ASSESSMENT REPORT PRO-KINETIC DRUGS

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1 ASSESSMENT REPORT PRO-KINETIC DRUGS Safety and dosing advice Conclusion: Dosing: Child-Pugh A+B Metoclopramide: Domperidone: Child-Pugh C Metoclopramide: Domperidone: Child-Pugh A Metoclopramide: Domperidone: Child-Pugh B Metoclopramide: Domperidone: Child-Pugh C Metoclopramide: Domperidone: no additional risks known no additional risks known no additional risks known unsafe dose adjustment is not necessary dose adjustment is not necessary use half of the normal dose use a third of the normal dose use half of the normal dose no dosing advice (unsafe) Explanation: There were multiple studies retrieved where was used in patients with cirrhosis. Exposure to is approximately doubled in Child-Pugh B and C, so it is advised to use half of the normal dose. Domperidone is not well studied in patients with cirrhosis. Exposure is increased threefold in Child-Pugh B and it is recommended to use a third of the normal dose. There were no clinical studies in patients with Child-Pugh C cirrhosis and it is predicted that exposure increases. For these reasons it is classified as 'unsafe' in Child-Pugh C. Summary of literature Considerations The pharmacokinetics of were examined in four studies (level of evidence:, 4) with 7 cirrhotic subjects. Exposure to is in Child-Pugh (CTP) A cirrhosis comparable to healthy controls and there is no dose adjustment necessary. Exposure increases approximately twofold in CTP B and C cirrhosis. It is recommended to use half of the normal dose in these patients. Ten studies (level of evidence -4) looked at the safety of in 108 cirrhotic patients (CTP A/B/C 8/1/; n=86 unknown). The occurring adverse events were similar to healthy controls. Metoclopramide is classified as no additional risks known. An increase in aldosterone could cause fluid accumulation in cirrhotic patients and should be stopped if this occurs. Metoclopramide is not recommended for patients suffering from gynaecomastia, because it can increase prolactin. No pharmacokinetic studies were found where domperidone was used in cirrhotic patients. The product information does describe a study of the manufacturer, which found comparable pharmacokinetics in patients with CTP A cirrhosis and healthy controls. In CTP B patients, exposure increased by 190% and the free fraction by 5%. In a modelling study, an increase of 87% in exposure in CTP A was predicted, 06% in CTP B and almost 400% in CTP C. Two single-dose studies (level of evidence ) were included that looked at the safety of domperidone in patients with cirrhosis (CTP A/B/C 5/6/1, 10 unknown). Domperidone was tolerated well after a single-dose. Domperidone is classified as no additional risks known in CTP A cirrhosis and no dose adjustment is recommended. In CTP B it is also classified as no additional risks known if the dose is reduced to a third of the normal dose. Based on the (predicted) highly altered exposure in CTP C patients and the limited clinical data, it is classified as unsafe. 1

2 Pharmacokinetic data Absorption: Metoclopramide has a variable bioavailability of %. One pharmacokinetic study found 60% higher maximum plasma concentrations (C max) in patients with CTP C cirrhosis. The bioavailability of domperidone is low (approx. 