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 maprotiline and abarelix. Please also consult the relevant specialist information.
|Maprotiline||1 [0.44,3.53] 1||1|
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 maprotiline, when combined with abarelix (100%). The AUC is between 44% and 353% depending on the CYP2D6
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Maprotiline has a high oral bioavailability [ F ] of 84%, which is why the maximum plasma level [Cmax] tends to change little during an interaction. The terminal half-life [ t12 ] is rather long at 42.5 hours and constant plasma levels [ Css ] are only reached after more than 170 hours. The protein binding [ Pb ] is moderately strong at 88% and the volume of distribution [ Vd ] is very large at 983 liters, Since the substance has a low hepatic extraction rate of 0.09, displacement from protein binding [Pb] in the context of an interaction can lead to increased exposure. The metabolism takes place via CYP1A2 and CYP2D6, among others.
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.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither maprotiline nor abarelix increase serotonergic activity.
|Kiesel & Durán b||2||++||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: Maprotiline modulates the anticholinergic system to a moderate extent. 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, maprotiline and abarelix can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||map||aba|
|Blurred vision||8.0 %||8.0||n.a.|
|Feeling nervous||6.0 %||6.0||n.a.|
|Myocardial infarction||0.0 %||0.0||n.a.|
Paralytic ileus: maprotiline
Cerebrovascular accident: maprotiline
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: No Abstract available
Abstract: Six male subjects received simultaneously single 50-mg oral doses of a maprotiline hydrochloride tablet and a trideuterated maprotiline hydrochloride aqueous solution. No side effects or other problems were encountered. The blood levels of unlabeled and isotope-labeled maprotiline for each subject were essentially superimposable. Peak levels, averaging about 50 ng/ml, were attained between 8 and 24 hr after drug. The biologic t1/2 (beta-phase) averaged 58 hr for the unlabeled and 60.5 hr for the labeled drug. The total areas under the curves (extended to time infinity) averaged 3,862 and 3,944 ng . hr/ml for maprotiline and trideuterated maprotiline, respectively (differences between the two are not significant). At the 95% degree of confidence the Westlake confidence limits show less than 10% differences between the formulations with respect to area under the curve data (calculated both to 168 hr and extended to time infinity), peak blood levels, and biologic t1/2s. There were no differences between formulations with respect to times of peak concentrations. Estimates were made for apparent volumes of distribution (about 1,000 l), apparent blood clearance (about 14 l/hr), lag times (about 1.42 hr for tablets and 1.31 hr for solution), and absorption rate constants (about 0.34 hr-1 for the tablets and 0.42 hr-1 for the solution).
Abstract: The kinetics of maprotiline have been evaluated in six normal volunteers following rapid intravenous administration of 75 mg. Blood levels could be resolved using a biexponential equation. Mean estimates of half-life, volume of distribution and systemic clearance were 40 +/- 15 h, 51.7 +/- 18.01/kg and 0.92 +/- 0.24/kg/h, respectively. Blood/plasma concentrations varied between subjects from 0.77 to 1.64. A comparison of the bioavailability of two oral doses (a 75 mg tablet and three 25 mg tablets) was carried out in the same volunteers. No significant difference was observed between the maprotiline concentrations obtained for the two doses at sampling times up to 26 h. No significant difference was found in the area under the concentration vs. time curves for the two doses. Equivalent bioavailability can be assumed. On the basis of the intravenous injection study, systemic bioavailability averaged 66% and 70% for the 75 mg and three 25 mg tablets respectively.
Abstract: The authors report the case of a patient who presented with wave burst arrhythmia related to long-term treatment with maprotiline. This case is interesting, as few cases of this type of complication have been reported in patients receiving long-term tetracyclic antidepressants, and the development of such a complication indicates the need for regular electrocardiographie surveillance of patients treated with heterocyclic antidepressants. Lastly, prolonged intensive care monitoring is required in the case of maprotiline-induced wave burst arrhythmia.
Abstract: No Abstract available
Abstract: From case reports of patients treated with the tetracyclic antidepressant drug maprotiline, it appears that this drug is subject to polymorphic metabolism. Thus, we studied formation of the major maprotiline metabolite desmethylmaprotiline to identify the human cytochrome P-450 enzymes (CYP) involved. In incubations with human liver microsomes from two different donors, the substrate maprotiline was used at five different concentrations (5 to 500 microM). For selective inhibition of CYPs, quinidine (0.5-50 microM; CYP2D6), furafylline (0.3-30 microM; CYP1A2), ketoconazole (0.2-20 microM; CYP3A4), mephenytoin (20-200 microM; CYP2C19), chlorzoxazone (1-100 microM; CYP2E1), sulphaphenazole (0.2-100 microM; CYP2C9) and coumarin (0.2-100 microM; CYP2A6) were used. Desmethylmaprotiline concentrations were measured by HPLC, and enzyme kinetic parameters were estimated using extended Michaelis-Menten equations with non-linear regression. Relevant inhibition of the desmethylmaprotiline formation rate was observed in incubations with quinidine, furafylline and ketoconazole only. Formation rates of desmethylmaprotiline were consistent with a two enzyme model with a high (K(M)=71 and 84 microM) and a low (K(M)=531 and 426 microM) affinity site for maprotiline in the two samples, respectively. The high affinity site was competitively inhibited by quinidine (K(i,nc) 0.13 and 0.61 microM), the low-affinity site was non-competitively inhibited by furafylline (K(i,nc) 0.11 and 1.3 microM). Thus it appears that CYP2D6 and CYPIA2 contribute to maprotiline demethylation. Based on the parameters obtained, for plasma concentrations of 1 microM 83% (mean) of desmethylmaprotiline formation in vivo is expected to be mediated by CYP2D6 while 17% only may be attributed to CYPIA2 activity.
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.