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 abarelix and cimetidine. 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 abarelix, when combined with cimetidine (100%). We do not expect any change in exposure for cimetidine, when combined with abarelix (100%).
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
The bioavailability of abarelix is unknown. The terminal half-life [ t12 ] is rather long at 316.8 hours and constant plasma levels [ Css ] are only reached after more than 1267.2 hours. The protein binding [ Pb ] is 97.5% strong. The metabolism via cytochromes is currently still being worked on.
Cimetidine has a mean oral bioavailability [ F ] of 65%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather short at 1.6333333 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is very weak at 19% and the volume of distribution [ Vd ] is very large at 91 liters. The metabolism does not take place via the common cytochromes and the active transport takes place partly via BCRP and PGP.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither abarelix nor cimetidine increase serotonergic activity.
|Kiesel & Durán b||1||Ø||+|
Recommendation: As a precaution, attention should be paid to anticholinergic symptoms, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Cimetidine only has a mild effect on the anticholinergic system. The risk of anticholinergic syndrome with this medication is rather low if the dosage is in the usual range. According to our knowledge, abarelix does not increase anticholinergic activity.
QT time prolongation
Rating: In combination, abarelix and cimetidine can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||aba||cim|
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: Recently, the use of astemizole and terfenadine, both non-sedating H1-antihistamines, caused considerable concern. Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia. The increased risk of both H1-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine. To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied. Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals. The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low. Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.
Abstract: Astemizole (Hismanal), an antihistamine agent, has been reported to be associated with ventricular arrhythmias. In this paper we present a case of QT prolongation and torsades de pointes (TdP) in a 77-year-old woman who had been taking astemizole (10 mg/day) for 6 months because of allergic skin disease. At the time of admission, the serum concentration of astemizole and its metabolites was markedly elevated at 15.85 ng/ml, approximately 3 times the normal level. The patient was also taking cimetidine, a known inhibitor of cytochrome P-450 enzymatic activity, and during her admission was diagnosed as having vasospastic angina. To the best of our knowledge, this is the first report of astemizole-induced QT prolongation and TdP in Japan.
Abstract: Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ultraviolet (HPLC/UV) methods. Renal tubular secretion (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
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.