Allongement du temps QT
Événements indésirables médicamenteux
Variantes ✨Pour une évaluation intensive des variantes par ordinateur, veuillez choisir l'abonnement standard payant.
Explications concernant les substances pour les patients
Formellement contre-indiquée: abiratérone et amantadine
Selon le résumé suisse des caractéristiques du produit pour la amantadineExtrait de texte : … traitement concomitant avec des médicaments allongeant l'intervalle QT (voir « Interactions ») …
Les changements d'exposition rapportés correspondent aux changements de la courbe concentration-temps plasmatique [ AUC ]. Nous ne prévoyons aucun changement dans l'exposition à la amantadine, lorsqu'il est associé à la abiratérone (100%). Nous ne prévoyons aucun changement dans l'exposition à la abiratérone, lorsqu'il est associé à la amantadine (100%).
Les paramètres pharmacocinétiques de la population moyenne sont utilisés comme point de départ pour calculer les changements individuels d'exposition dus aux interactions.
La amantadine a une biodisponibilité orale élevée [ F ] de 88%, c'est pourquoi la concentration plasmatique maximale [Cmax] a tendance à peu changer au cours d'une interaction. La demi-vie terminale [ t12 ] est de 20.5 heures et des taux plasmatiques constants [ Css ] sont atteints après environ 82 heures. La liaison aux protéines [ Pb ] est plutôt faible à 67% et le volume de distribution [ Vd ] est très grand à 294 litres. Environ 90.0% d'une dose administrée sont excrétés sous forme inchangée par les reins et cette proportion est rarement modifiée par les interactions. Le métabolisme ne se fait pas via les cytochromes communs.
La abiratérone a une biodisponibilité orale moyenne [ F ] de 50%, c'est pourquoi les concentrations plasmatiques maximales [Cmax] ont tendance à changer avec une interaction. La demi-vie terminale [ t12 ] est de 18 heures et des taux plasmatiques constants [ Css ] sont atteints après environ 72 heures. La liaison aux protéines [ Pb ] est très forte à 99.8% et le volume de distribution [ Vd ] est très grand à 2815 litres, Le métabolisme se fait principalement via CYP3A4.
|Effets sérotoninergiques a||0||Ø||Ø|
Note: À notre connaissance, ni la amantadine ni la abiratérone n'augmentent l'activité sérotoninergique.
|Kiesel & Durán b||2||++||Ø|
Recommandation: Par mesure de précaution, une attention particulière doit être portée aux symptômes anticholinergiques, en particulier après augmentation de la dose et à de celles situées dans la marge thérapeutique supérieure.
Notation: La amantadine module modérément le système anticholinergique. Le risque de syndrome anticholinergique avec ce médicament est plutôt faible si la dosage est respecté. À notre connaissance, la abiratérone n'augmente pas l'activité anticholinergique.
Allongement du temps QT
Note: En association, la amantadine et la abiratérone peuvent potentiellement déclencher des arythmies ventriculaires de type torsades de pointes.
Effets indésirables généraux
|Effets secondaires||∑ fréquence||ama||abi|
|Œdème périphérique||22.4 %||3.0||20.0|
|Infection urinaire||19.0 %||10.0||10.0|
|ALT élevé||13.0 %||n.a.||13.0|
|AST élevé||13.0 %||n.a.||13.0|
|La nausée||7.5 %||7.5||n.a.|
|La diarrhée||5.5 %||n.a.||5.5|
Septicémie (5.5%): abiratérone
Anxiété (4%): amantadine
La dépression (3.5%): amantadine
Agitation (3%): amantadine
Trouble du rêve (3%): amantadine
Nervosité (3%): amantadine
Hallucinations (3%): amantadine
Perte d'appétit (3.5%): amantadine
Constipation (3%): amantadine
Xérostomie (3%): amantadine
Hypotension orthostatique (3%): amantadine
Fibrillation auriculaire (2.6%): abiratérone
Angine de poitrine (1.6%): abiratérone
Insuffisance cardiaque: amantadine
Ataxie (3%): amantadine
Syndrome malin des neuroleptiques: amantadine
Sur la base de vos réponses et des informations scientifiques, nous évaluons le risque individuel d'effets secondaires indésirables. Ces recommandations sont destinées à conseiller les professionnels et ne se substituent pas à la consultation d'un médecin. Dans la version d'essai (alpha), le risque de toutes les substances n'a pas encore été évalué de manière concluante.