15%), caused by a high first-pass effect. There were no studies found with domperidone in cirrhotic patients. The product information describes a study were C max was 50% higher in patients with CTP B compared to healthy controls. There were no differences found for CTP A patients. Distribution: 1-% of is bound to plasma proteins. The volume of distribution was no different in patients with cirrhosis in two studies. Domperidone is highly protein bound (91-9%). The free fraction increased by 5% in patients with CTP B cirrhosis (product information). Metabolism: Metoclopramide is metabolized to a sulphur conjugate. None of the pharmacokinetic studies also measured this metabolite. Domperidone is subject to extensive metabolism in the liver by hydroxylation and N-dealkylation (CYPA4, CYP1A and CYPE1). No data are available on this metabolism in cirrhosis. Elimination: Metoclopramide is mainly renally excreted with an elimination half-life of 5-6 hours. In two studies, clearance of was significantly reduced in patients with cirrhosis. The elimination half-life was prolonged to 15.4 hours in patients with CTP C cirrhosis. Domperidone is excreted in bile for 66% with an elimination half-life of 7-9 hours. According to the product information, elimination half-life was prolonged to hours in patients with CTP B. Exposure: Exposure to was comparable to healthy controls in one pharmacokinetic study, while it was increased in three other studies. In a study with CTP C patients, AUC was found to be 16% higher in the cirrhotic patients. A pharmacokinetic modelling study predicted an increase in AUC of % in CTP A, 88% in CTP B and 158% in CTP C. Exposure to unbound was even more increased (+8% CTP A, 119% CTP B and 11% CTP C). The last study observed an increase of 54% in exposure in patients without ascites and 70% in patients with ascites. Exposure to domperidone was slightly decreased in CTP A patients compared to healthy controls and increased by 190% in patients with CTP B. The modelling study predicted a 87% enlargement in exposure to unbound domperidone in CTP A, a tripled exposure in CTP C and a five-fold increased exposure in CTP C. Safety data Multiple studies assess the safety of in patients with cirrhosis. Metoclopramide is tolerated well in most and only mild adverse events occurred. It was also noted that can increase aldosterone and prolactin concentrations, which can have more severe consequences in cirrhotic patients (i.e. fluid accumulation, worsening of gynaecomastia). In a case-report a cirrhotic patient suffered from extrapyramidal side effects after using 0 mg for four days. Domperidone was used by cirrhotic patients in two studies and was well tolerated in a single dose of 10 mg.

3 ASSESSMENT REPORT PROKINETIC DRUGS 1. Data from the product information Domperidone Section Motilium filmomhulde tabletten 10 mg (domperidonmaleaat) - Dutch SPC Absorption F: 15% a tmax: 1 h Domperidon wordt snel geabsorbeerd na orale toediening, met piekplasmaconcentraties ongeveer 1 uur na toediening. Binnen het dosisbereik van 10 mg tot 0 mg namen de C max- en AUC-waarden van domperidon evenredig met de dosis toe. Een twee- tot drievoudige accumulatie in de AUC van domperidon werd waargenomen bij herhaalde doseringen domperidon van 4 maal per dag (om de 5 uur) gedurende 4 dagen. Hoewel de biologische beschikbaarheid van domperidon versterkt is bij gewone proefpersonen bij inname na een maaltijd, moeten patiënten met maagdarmklachten domperidon 15-0 minuten vóór een maaltijd innemen. De absorptie van domperidon wordt verminderd door een laag zuurgehalte in de maag. De orale biobeschikbaarheid is verminderd door voorafgaande gelijktijdige toediening van cimetidine en natriumbicarbonaat. Gebaseerd op de C max na herhaalde toediening van 60 mg zetpillen tweemaal per dag, wordt verwacht dat toediening van tweemaal per dag van een 0 mg zetpil dezelfde piekplasmaconcentraties geeft als deze van een 10 mg orale dosis viermaal per dag toegediend. Distribution fb: 91-9% Vd: Domperidon bindt voor 91-9% aan plasmaproteïnen. Onderzoek naar de distributie met radioactief gemerkt geneesmiddel bij dieren heeft een brede weefseldistributie aangetoond, maar een