Beoordelingsrapport paracetamol

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1 Beoordelingsrapport Veiligheid en doseeradvies Conclusie: Child-Pugh A+B+C Veilig Dosering: Aanpassing van de dosering is niet nodig Toelichting: De halfwaardetijd van is verlengd bij cirrose, maar dit leidde bij meerdaagse toediening niet tot accumulatie. Ook heeft dit geen invloed op de hepatotoxiciteit van. Aanpassing van de dosering op basis van de cirrose is dus niet nodig. Samenvatting literatuur Overwegingen Er zijn negen studies (bewijsniveau 3-) uitgevoerd naar de farmacokinetiek van bij 86 patiënten met cirrose. De meeste studies vonden een verlengde halfwaardetijd van bij patiënten met cirrose, dit bleek in twee studies niet tot accumulatie te zorgen bij toediening gedurende vijf dagen. Het metabolisme van is vertraagd bij cirrose, maar de verhouding metabolieten in de urine bleek vergelijkbaar met controles zonder cirrose. Er is geen reden om aan te nemen dat de hoeveelheid van de hepatotoxische metaboliet NAPQI (N-acetyl benzoquinonimine) verhoogd is bij cirrose. Dit bleek ook uit zes studies naar de veiligheid (bewijsniveau 2-) met 156 cirrotische deelnemers. Er werden geen hepatotoxische bijwerkingen van waargenomen, ook niet na twee weken gebruik van gram per dag. Paracetamol kan veilig gebruikt worden en er is geen dosisaanpassing nodig. Er is geen onderzoek gedaan bij patiënten met cirrose en risicofactoren voor hepatotoxiciteit (bv. ondervoeding of alcoholgebruik). Aangeraden wordt bij deze patiënten de geldende standaarden te volgen (maximaal 2 gram per dag). Farmacokinetische gegevens Absorptie: Na orale toediening wordt snel en bijna volledig geabsorbeerd. Uit twee farmacokinetische studies bleek dat de maximale plasmaspiegels van weinig verschillen tussen patiënten met cirrose en gezonde controles (maximaal +28% bij Child-Pugh C-patiënten). Distributie: De plasma-eiwitbinding van is te verwaarlozen en heeft een verdelingsvolume van 1 L/kg. Dit verdelingsvolume was vergelijkbaar bij cirrotische patiënten. Metabolisme: Paracetamol wordt met name geglucuronideerd (ca. 60%) en gesulfateerd (ca. 35%). Minder dan 5% wordt via CYP2E1 omgezet in de hepatotoxische metaboliet NAPQI (N-acetyl benzoquinonimine). Eliminatie: Paracetamol wordt, voornamelijk als metaboliet, uitgescheiden met de urine. Het heeft een eliminatiehalfwaardetijd van 1- uur. Het metabolisme van blijkt vertraagd bij cirrose, gezien een verminderde klaring en een verlengde halfwaardetijd. De halfwaardetijd nam in de farmacokinetische studies toe met % tot 2-,5 uur (gemiddeld +72%). In meerdere studies werd een correlatie gevonden tussen verlenging van de halfwaardetijd of vermindering van de klaring en het serumalbumine en de protrombinetijd. Toediening gedurende vijf dagen zorgde niet voor accumulatie van in twee studies. De hoeveelheid sulfaat-, glucuronidine- en NAPQI-(cysteïne- en mercaptuurzuur) metabolieten in de urine van cirrose-patiënten bleek vergelijkbaar met controles zonder cirrose. Blootstelling: De blootstelling aan bleek uit twee studies verhoogd bij patiënten met cirrose. Eén studie vond een stijging van de AUC met 66% bij CTP A en B en met 86% bij CTP C. Een andere studie vond een stijging van de AUC met 30-1% bij patiënten met cirrose. Veiligheid Studies waarbij patiënten met cirrose gebruikten, vonden geen veranderingen in de hepatische laboratoriumwaardes. In één studie werd vier keer daags 1 gram gedurende twee weken toegediend, zonder hepatische bijwerkingen. Twee case-controle studies vonden geen verband tussen gebruik door patiënten met cirrose en opname in het ziekenhuis voor acute leverdecompensatie. Er zijn geen studies gedaan bij patiënten met cirrose en andere mogelijke risicofactoren voor hepatotoxiciteit (bv. alcoholgebruik, ondervoeding). Aangeraden wordt de geldende standaarden te volgen als er sprake is van risicofactoren (maximaal 2 gram per dag). 1

