Verlängerung der QT-Zeit
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Eklärungen für Patienten zu den Wirkstoffen
Für die Kombination von Astemizol und Ceritinib liegen uns keine zusätzlichen Warnhinweise vor. Bitte konsultieren Sie zusätzlich die jeweiligen Fachinformationen.
Die genannten Expositionsveränderungen beziehen sich jeweils auf Veränderungen der Plasmakonzentrations-Zeit-Kurve [ AUC ]. Eine Veränderung der Exposition von Astemizol haben wir nicht erkannt. Den Einfluss von Ceritinib können wir aktuell nicht abschätzen. Eine Veränderung der Exposition von Ceritinib haben wir nicht erkannt. Den Einfluss von Astemizol können wir aktuell nicht abschätzen.
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Astemizol hat eine tiefe orale Bioverfügbarkeit [ F ] von 3%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell stark verändern. Die terminale Halbwertszeit [ t12 ] beträgt 22 Stunden und konstante Plasmaspiegel [ Css ] werden ungefähr nach 88 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 97% stark. Die Metabolisierung findet unter anderem über CYP2D6 und CYP3A4 statt. Unter anderem ist Astemizol ein Hemmer von CYP3A4 und PGP.
Ceritinib hat eine tiefe orale Bioverfügbarkeit [ F ] von 40%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell stark verändern. Die terminale Halbwertszeit [ t12 ] ist mit 41 Stunden eher lang und konstante Plasmaspiegel [ Css ] werden erst nach mehr als 164 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 97% stark. da die Substanz eine tiefe hepatische Extraktionsrate von 0.24 besitzt, kann eine Verdrängung aus der Proteinbindung [Pb] im Rahmen einer Interaktion die Exposition erhöhen. Die Metabolisierung findet vor allem über CYP3A4 statt und der aktive Transport erfolgt insbesondere über PGP. Unter anderem ist Ceritinib ein Hemmer von CYP3A4.
|Serotonerge Effekte a||0||Ø||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöhen weder Astemizol noch Ceritinib die serotonerge Aktivität.
|Kiesel & Durán b||0||Ø||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöhen weder Astemizol noch Ceritinib die anticholinerge Aktivität.
Verlängerung der QT-Zeit
Bewertung: In Kombination können Astemizol und Ceritinib potentiell ventrikuläre Arrhythmien vom Typ Torsades de pointes auslösen.
|Verlust von Appetit||34.0 %||n.a.||34.0|
Nierenversagen (2%): Ceritinib
Atemnot (2%): Ceritinib
Lungenentzündung (2%): Ceritinib
Interstitielle Lungenerkrankung: Ceritinib
Erhöhte ALT: Ceritinib
Erhöhte AST: Ceritinib
Basierend auf Ihren
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: We previously reviewed the cardiovascular safety of 16 tyrosine kinase inhibitors (TKIs), approved for use in oncology as of 30 September 2012. Since then, the indications for some of them have been widened and an additional nine TKIs have also been approved as of 30 April 2015. Eight of these nine are indicated for use in oncology and one (nintedanib) for idiopathic pulmonary fibrosis. This report is an update on the cardiovascular safety of those 16 TKIs, including the post-marketing data concerning their pro-arrhythmic effects, and reviews the cardiovascular safety of the nine new TKIs approved since (afatinib, cabozantinib, ceritinib, dabrafenib, ibrutinib, lenvatinib, nintedanib, ponatinib, and trametinib). As before, we focus on specific aspects of cardiovascular safety, namely their potential to induce QT interval prolongation, left ventricular (LV) dysfunction and hypertension but now also summarise the risks of arterial thromboembolic events (ATEs) associated with these agents. Of the newer TKIs, cabozantinib and ceritinib have been shown to induce a mild to moderate degree of QTc interval prolongation while cardiac dysfunction has been reported with the use of afatinib, dabrafenib, lenvatinib, ponatinib and trametinib. The label for axitinib was revised to include a new association with cardiac dysfunction. Hypertension is associated with cabozantinib, lenvatinib, nintedanib, ponatinib and trametinib. Ponatinib, within 10 months of its approval in December 2012, required voluntary (temporary) suspension of its marketing until significant safety revisions (restricted indication, additional warnings and precautions about the risk of arterial occlusion and thromboembolic events and amended dose) were made to its label. Compared with the previous 16 TKIs, more of the recently introduced TKIs are associated with the risk of LV dysfunction, and fewer with QT prolongation. Available data on morbidity and mortality associated with TKIs, together with post-marketing experience with lapatinib and ponatinib, emphasise the need for effective pharmacovigilance and ongoing re-assessment of their risk/benefit after approval of these novel agents. If not adequately managed, these cardiovascular effects significantly decrease the quality of life and increase the morbidity and mortality in a population already at high risk. Evidence accumulated over the last decade suggests that their clinical benefit, although worthwhile, is modest and extends only to progression-free survival and complete response without any effect on overall survival. During uncontrolled use in routine clinical practice, their risk/benefit is likely to be inferior to that perceived from highly controlled clinical trials.
Abstract: Ceritinib is a potent inhibitor of anaplastic lymphoma kinase (ALK), which has shown acceptable safety and substantial antitumor activity in ALK-positive non-small cell lung cancer (NSCLC) patients. Two food-effect studies were conducted in healthy adults to investigate the influence of food on the oral bioavailability of ceritinib: a study with low- or high-fat meals at 500 mg and a study with a light snack at 750 mg. Compared with the fasted state, AUC0-∞ (90%CI) of ceritinib was increased by 58% (34%, 86%) after the intake of a low-fat meal, by 73% (46%, 105%) after the intake of a high-fat meal, and by 54% (19%, 99%) after the intake of a light snack. Safety assessments also suggested that food may improve gastrointestinal (GI) tolerability after a single ceritinib dose. Based on the pharmacokinetic results, it is essential to avoid any type of meal during dosing of ceritinib because the intake of food may increase the occurrence of exposure-dependent, non-GI toxicities at the labeled dose of 750 mg daily during fasting. A randomized trial is ongoing to determine an alternative way to give ceritinib (450 mg or 600 mg with food) that may enhance GI tolerability in ALK-positive NSCLC patients.
Abstract: An increasing number of tyrosine kinase inhibitors (TKIs) are available for the treatment of non-small cell lung cancer (NSCLC). QT prolongation is one of the known, but relatively rare, adverse events of several TKIs (e.g. osimertinib, crizotinib, ceritinib). Screening for QT prolongation in (high risk) patients is advised for these TKIs. When a QT prolongation develops, the physician is challenged with the question whether to (permanently) discontinue the TKI. In this perspective, we report on a patient who developed a grade III QT prolongation during osimertinib (a third-generation epidermal growth factor receptor [EGFR]-TKI) treatment. On discontinuation of osimertinib, she developed a symptomatic disease flare, not responding to subsequent systemic treatment. The main aim of this perspective is to describe the management of QT prolongation in stage IV EGFR driver mutation NSCLC patients. We also discuss the ethical question of how to weigh the risk of a disease flare due to therapy cessation against the risk of sudden cardiac death. A family history of sudden death and a prolonged QT interval might indicate a familiar long QT syndrome. We have summarised the current monitoring advice for TKIs used in the treatment of lung cancer and the most common drug-TKI interactions to consider and to optimise TKI treatment in lung cancer patients.