lage concentratie in de hersenen. Kleine hoeveelheden van het geneesmiddel dringen door de placenta bij ratten. Metabolism M: ++ Liver: yes, CYPA4, CYP1A, CYPE1 Domperidon ondergaat een snel en uitgebreid levermetabolisme door hydroxylering en N-dealkylering. In-vitro experimenten naar het metabolisme met diagnostische remmers hebben aangetoond dat CYPA4 een van de voornaamste isozymen is van cytochroom P-450 dat betrokken is bij de N- dealkylering van domperidon, terwijl CYPA4, CYP1A en CYPE1 betrokken zijn bij de aromatische hydroxylering van domperidon. Elimination t1/: 7-9 h HE: 66% RE: 1% De urinair en fecaal uitgescheiden hoeveelheid bedraagt respectievelijk 1 en 66% van de orale dosis. De proportie van het in onveranderde vorm uitgescheiden geneesmiddel is klein (10% van de fecale uitscheiding en ongeveer 1% van urine-uitscheiding). De plasmahalfwaardetijd na een éénmalige orale dosis is 7-9 uur bij gezonde proefpersonen, maar is langer bij patiënten met een ernstige nierinsufficiëntie. hepatic impairment Bij proefpersonen met matige leverinsufficiëntie (Pugh Score 7 tot 9, Child-Pugh score B) zijn de AUC en C max van domperidon respectievelijk,9- en 1,5 maal groter dan bij gezonde proefpersonen. De vrije fractie neemt met 5% toe, en de terminale eliminatiehalfwaardetijd is verlengd van 15 tot uur. Patiënten met lichte leverinsufficiëntie vertonen een iets lagere systemische blootstelling dan gezonde proefpersonen op basis van de C max en de AUC, zonder verandering in eiwitbinding of terminale halfwaardetijd. Proefpersonen met ernstige leverinsufficiëntie werden niet bestudeerd. Domperidon is gecontra-indiceerd bij patiënten met matige tot ernstige leverinsufficiëntie Motilium is gecontra-indiceerd bij matige of ernstige leverinsufficiëntie. De dosis hoeft echter niet te worden aangepast bij lichte leverinsufficiëntie. FDA-Label Not licensed in the USA A. KNMP kennisbank

4 Metoclopramide Section Primperan drank, drank 5 mg/5 ml - Dutch SPC Absorption F: % tmax: 0.5- h Na orale toediening bedraagt de relatieve biologische beschikbaarheid in vergelijking met de intraveneuze toepassing 60 tot 100 %. Piekplasmaspiegels worden bereikt binnen 0,5 tot uur. Distribution fb: 1-% Vd: - L/kg Het verdelingsvolume is - l/kg; 1-% wordt gebonden aan plasmaeiwitten. Metabolism M: + Liver:? De voornaamste metaboliet is N-4 zwavelconjugaat. Elimination t1/: 5-6 h HE: RE: ++ Metoclopramide wordt voornamelijk uitgescheiden in de urine, zowel in onveranderde vorm als in sulfaat- of glucuronideconjugaat vorm. De plasmaeliminatie-halfwaardetijd is 5 tot 6 uur, ongeacht de toedieningsweg. Hepatic impairment Bij patiënten met levercirrose werd accumulatie van waargenomen, gepaard gaand met een daling van 50% in plasmaklaring. Bij patiënten met een ernstige leverfunctiestoornis dient de dosis te worden verlaagd met 50%. FDA-Label Metoclopramide tablet Unit Dose Services Because produces a transient increase in plasma aldosterone, certain patients, especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid retention and volume overload. If these side effects occur at any time during therapy, the drug should be discontinued. 4

5 . Literature review Search strategy Pubmed ("Liver cirrhosis"[mesh] OR cirrho*[ti] OR "hepatic impairment"[ti] OR "liver impairment"[ti] OR "hepatic dysfunction"[ti] OR "liver dysfunction"[ti] OR "hepatic insufficiency"[ti] OR "liver insufficiency"[ti]) AND ("Metoclopramide"[Mesh] OR "Domperidone"[Mesh] OR ""[tiab] OR "domperidone"[tiab]) AND "humans"[mesh Terms] Embase 'liver cirrhosis'/exp OR cirrho*:ti OR 'hepatic impairment':ti OR 'liver impairment':ti OR 'hepatic dysfunction':ti OR 'liver dysfunction':ti OR 'hepatic insufficiency':ti OR 'liver insufficiency':ti AND ('domperidone'/exp OR ''/exp OR 'domperidone':ab,ti OR '':ab,ti) AND [humans]/lim Flowchart Records founds in databases Pubmed: n= Embase: n=155 Title and abstract screened (n=187) Excluded records (n=1) No cirrhosis (n=15) o Hepatitis (n=) o Transplantation (n=5) o Other (n=8) Not specifically prokinetic drug (n=47) DILI (n=6) Animal study (n=) Other (n=5) Removal of duplicate studies (n=5) Complete study screened (n=40) Excluded records (n=1) Not specifically prokinetic drug (n=1) Not specifically cirrhosis (n=1) Other outcome (n=11) Other (n=18) Additional records found References: n= Citation tracking via Web of Science: n= Included studies (n=14) 5

6 . Summary tables of literature Pharmacokinetic data Level of evidence 4 Maguer; 1991 Albani; 1991 Bernardi; 1987 Steelandt 015 Design Clinical Clinical Clinical PK modellings study Reference Intervention Single dose of 0 mg IV and 0 mg PO (15.4 and 17 mg base, resp.) Single dose of IV (17.8 mg as base) 0 mg PO Metoclopramide Domperidon PO Domperidon IV Results Healthy Cirrhotic patients Remarks controls CTP A CTP B CTP C n=8 n=8 A 50% reduction in dose AUC (ng.h/ml) 749 ± ± 749* is recommended in Ratio.6 patients with severe liver V (L/kg).4 ± 1..1 ± 0.8 cirrhosis t1/ (h) 7. ± ± 5.0* Cl (ml/min) 70 ± ± 76** Cmax (ng/ml) 6 ± ± 7* Ratio 1.60 AUC (ng.h/ml) 689 ± ± 905* Ratio.6 tmax (h; range) 1.9 ± ±.5 t1/ (h) 8.6 ±.8 1. ± 4.0 F (%) 84.5 ± ± 18.8 n=6 No ascites n=6 Ascites n=6 The only side effect AUC (ng.h/ml) 570 (00) 877 (177) 970 (6) Ratio V (L/kg) 4.45 (0.8) 5.16 (0.97) 4.71 (1.09) t1/ (h) 6.40 (1.59) 9.90 (1.4)* 11.9 (.94)* Cl (L.h/kg) 0.5 (0.) 0.6 (0.06)* 0.9 (0.05)* Ae (%) 1 a 6 a 4 ClR (ml/min) 16 (5) a 11 (14) a 100 (15) ClCR (ml/min) 10 (0) 110 (45) 90 (16)** ascribed to administration was mild somnolence, reported in patients and controls. Plasma clearance and creatinine clearance were not correlated Inpatients n=6 No ascites n=9 Ascites n=8 Abstract AUC0-48 (ng.h/ml) 105 ± ± 1 98 ± 185 Ratio V (L/kg.h) 0.4 ± ± 0.0 t1/ (h) 9.7 ± ± ± 1.1 AUC ratiototal predict Domperidone: 0.75 CYPA4 AUC ratiounbound predict Metoclopramide: 0.44 AUC ratiototal predict CYPD6 AUC ratiounbound predict AUC ratiototal predict AUC ratiounbound predict Results are expressed as mean±sd or as mean±sem. Predict.=predicted AUC by PK modelling, ratio= ratio [cirrhotic patients/healthy controls].*p<0.05, **p<0.01 in comparison with healthy controls. a. n=5 6

7 Safety data Level of evidence Reference Kleber; 1991 Hosking; 1988 Mastai; 1986 Uribe; 1985 Design Patients Intervention Double-blind randomized Single-blind randomized Double-blind RCT Double-blind randomized cross-over Cirrhosis + portal hypertension + oesophageal varices Cirrhosis + active lower variceal bleeding Cirrhosis + severe portal hypertension (n=) Cirrhosis + mild chronic PSE (n=8) PSE= portal-systemic encephalopathy, TID= three times daily Single dose of 0 mg IV (n=9; CTP A/B/C 7//0) Single dose of 0 mg IV (n=11; CTP A/B/C 5/5/1) Single dose of 0 mg IV (n=1; CTP A/B/C 6/5/1) or domperidone 10 mg IV (n=1; CTP A/B/C 5/6/1) Metoclopramide 0 mg TID for weeks Control Results Remarks Placebo (n=10; CTP A/B/C 5//) No treatment (n=11; CTP A/B/C 4/7/0) Placebo (n=9; CTP A/B/C 5/4/0) Placebo for weeks Blood pressure and heart rate were not significantly influenced by or placebo No patient experienced any complications as a result of the study Domperidone and had no significant effect on systemic and hepatic hemodynamics, indicating that at the dose used in this study, these drugs have no significant circulatory effects in patients with cirrhosis No complications occurred, and there were no side effects following the administration of placebo, and domperidone. In a single patient somnolence (but no coma) transiently appeared during administration (electroencephalogram and ammonia levels were unchanged). No signs of galactorrhea, gynecomastia, or breast pain were referred or observed in any patient. No extrapyramidal signs were noticeable during the study. Metoclopramide produced a significant elevation of prolactin serum levels 7

