QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of astemizole and moxifloxacin. Please also consult the relevant specialist information.
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We do not expect any change in exposure for astemizole, when combined with moxifloxacin (100%). We did not detect any change in exposure to moxifloxacin. We currently cannot estimate the influence of astemizole.
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Astemizole has a low oral bioavailability [ F ] of 3%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is 22 hours and constant plasma levels [ Css ] are reached after approximately 88 hours. The protein binding [ Pb ] is 97% strong. The metabolism takes place via CYP2D6 and CYP3A4, among others.
Moxifloxacin has a high oral bioavailability [ F ] of 86%, which is why the maximum plasma level [Cmax] tends to change little during an interaction. The terminal half-life [ t12 ] is 12.1 hours and constant plasma levels [ Css ] are reached after approximately 48.4 hours. The protein binding [ Pb ] is rather weak at 47%. The metabolism does not take place via the common cytochromes and the active transport takes place in particular via PGP.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither astemizole nor moxifloxacin increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither astemizole nor moxifloxacin increase anticholinergic activity.
QT time prolongation
Rating: In combination, astemizole and moxifloxacin can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||ast||mox|
|Abdominal pain||2.0 %||n.a.||2.0|
|Pain in eye||1.0 %||n.a.||+|
Feeling nervous: moxifloxacin
Renal failure: moxifloxacin
Stevens johnson syndrome: moxifloxacin
Toxic epidermal necrolysis: moxifloxacin
Clostridium difficile diarrhea: moxifloxacin
Aplastic anemia: moxifloxacin
Hemolytic anemia: moxifloxacin
Liver failure: moxifloxacin
Hypersensitivity reaction: moxifloxacin
Myasthenia gravis: moxifloxacin
Rupture of tendon: moxifloxacin
Disturbance of attention: moxifloxacin
Memory impairment: moxifloxacin
Peripheral neuropathy: moxifloxacin
Pseudotumor cerebri: moxifloxacin
Raised intracranial pressure: moxifloxacin
Aortic aneurysm: moxifloxacin
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: Astemizole is a long-acting, highly selective histamine1-receptor antagonist with minimal central and anticholinergic effects. Comparison studies have shown astemizole to be equal or superior to currently available antihistamines, beclomethasone nasal spray, and cromolyn sodium in relieving allergic symptoms of seasonal and perennial allergic rhinitis. Other uses include treatment of allergic conjunctivitis and chronic urticaria. Astemizole is not as effective for treatment of acute allergic symptoms because of its delayed onset of action. Astemizole and its active metabolite, desmethylastemizole, have long elimination half-lives permitting once-daily dosing. The incidence of sedation is lower than with conventional antihistamines, but increased appetite and weight gain do occur. Astemizole should be useful for both maintenance and prophylactic therapy in patients with chronic allergic conditions who cannot tolerate the sedative or anticholinergic effects of conventional antihistamines.
Abstract: Astemizole is an H1-histamine receptor antagonist with a long duration of action permitting once daily administration. Its efficacy in seasonal and perennial allergic rhinitis has been convincingly demonstrated, and several comparative studies suggest that astemizole is at least as effective as some other H1-histamine receptor antagonists. A few smaller studies have shown beneficial effects on the symptoms of allergic conjunctivitis and chronic urticaria (but not atopic dermatitis). While astemizole appears to share with other H1-histamine receptor antagonists a tendency to increase appetite and cause weight gain after prolonged use, it offers the important advantage of an absence of significant central nervous system depression or anticholinergic effects with usual doses. Thus, astemizole offers a worthwhile improvement in side effect profile over 'traditional' H1-histamine receptor antagonists, especially in patients bothered by the sedative effects of these drugs.