2 Beoordelingsrapport 1. Farmacokinetische gegevens Paracetamol Section Sinaspril 120 vloeibaar, stroop 120 mg/5 ml- SPC Absorptie F: bijna volledig tmax: 0,5-2 uur Na orale toediening wordt snel en bijna volledig geabsorbeerd. De maximale concentratie wordt na 30 minuten tot 2 uur bereikt. Distributie fb: te verwaarlozen Vd: 1 L/kg Het verdelingsvolume van bedraagt ca. 1 l/kg lichaamsgewicht. Bij therapeutische doseringen is de plasma-eitwitbinding te verwaarlozen. Metabolisme M: 95% Lever: ja Paracetamol wordt bij volwassenen in de lever geconjugeerd met glucuronzuur (ca. 60%), sulfaat (ca. 35%) en cysteïne (ca. 3%). Bij neonaten en kinderen tot 12 jaar is sulfaatconjugatie de overwegende eliminatieroute en vindt glucuronidering in mindere mate plaats dan bij volwassenen het geval is. De totale eliminatie bij kinderen is als gevolg van een verhoogde sulfateringscapaciteit echter globaal vergelijkbaar met die van volwassenen. Eliminatie t1/2: 1- uur HE: RE: Paracetamol wordt uitgescheiden met de urine, voornamelijk in de vorm van het glucuronide en het sulfaatconjugaat, en ca. 5% in onveranderde vorm. De eliminatiehalfwaardetijd varieert van 1 tot uur. Leverinsufficiëntie Voorzichtigheid is geboden bij lever- en nierfunctiestoornissen. Voorzichtigheid is geboden bij chronisch alcoholisme, de dagdosering dient dan de 2 gram niet te overschrijden FDA-Label OFIRMEVacetaminophen injection, solution Acetaminophen is contraindicated in patients with severe hepatic impairment or severe active liver disease and should be used with caution in patients with hepatic impairment or active liver disease. A reduced total daily dose of acetaminophen may be warranted FDA-label propoxyphene napsylate and acetaminophen tablet, film coated Compared to healthy subjects, acetaminophen had a lower total clearance and longer half-life in patients with liver disease. Decreased metabolite formation clearance (8-2%) was observed in subjects with liver disease compared to healthy subjects after both single and multiple-doses (at steady state). In addition, there is an increase in the amount of acetaminophen excreted unchanged in the urine (.7% vs. 2.5%) in patients with liver disease compared to healthy subjects after repeat doses, suggesting that more acetaminophen was excreted by renal elimination in the liver disease state. 2

3 2. Literatuuronderzoek Zoektermen 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 ("acetaminophen"[mesh] OR "acetaminophen"[tiab] OR ""[tiab]) AND "humans"[mesh Terms] Embase 'liver cirrhosis'/exp/mj 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 (''/exp OR '' OR '':ab,ti OR 'acetaminophen':ab,ti) AND [humans]/lim Zoekstrategie Publicaties gevonden in databases Pubmed: n=100 Embase: n=153 Titel en abstract gescreend (n=253) Aantal exclusies (n=203) Geen cirrose (n=27) o Hepatitis (n=5) o Transplantatie (n=5) o Cholestatische leverziekte (n=12) o Anders (n=5) Niet specifiek (n=97) DILI (n=5) Cel/mol.niveau (n=6) Anders (n=19) Dubbele publicaties verwijderd (n=17) Volledige artikelen geraadpleegd (n=33) Aantal exclusies (n=13) Andere uitkomst (n=1) Niet specifiek cirrose (n=2) Niet beschikbaar (n=10) Aanvullende publicaties gevonden in andere bronnen: Referentielijsten: n=1 Citation tracking via Web of Science: n=0 Anders: n=0 Artikelen opgenomen in kwalitatieve synthese (n=21) 3