8 Level of evidence Reference D Arienzo; 1985 Bernardi; 1988 Bernardi; 1985 Design Patients Intervention Randomized single blindstudy Clinical Clinical Cirrhosis + ascites Cirrhosis (n=) Cirrhosis (n=18; 9 without ascites (G1), 10 with (G)) UnaV= renal sodium excreation, PA=plasma aldosterone. Single dose of 10 mg (n=10) Single dose of 10 mg IV Singled dose of 10 mg IV Control Results Remarks Single dose of domperidone 10 mg (n=10) Healthy (n=8) Healthy (n=8) In response to administration of 10 mg of, plasma aldosterone increased from the basal value of 88 ± 74 to 54 ± 90 pg per ml at 60 min (p < 0.01). After domperidone administration, no significant change was observed in plasma aldosterone levels which decreased slightly from the basal value of 9. ±67 to 7 ±71 pg/ml at 60 min Between Days 1 and after, there were significant decreases in natriuresis [5 ± 7% (10/10 patients, p<0.001)] and urine output [4± 7% (10/10 patients, p <0.001)] and a significant rise in urinary potassium [4 ± 7% (10/10 patients, p <0.001)]. There were no side effects of medications during the study. AUC0-h, of plasma concentration did not differ among controls and the groups of patients considered. Metoclopramide did not significantly influence plasma renin activity, whereas both plasma aldosterone and plasma prolactin rose significantly. The incremental areas under the curves did not differ among controls and cirrhotic patients without and with ascites. No significant correlations between plasma prolactin and aldosterone, either under basal conditions or after administration, were found in either controls or patients. GFR and plasma sodium and potassium concentrations did not change either in controls or patients. The dopaminergic control of aldosterone secretion does not appear to be significantly altered in cirrhosis. Metoclopramide administration to cirrhotic patients with ascites leads to an increase in plasma aldosterone that may enhance renal sodium retention. Metoclopramide led to significant increases of plasma aldosterone, in all groups, whereas plasma renin activity was not affected. The h response above basal levels was not different in controls, GI and G. GFR did not change. UNaV of G was inversely related to PA under basal conditions (r=-0.94; p<0.001), but slighty decreased after (0.1>p>0.05). No changes in controls' and G1 UNaV were found. The -induced increase of plasma aldosterone does not assume clinical relevance, since sodium excretion was virtually not affected. Regardless of the mechanism for its antinatriuretic effect, should be avoided during diuretic therapy in cirrhotic patients with ascites. In these circumstances domperidone is preferred. 8

9 Level of evidence 4 Reference Uribe; 198 Bernardi; 1986 BID=twice daily, TID=three times daily Design Patients Intervention Cirrhosis + Metoclopramide 0 mg portal Double-blind systemic TID for encephalopa wks thy (n=4) Case-report Cirrhotic patient 4 days of 10 mg BID Control Results Remarks Placebo for wks - The clinician evaluating the patients was unable to detect any significant mental or neurological change, either with placebo or Continuous severe orofacial dyskinesia and blepharospasm appeared after 4 days The patient was also treated, because of PSE (grade I1 at the admission], with oral lactulose and MgSO, enemas. He also received cimetidine 400 mg b.i.d. because of a duodenal ulcer. Glomerular filtration rate was normal and computed tomography scan