results even after cessation of therapy. Therefore further tests should be performed after a drug free period of at least 2 and preferably 4 weeks.
Use with CNS Depressants: Astemizole had no potentiating effects with alcohol or other CNS depressants in clinical and laboratory studies.
Drug Interactions: The main metabolic pathway of astemizole is through the hepatic CYP 3A4 isoenzyme. The concomitant use of drugs that significantly inhibit these enzymes may result in increased plasma levels of astemizole, which could enhance the risk of QT-prolongation. Therefore, the use of such drugs is contraindicated. Examples are: an oral or parenteral formulation of azole antifungals; macrolide antibiotics; serotonin reuptake inhibitors; HIV protease inhibitors such as ritonavir and indinavir; in vitro studies suggest that saquinavir is only a weak inhibitor.
In the absence of clinical studies demonstrating safety, coadministration of astemizole with drugs that have shown significant CYP 3A inhibition is not recommended.
Concomitant administration of astemizole with therapeutic doses of quinine is contraindicated.
Astemizole is contraindicated in patients where conditions or the use of other drugs favor the prolongation of the QT interval.
See Contraindications and Warnings for discussion of information regarding potential drug interactions.
Food Interactions : As the medical literature indicates that there is a potential for grapefruit juice to influence the metabolism of drugs whose metabolism is highly CYP 3A4 dependent and until the clinical significance is fully established, the ingestion of grapefruit juice by patients taking astemizole should be avoided.
In an open study, the influence of the consumption of grapefruit juice on the steady-state pharmacokinetics and cardiovascular safety of astemizole and desmethylastemizole was investigated. Twelve healthy volunteers took 30 mg astemizole for 4 days, followed by 10 mg astemizole daily for 20 days. After reaching steady-state, a total of 4 glasses of 200 mL of grapefruit juice, one every 4 hours, were drunk. The results of the study demonstrate that grapefruit juice does not interact with the kinetics of astemizole. Until confirmation is obtained in a larger, more comprehensive study, a potential food interaction between grapefruit juice and astemizole cannot be excluded.
Adverse Reactions: The incidence of adverse experiences during astemizole treatment was comparable to that during placebo control treatment.
During chronic treatment, body weight tended to increase. This is probably due to an increase in appetite.
Rare cases spontaneously reported from postmarketing experience with astemizole include hypersensitivity reactions such as: angioedema, bronchospasm, photosensitivity, pruritus, rash, anaphylactoid reactions and serious, life-threatening cardiovascular adverse events (see Warnings). There have also been isolated cases of convulsions, benign paresthesias, myalgia/arthralgia, edema, mood disturbance, insomnia, nightmares, liver enzyme elevations and hepatitis. In most cases, a causal relationship with astemizole is unclear.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdoses with astemizole with doses as low as 2 to 3 times the recommended daily dose (20 or 30 mg) have been associated with cardiac adverse effects. In cases of overdose, or when adverse effects are suspected, cardiac monitoring should be instituted and continued until the QT interval has returned to normal. With overdoses, the standard measures to remove any unabsorbed drug (emesis, gastric lavage, charcoal) also should be carried out. Hemodialysis does not increase the clearance of the drug. Consideration should be given to the fact that the half-life of elimination for astemizole and its major active metabolite, desmethylastemizole, is at least 10 to 14 days. Appropriate antiarrhythmic treatment may be needed but treatment with antiarrhythmics known to prolong the QT interval should be avoided.
In some cases, severe arrhythmias have been preceded by or associated with 1 or more episodes of syncope. Therefore, syncope in patients receiving astemizole should lead to immediate discontinuation of treatment and appropriate clinical evaluation, including ECG testing.
In 2 overdose cases (100 to 270 mg), patients experienced seizures that were caused by anoxia and metabolic acidosis secondary to overdose and cardiac arrest.
Dosage And Administration: Adults and children 12 years and over: 10 mg once a day.
The following dosage may guide the physician when prescribing astemizole for children under 12 years of age: Children between 6 and 12 years of age: 5 mg once a day. Astemizole tablets are not suited for children below 6 years of age.
Do not exceed the recommended dosage.
Note: Although loading doses are not, and never were, recommended in Canada, other regulatory agencies have approved this practice. Such a dosage regimen can be dangerous and should never be used.
Astemizole should not be taken with grapefruit juice.
Clinical studies indicate that the onset of symptomatic relief with astemizole is comparable to that of other antihistamines. Patients should be instructed that peak symptomatic relief may not be achieved for up to 3 days. It is therefore important that daily therapy be continued for at least this long in order to obtain and maintain this relief. Clinical effects of the medication may be seen for several days following discontinuation of therapy.
Prolonged use should be only as directed by a physician.
Availability And Storage: Each white, round, scored, compressed tablet contains: astemizole 10 mg. Nonmedicinal ingredients: anhydrous silica, cornstarch, lactose, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized potato starch and sodium lauryl sulfate. Bisulfite-, gluten- and tartrazine-free. Blister packs of 6, 12, 18 and 24 (on a seasonal basis). (Shown in Product Recognition Section)
HISMANALÂ® Johnson & Johnson Â Merck Astemizole Histamine H1-Antagonist