Abstract: An overdose of astemizole predisposes the myocardium to ventricular dysrhythmias, including torsades de pointes. Herein we describe a case of astemizole-induced torsades de pointes ventricular tachycardia and also review previous case reports in the literature. All the patients were young, and dysrhythmias developed only in those with corrected QT intervals greater than 500 ms. Although several mechanisms have been postulated, no clear explanation has been provided for why astemizole promotes myocardial dysrhythmias. Treatment of astemizole-induced torsades de pointes includes discontinuing use of astemizole, intravenous administration of magnesium sulfate and isoproterenol, temporary cardiac pacing, and, when necessary, direct current cardioversion. A cardiac cause of syncope or convulsions must not be overlooked, especially in patients taking H1 antagonists because they often have these symptoms before hospitalization or detection of torsades de pointes (or both).
Abstract: No Abstract available
Abstract: A 26 year-old woman was admitted to the hospital two hours after astemizole overdose. Electrocardiograph showed a prolonged QT interval. Torsade de pointes occurred 13 h after ingestion. Plasma levels of astemizole plus hydroxylated metabolites showed an apparent plasma half-life of 17 h. The possible occurrence of torsade de pointes in astemizole overdose, and the long elimination time of astemizole and hydroxylated metabolites, makes it necessary to maintain ECG monitoring until QT interval has returned to normal.
Abstract: AIMS: The aim of this study was to investigate the influence of chronic itraconazole treatment on the pharmacokinetics and cardiovascular effects of single dose astemizole in healthy subjects was studied. METHODS: Twelve male volunteers were taking orally 200 mg twice daily itraconazole or placebo for 14 days with a washout period of 4 weeks in between. Approximately 2 h after the morning dose of itraconazole or placebo on day 11, 10 mg astemizole was orally administered. The plasma concentrations of astemizole and desmethylastemizole were measured by radioimmunoassay up to 504 h after administration; electrocardiograms with analysis of the QTc interval were recorded up to 24 h post administration. RESULTS: Itraconazole treatment did not significantly change the peak concentration of astemizole (0.74 vs 0.81 ng ml-1) but it increased the area under the curve from 0 to 24 h (5.46 to 9.95 ng ml-1 h) and from 0 to infinity (17.4 to 48.2 ng ml-1 h), and the elimination half-life (2.1 to 3.6 days). The systemic bioavailability of desmethylastemizole was also increased. The QTc interval did not increase after astemizole administration and there was no difference in the QTc intervals between the itraconazole and placebo session. CONCLUSIONS: Chronic administration of itraconazole influences the metabolism of single dose astemizole in normal volunteers without changes of cardiac repolarization during the first 24 h after astemizole administration. However, the reduction in astemizole clearance under concomitant administration of itraconazole may result in a marked increase in astemizole plasma concentrations and QTc alterations during chronic combined intake of astemizole with itraconazole.
Abstract: Second-generation histamine H1 receptor antagonists (antihistamines) have been developed to reduce or eliminate the sedation and anticholinergic adverse effects that occur with older H1 receptor antagonists. This article evaluates second-generation antihistamines, including acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine, ketotifen, loratadine, mizolastine and terfenadine, for significant features that affect choice. In addition to their primary mechanism of antagonising histamine at the H1 receptor, these agents may act on other mediators of the allergic reaction. However, the clinical significance of activity beyond that mediated by histamine H1 receptor antagonism has yet to be demonstrated. Most of the agents reviewed are metabolised by the liver to active metabolites that play a significant role in their effect. Conditions that result in accumulation of astemizole, ebastine and terfenadine may prolong the QT interval and result in torsade de pointes. The remaining agents reviewed do not appear to have this risk. For allergic rhinitis, all agents are effective and the choice should be based on other factors. For urticaria, cetirizine and mizolastine demonstrate superior suppression of wheal and flare at the dosages recommended by the manufacturer. For atopic dermatitis, as adjunctive therapy to reduce pruritus, cetirizine, ketotifen and loratadine demonstrate efficacy. Although current evidence does not suggest a primary role for these agents in the management of asthma, it does support their use for asthmatic patients when there is coexisting allergic rhinitis, dermatitis or urticaria.