excluded brain lesions. The dyskinesia appeared when symptoms of hepatic encephalopathy were improving, and progressively disappeared within a week of discontinuation Randomisation not mentioned Abstract (-) Letter to the editor Reviews (level 5 evidence) Level of evidence 5 Reference Outcome Expert opinion Rodighiero; 1999 Pharmacokinetic parameters Metoclopramide is subject to a first-pass effect, but there are wide interindividual variations; the oral bioavailability ranges from to 97%. It is about 40% bound to plasma proteins and metabolised to sulphate and glucuronide conjugates, 0% being excreted unchanged in the urine. In 8 patients with severe alcoholic cirrhosis and marked hepatic impairment (Child- Pugh class C) given single intravenous and oral doses of 0mg a 50% decrease in CL was observed. [Magueur 1991] This decrease resulted in a corresponding prolongation of t1 (15 vs 7h in healthy volunteers) and similar increases in AUC after both intravenous and oral administration (AUCIV 1689 vs 749 μg/l h, AUCoral 1559 vs 689 μg/l h). Changes in kinetics were also found in another study.[study Hellstern, not available] 18 cirrhotic patients with varices, characterised with antipyrine and ICG clearance, were studied after administration of single intravenous and oral doses of 0.5 mg/kg. The presence of hepatic blood shunting determined an increase in bioavailability and consequently a higher AUC (F 8 vs 60% in controls and AUC 4 vs 180 μg/l h). Dosage adjustments are advisable in patients with cirrhosis, especially in the case of prolonged therapy; a 50% reduction of the dosage is recommended. In these studies, the authors did not report the renal function of patients with cirrhosis. This parameter is important because 0% of is excreted unchanged in the urine. Patients with renal impairment have a reduced elimination of the drug. Thus, when severe hepatic impairment and reduced kidney function coexist, the use of is probably best avoided. 9

10 4. References 1. Magueur E, et al. Pharmacokinetics of in patients with liver cirrhosis. Br J Clin Pharmacol (): Albani F, et al. Kinetics of intravenous in patients with hepatic cirrhosis. Eur J Clin Pharmacol (4):4-5. Bernardi M, et al. Metoclopramide pharmacokinetics in cirrhosis. J. Hepatol 1987 suppl. 5, S Steelandt J, et al. A Prediction Model of Drug Exposure in Cirrhotic Patients According to Child Pugh Classification. Clin Pharmacokin (1): Kleber, et al. Reduction of transmural oesophageal variceal pressure by. J Hepatol (): Hosking SW, et al. Pharmacological constriction of the lower oesophageal sphincter: A simple method of arresting variceal haemorrhage. Gut (1988) 9:8 ( ). 7. Mastai R, et al. Effects of and domperidone on azygos venous blood flow in patients with cirrhosis and portal hypertension. Hepatol (6): Uribe M, et al. Successful administration of for the treatment of nausea in patients with advanced liver disease. A double-blind controlled. Gastroenterol (): D'Arienzo A, et al. A randomized comparison of and domperidone on plasma aldosterone concentration and on spironolactone-induced diuresis in ascitic cirrhotic patients. Hepatol (5): Bernardi M, et al. Unaltered dopaminergic modulation of aldosterone secretion in cirrhosis. Clin Sci (Lond) (): Bernardi M, et al. Effect of dopaminergic receptor blockade on plasma aldosterone concentration and sodium excretion in cirrhosis (abstr). J Hepatol (Amst) 1985;Suppl. :s Uribe M, et al. Do dopamine antagonist drugs induce hepatic encephalopathy? A double blind evaluation. Hepatol (198) :5 (No. 9) 1. Bernardi M, et al. Metoclopramide administration in advanced liver cirrhosis. Gastroenterol , Rodighiero VV, et al. Effects of liver disease on pharmacokinetics. An update. Clin Pharmacokin (5):