Abstract: To study the disposition of amantadine hydrochloride in patients with impaired renal function, 100 mg was administered orally to 13 patients with creatinine clearances ranging from 48 to 10 ml/min/1.73 m2 body surface area. Six adults with normal renal function served as controls. Plasma half-life averaged 68.5 +/- 9.5 SEM hours in the renal patients (range: 27 to 144), versus 12.6 +/- 1.7 hours in controls. Plasma half-life correlated significantly with serum creatinine (r = 0.8476, P less than 0.001) and serum urea nitrogen levels (r = 0.8791, P less than o.001). Similarly, plasma elimination constant correlated with creatinine clearance/1.73 m2 body surface area (r = 09201, P less than 0.001). Renal amantadine clearance also correlated with creatinine clearance/1.73 m2 body surface area (r = 0.8217, P less than 0.001). However, renal amantadine clearance regularly exceeded creatinine clearance, suggesting that tubular secretion plays a role in the elimination of this drug. Amantadine excretion is decreased in patients with impaired renal function. The amount by which dosage must be reduced can be estimated based on creatinine clearance.
Abstract: Amantadine is useful for the prevention and treatment of influenza A and for the treatment of Parkinson's disease and drug-induced extrapyramidal disorders. We have compared the pharmacokinetics of amantadine in patients with impaired or negligible renal function to that in normal subjects. The half-life of elimination in subjects with normal renal function was 11.8 +/- 2.1 hours (range, 9.7 to 14.5 h). Eight patients with various degrees of renal insufficiency (creatinine clearance from 43.1 to 5.9 mL/min . 1.73 m2) had half-lives of elimination from 18.5 h to 33.8 days. We also studied 10 patients on thrice-weekly hemodialysis. Assuming complete bioavailability of the drug, less than 5% of the dose was removed by each 4-hour hemodialysis. The mean half-life of elimination during chronic hemodialysis was 8.3 days (range, 7.0 to 10.3). We present guidelines for use of amantadine in patients with impaired renal function, including those on maintenance hemodialysis.
Abstract: INTRODUCTION: Amantadine hydrochloride is an antiviral medication used as therapy for parkinsonism and as a cognitive enhancer. We report 2 cases of massive, acute ingestion of amantadine hydrochloride confirmed with serial serum levels. CASE REPORTS: A 47-year-old woman presented to the emergency department (ED) 30 minutes after ingesting 10 g of amantadine (150 mg/kg) by her report. Initial ECG revealed a sinus rhythm with rate of 93 bpm, and a QRS of 84 msec. While in the ED, the patient sustained a pulseless cardiac arrest and the monitor revealed ventricular tachycardia. She was successfully defibrillated. Postdefibrillation ECG showed a sinus rhythm (rate = 82 bpm), QRS of 236 msec, and QTc of 567 msec. The serum potassium was 1.0 mEq/L (1.0 mmol/L). The patient was given 300 ml (300 cc) 3% sodium chloride IV over 10 minutes. Ten minutes after completion of the hypertonic saline infusion, the patient's ECG abnormalities resolved and the QRS was 88 msec. Her potassium was repleted over the next 11 hours postpresentation, and she also received an IV bolus of 4 g of magnesium sulfate immediately after the cardiac arrest. No further hypotension, dysrhythmia, conduction delay, or ectopy was noted during the patient's hospital stay. The second case involved a 33-year-old female patient who presented 1 hour after ingesting 100 tablets of amantadine hydrochloride (100 mg/tab). Initial ECG revealed sinus tachycardia with a QRS of 113 msec, an R wave in lead aVR of 4-5 mm and a QTc of 526 msec. Her serum potassium was 3.0 mEq/L (3.0 mmol/L), her serum calcium was 9.4 mg/dl (2.35 mmol/L), and serum magnesium was 2.1 mg/dl (0.86 mmol/L) on labs drawn at initial presentation. The patient was intubated for airway protection, and her potassium was repleted and corrected over the next 9 hours. Her ECG abnormalities improved 8 hours after initial presentation and normalized at approximately 14 hours postingestion. The patient was discharged home 11 days after her ingestion. CONCLUSION: Acute amantadine toxicity manifests with life-threatening cardiotoxicity. Concurrent, often profound, hypokalemia may complicate the administration of sodium bicarbonate in the management of cardiac dysrhythmias.