Abstract: AIMS: The aims of the present study were to investigate the metabolism of astemizole in human liver microsomes, to assess possible pharmacokinetic drug-interactions with astemizole and to compare its metabolism with terfenadine, a typical H1 receptor antagonist known to be metabolized predominantly by CYP3A4. METHODS: Astemizole or terfenadine were incubated with human liver microsomes or recombinant cytochromes P450 in the absence or presence of chemical inhibitors and antibodies. RESULTS: Troleandomycin, a CYP3A4 inhibitor, markedly reduced the oxidation of terfenadine (26% of controls) in human liver microsomes, but showed only a marginal inhibition on the oxidation of astemizole (81% of controls). Three metabolites of astemizole were detected in a liver microsomal system, i.e. desmethylastemizole (DES-AST), 6-hydroxyastemizole (6OH-AST) and norastemizole (NOR-AST) at the ratio of 7.4 : 2.8 : 1. Experiments with recombinant P450s and antibodies indicate a negligible role for CYP3A4 on the main metabolic route of astemizole, i.e. formation of DES-AST, although CYP3A4 may mediate the relatively minor metabolic routes to 6OH-AST and NOR-AST. Recombinant CYP2D6 catalysed the formation of 6OH-AST and DES-AST. Studies with human liver microsomes, however, suggest a major role for a mono P450 in DES-AST formation. CONCLUSIONS: In contrast to terfenadine, a minor role for CYP3A4 and involvement of multiple P450 isozymes are suggested in the metabolism of astemizole. These differences in P450 isozymes involved in the metabolism of astemizole and terfenadine may associate with distinct pharmacokinetic influences observed with coadministration of drugs metabolized by CYP3A4.
Abstract: STUDY OBJECTIVE: To compare the rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin administration. DESIGN: Retrospective database analysis. INTERVENTION: Evaluation of reported rates of torsades de pointes in patients who received these quinolones between January 1, 1996, and May 2, 2001. MEASUREMENTS AND MAIN RESULTS: In the United States, 25 cases of torsades de pointes associated with these quinolones (ciprofloxacin 2, ofloxacin 2, levofloxacin 13, gatifloxacin 8, moxifloxacin 0) were identified. Ciprofloxacin was associated with a significantly lower rate of torsades de pointes (0.3 cases/10 million prescriptions, 95% confidence interval [CI] 0.0-1.1) than levofloxacin (5.4/10 million, 95% CI 2.9-9.3, p<0.001) or gatifloxacin (27/10 million, 95% CI 12-53, p<0.001 for comparison with ciprofloxacin or levofloxacin). When the analysis was limited to the first 16 months after initial U.S. approval of the agent, the rates for levofloxacin (16/10 million) and gatifloxacin (27/10 million) were similar (p>0.5). CONCLUSION: Levofloxacin should be administered with caution in patients with risk factors for QT prolongation. Gatifloxacin should be avoided in the same patient population, and the recommended dosage of 400 mg/day should not be exceeded.