4 3. Samenvatting belangrijkste onderzoeken Uitkomsten farmacokinetische studies Level of evidence 3 Zapater; Froomes; Ueshima; El-Azab; 1996 Design Reference Intervention of 1 g PO Single PO dose of 1 g Single PO dose of 1 g of 1 g PO Results Cirrhotic patients Remarks Healthy controls CTP A CTP B CTP C n=7 n=3 n=6 n=5 A not-significant Cmax (mg/l) 15.9 ± ± ± 7.0 Ratio AUC0-6h (mg.h/l) 38.8 ± ± ± 18.5 Ratio tmax (h; range) 1.0 ( ) 0.8 ( ) 0.7 ( ) t1/2 (h) 2.0 ± ± ± 0.6 Cl (ml/min) ± ± ± 60. Vd (L) 60.7 ± ± ± 18.0 UrinGLU, 0-2h (%) 59.9 ± ± ± 7. UrinSUL, 0-2h (%) 27.9 ±. 30. ± ± 7.9 UrinC+S, 0-2h (%) 9.7 ± ± ±. UrinAAP, 0-2h (%) 1.2 ± ± ± 0.5 correlation between AUC0 6h and CTP mean score was found (p=0.25). Our data shows clearly a faster appearance of acetaminophen in blood in patients with varices compared with patients without varices and healthy volunteers. n=5 n=0 n=3 n=7 The mean Vd did not differ between cirrhotic and Cl (ml/min) 36 ± ± 50* control subjects t1/2 (h) 2.3 ± ± 1 n=10 a n= a t1/2 increases -6 wk after t1/2 (h) 1.9 ± ± abstinence ke (L/h/kg) ± ± n= n= n= b n= b All patients suffered from young elderly young elderly schistosomiasis Cmax (µg/ml) 17.1 ± ± ± ± 3.1 The observed reduction in Ratio plasma AAP-glu is in good AUC agreement with the report 3.55± ± ± 0.29* 3.7 ± 0.1* (µg.min/ml) that glucuronyl Ratio transferase is decreased at all stages of tmax (min) 85.0 ± ± ± ± 3.2 schistosomiasis t1/2 (min) 12.5 ± ± ± 8.1* 25.8 ± 10.2* AUCGLU, (µg.min/ml) 3.7 ± ± ± 0.09* 1. ± 0.07* AUCSULF, 1.9 ± ± ± ± 0.07 (µg.min/ml) Urin Glu0-8h 9.13 ± ± ± ± 0.28* Urin Sul0-8h 17.9 ± ± ± 0.7* 8.76 ± 0.53* Urin AAP0-8h 0.73 ± ± ± 0.16* 1.7 ± 0.20* Results are expressed as mean ± SD or as mean ± SE [study El-azab]. GLU= glucuronide-metabolite, k=elimination rate, ratio= ratio [cirrhotic patients/healthy controls], SUL=sulfate-metabolite. a. all patients with alcoholic liver disease within 1 week after abstinence, b. all patients suffered from schistosomiasis

5 Level of evidence Poulsen; 1991 Forrest; 1979 Intervention Andreasen; 1979 Benson; 1983 Forrest; 1977 Design (pilot) Historically controlled Reference of 0.5 g of 1.5 g PO of 1 g 1 g TID for 5 days x 1 g/d PO for 5 days of 1.5 g PO Results Healthy Remarks Cirrhotic patients controls n=5 n=5 No significant differences ClAAP (l/min) ± ± 0.01 ClGLU (l/min) ± ± ClSUL (l/min) ± ± ClC+M (l/min) 0.0 ± ± n=5 n=8 a n=7 a mild b severe b t1/2 (h) 2.3 ± ± ± 1.15** C3h (µg/ml) UrinGLU, 0-2h (%) c 5 ± ± ± 3.7 UrinSUL, 0-2h (%) c 33 ± ± ± 3.1 UrinCYS, 0-2h (%) c 3.8 ± 0.1. ± ± 0.9 UrinMCP, 0-2h (%) c.8 ± ± ± 0.6 UrinAAP, 0-2h (%) c 3.7 ± ± ± 0,8 UrinTOT, 0-2h (%) c 92 ± ± ± 5.5 There was a significant correlation between t1/2 and serum albumin and PTT Patient with lieno-renal shunt had considerably prolonged t1/2 at hr and low CGLU and CSUL n=12 n=11 5-day dosing did not influence the Cl (ml/min) 355 ± ± 51** t1/2 of and did not t1/2 (h) C6h (µg/ml) 2.1 ± 0.6 n= ± 0.8** n= 9.2** cause accumulation PTT was closely related to the plasma clearance in both groups Sings of clinical hepatotoxicity or C12h (µg/ml) ** significant changes in the values of ALAT, AF, PTT or serum bilirubin were not observed n=0 n=6 No progressive increase in Cplasma occurred over 5-day period Crange (µg/ml) No change in clinical status or in t1/2 (h) 3.2 ± 2.5 lab tests literature n=17 (13 cirrhosis) Significant correlation between t1/2 and serum albumin t1/2 (h) 2.0 ± ± 0.3 Patients with abnormal PTT and HE ratio 0.15 albumin had 100% increased t1/2 Results are expressed as mean ± SD. AAP=, egmr= estimated geometric mean ratio (cirrhosis/healthy subjects function), AAP=, CYS=cysteinmetabolite, C+M=cystein+mercapturic acid metolites, GLU= glucuronide-metabolite, MCP=mercapturic acid metabolite, SUL=sulphate-metabolite, TID= three times daily, TOT=total *p<0.05, **p<0.01 a. both groups had 6 cirrhotics, b. severity was based on abnormal serum albumin and prothrombin time ( severe ), c. these results are expressed as mean±se. 5