Abstract: Three open-label, single-dose studies investigated the impact of hepatic or renal impairment on abiraterone acetate pharmacokinetics and safety/tolerability in non-cancer patients. Patients (n = 8 each group) with mild/moderate hepatic impairment or end-stage renal disease (ESRD), and age-, BMI-matched healthy controls received a single oral 1,000 mg abiraterone acetate (tablet dose); while patients (n = 8 each) with severe hepatic impairment and matched healthy controls received 125- and 2,000-mg abiraterone acetate (suspension doses), respectively (systemic exposure of abiraterone acetate suspension is approximately half to that of tablet formulation). Blood was sampled at specified timepoints up to 72 or 96 hours postdose to measure plasma abiraterone concentrations. Abiraterone exposure was comparable between healthy controls and patients with mild hepatic impairment or ESRD, but increased by 4-fold in patients with moderate hepatic impairment. Despite a 16-fold reduction in dose, abiraterone exposure in patients with severe hepatic impairment was about 22% and 44% of the Cmax and AUC∞ of healthy controls, respectively. These results suggest that abiraterone pharmacokinetics were not changed markedly in patients with ESRD or mild hepatic impairment. However, the capacity to eliminate abiraterone was substantially compromised in patients with moderate or severe hepatic impairment. A single-dose administration of abiraterone acetate was well-tolerated.
Abstract: Two novel oral drugs that target androgen signaling have recently become available for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate inhibits the synthesis of the natural ligands of the androgen receptor, whereas enzalutamide directly inhibits the androgen receptor by several mechanisms. Abiraterone acetate and enzalutamide appear to be equally effective for patients with mCRPC pre- and postchemotherapy. Rational decision making for either one of these drugs is therefore potentially driven by individual patient characteristics. In this review, an overview of the pharmacokinetic characteristics is given for both drugs and potential and proven drug-drug interactions are presented. Additionally, the effect of patient-related factors on drug disposition are summarized and the limited data on the exposure-response relationships are described. The most important pharmacological feature of enzalutamide that needs to be recognized is its capacity to induce several key enzymes in drug metabolism. The potency to cause drug-drug interactions needs to be addressed in patients who are treated with multiple drugs simultaneously. Abiraterone has a much smaller drug-drug interaction potential; however, it is poorly absorbed, which is affected by food intake, and a large interpatient variability in drug exposure is observed. Dose reductions of abiraterone or, alternatively, the selection of enzalutamide, should be considered in patients with hepatic dysfunction. Understanding the pharmacological characteristics and challenges of both drugs could facilitate decision making for either one of the drugs.
Abstract: We present a case of a 77 year-old gentleman with previous coronary artery bypass grafting, admitted to hospital with recurrent torsades de pointes (TdP) due to abiraterone-induced hypokalaemia and prolonged QTc. The patient was on abiraterone and prednisone for metastatic prostate cancer. He required multiple defibrillations for recurrent TdP. Abiraterone is a relatively novel drug used in metastatic prostate cancer and we discuss this potential adverse effect and its management in this unusual presentation.
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.
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.
Abstract: Drug transporters play an essential role in disposition and effects of multiple drugs. Plasma concentrations of the victim drug can be modified by drug-drug interactions occurring in enterocytes (e.g., P-glycoprotein), hepatocytes (e.g., organic anion-transporting polypeptide 1B1 (OATP1B1)), and/or renal proximal tubular cells (e.g., organic cation transporter 2 (OCT2)/multidrug and toxin extrusion 1 and 2-K (MATE1/MATE2-K)). In addition, transporter-mediated drug-drug interactions can cause altered local tissue concentrations and possibly altered effects/toxicity (e.g., in liver and kidneys). During drug development, there is now an intensive in vitro screening of new molecular entities as transporter substrates and inhibitors, followed if necessary by drug-drug interaction studies in healthy volunteers. Nevertheless, there are still unresolved issues, which will also be discussed in this review article (e.g., the clinical significance of transporter-mediated drug-drug interactions of particular relevance to the elderly who are prescribed multiple drugs, with additional impaired liver or kidney function, and the extent to which medication safety in real life could be improved by a reduction of those interactions).