Abstract: Recent attention has been called to the interpretation of studies of antiinfective agents demonstrating effects on the QTc interval. It seems that the effects of many of these agents on the QTc interval are small, but in some patient populations, these drugs may cause morbidity and mortality related to TdP. It would be beneficial to researchers and clinicians alike for the FDA to standardize the types of studies designed to assess the QTc interval prolongation potential of a drug, methodologies, and interpretation criteria. To this end, it would increase the efficiency of the drug-approval process, give regulatory agencies and clinicians guidance, and increase patient safety. In summary we congratulate Dr. Frothingham for attempting to address the challenging issue of postmarketing safety surveillance. A critical review of his analysis of fluoroquinolone-associated TdP as well as other data on this potentially life-threatening adverse event support the following conclusions: Information from spontaneous reports is generally useful as an early warning system for excess adverse events, but reporting rates are not synonymous with incidence rates. The deficiencies of Dr. Frothingham's analysis lead to serious questions regarding the validity of both the numerators and denominators used in the incidence calculations (e.g., exclusion of European results, use ot extrapolated outpatient prescriptions, failure to account for inpatient versus outpatient utilization, failure to apply the appropriate statistical test to a rarely occurring, adverse event) and call into question conclusions about the relative risk of TdP with different fluoroquinolones. The association between which of the fluoroquinolones was administered to high-risk patients, which is important in the multiple-hit hypothesis, remains nebulous (e.g., failure to separate cases by route of drug administration and failure to identify which fluoroquinolones were given to patients with electrolyte abnormalities, concurrent QT interval-prolonging drugs, comorbid disease states). Preclinical and clinical trial data, as well as data from phase IV studies, indicate that levofloxacin, moxifloxacin, and gatifloxacin prolong the QTc interval, and the potential for TdP to develop as a result is rare and is influenced by many independent variables (e.g., concurrent drug administration of class Ia and III antiarrhythmic agents). These results should make clear that assessment of the cardiotoxicity of any new drug must take into account information (and its limitations) from several sources: preclinical studies that test effects on mechanisms underlying potential toxic reactions, controlled toxicodynamic studies in human volunteers safety results from controlled clinical trials, findings from phase IV studies, and postmarketing surveillance that includes spontaneously reported adverse events. One message that must not be lost in this discussion over the use of this reporting system to calculate incidences to incriminate certain agents is its overall importance, over time, in assisting governing bodies and clinicians alike in identifying compounds that may place certain patient populations at risk. It is imperative that clinicians not only submit adverse event reports to the FDA, but provide complete and accurate information. For moxifloxacin, levofloxacin, and gatifloxacin, the point must be clear that these agents should not be used in patients with risk factors predisposing them to TdP.
Abstract: The new respiratory fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and on the horizon, garenoxacin) offer many improved qualities over older agents such as ciprofloxacin. These include retaining excellent activity against Gram-negative bacilli, with improved Gram-positive activity (including Streptococcus pneumoniae and Staphylococcus aureus). In addition, gatifloxacin, moxifloxacin and garenoxacin all demonstrate increased anaerobic activity (including activity against Bacteroides fragilis). The new fluoroquinolones possess greater bioavailability and longer serum half-lives compared with ciprofloxacin. The new fluoroquinolones allow for once-daily administration, which may improve patient adherence. The high bioavailability allows for rapid step down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve quality of life of patients. Clinical trials involving the treatment of community-acquired respiratory infections (acute exacerbations of chronic bronchitis, acute sinusitis, and community-acquired pneumonia) demonstrate high bacterial eradication rates and clinical cure rates. In the treatment of community-acquired respiratory tract infections, the various new fluoroquinolones appear to be comparable to each other, but may be more effective than macrolide or cephalosporin-based regimens. However, additional data are required before it can be emphatically stated that the new fluoroquinolones as a class are responsible for better outcomes than comparators in community-acquired respiratory infections. Gemifloxacin (except for higher rates of hypersensitivity), levofloxacin, and moxifloxacin have relatively mild adverse effects that are more or less comparable to ciprofloxacin. In our opinion, gatifloxacin should not be used, due to glucose alterations which may be serious. Although all new fluoroquinolones react with metal ion-containing drugs (antacids), other drug interactions are relatively mild compared with ciprofloxacin. The new fluoroquinolones gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin have much to offer in terms of bacterial eradication, including activity against resistant respiratory pathogens such as penicillin-resistant, macrolide-resistant, and multidrug-resistant S. pneumoniae. However, ciprofloxacin-resistant organisms, including ciprofloxacin-resistant S. pneumoniae, are becoming more prevalent, thus prudent use must be exercised when prescribing these valuable agents.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.