6 Uitkomsten studies naar veiligheid Level of Evidence 2 2 Reference Zapater; 2015 Benson; 1983 Fenkel; 2010 Khalid; 2009 Design Patients Intervention Observerblind RCT during 3 days Double-blind randomized cross-over Case-control study Matched casecontrol study Cirrhosis Liver disease (n=20; 6 cirrhosis) Cirrhotics admitted with liver-associated event (n=89) Hospitalized decompensated cirrhosis (n=91; (CTP A/B/C 7/1/3) Paracetamol 500 mg TID (n=15; mean CTP score 6.7±1.7) Paracetamol times daily 1g for 13 days Comparison of OTCanalgesic use Comparison of OTC medication used in past 30 days APAP = OTC=over-the-counter medication, TID= three times daily Control Results Remarks Metamizole 575 mg TID (n=1; mean CTP score 7.0 ±1.5) Placebo for 13 days Outpatients with compensated cirrhosis (n=12) -nonhospitalized cirrhotics (n=153; CTP A/B/C 107/0/5) -hospitalized controls (n=89) Use of or metamizole was not associated with significant changes in serum cystatin C or creatinine levels versus baseline values in most patients with cirrhosis. 2 patients treated with metamizole and 1 one with developed haematuria There were no significant changes from baseline in both groups of patients, treated with either dipyrone or, in any clinical and laboratory parameter recorded throughout the study. There was no change in the clinical status after 13- day treatment. Laboratory tests were not different from baseline (all liver parameters). Only albumin was slightly higher after treatment. 1 cirrhotic patient developed nausea, malaise, abdominal discomfort and right upper abdominal pain starting at placebo and worsening while receiving (t1/2 was 2.7h). Rechallenge of g/d during 10 days did not cause AEs. Earlier symptoms were the result of an exacerbation of his chronic liver disease. 17 cases (19%) and 32 controls (26%) used in the last 30 days. No significant difference found (OR 0.68, ; p=0.253), neither in multivariable analysis (ORadj 0.77, ; p=0.161) In cirrhotic cases, the highest dose of APAP used in a single day was 1500 mg (for 2 consecutive days) by 1 patient. The highest dose of APAP used by a cirrhotic case in a 30-day period was 39 grams (1300 mg per day for each of the 30 days). The highest dose of APAP used by a cirrhotic control patient in a single day was 3 grams during 2 consecutive days. The highest dose of APAP used by a cirrhotic control patient in a 30-day period was 2. grams (975 mg/day for 25 days). 17 patients (19%), 38 cirrhotic controls (25%) and 37 non-cirrhotic controls (2%) used in the 30-day period. Paracetamol use did not differ between the cirrhotic groups, it did differ between healthy controls and cirrhotics (p=0.001) Low dosing of both treatments No severity of cirrhosis No severity of cirrhosis Lack of specific dosage data APAP at a maximal daily dose of 3 g/day (for up to 2 days) or at a daily dose of 1 g/day (for up to 25 days) does not appear to be associated with acute hepatic decompensation 6

7 Uitkomsten reviews Level of evidence 5 5 Hayward; 2016 Reference Bosilkovska; Outcome Safety PK Parameters Expert opinion Conclusions: Glutathion depletion: Although reduction of glutathione concentrations has been demonstrated in most liver disease aetiologies, there has been no change demonstrated in the ratio of thiol metabolites retrieved in urine, nor evidence of liver injury in these patients. Thus, in the absence of contributory factors, such as malnutrition, there is no strong evidence of impaired glutathione conjugation in CLD and therefore it is unlikely that glutathione store depletion alone increases risk of hepatotoxicity in the clinical setting. Indeed, case reports published on hepatotoxicity secondary to therapeutic doses of are often in severely underweight, malnourished or fasting patients suggesting that acute nutritional deficiency is likely a more important consideration than underlying liver disease when considering for these patients. Ethanol consumption: It would thus appear that is relatively safe to use in the average heavy drinker (who is not malnourished and either has no cirrhosis or early compensated cirrhosis) at doses up to g daily when clinically indicated for short periods of time, but the lack of data in decompensated alcoholic liver disease (ALD) makes dosing recommendations difficult in this group. While 3- g daily may be reasonable short term for acute pain, a maximum daily dose of 2-3 g in alcoholic cirrhosis may be a safer recommendation if analgesia is required for more than 1 days. Conclusion: Recent reviews have concluded that is a safe and effective first line agent in almost all patients regardless of liver disease aetiology. Although the need for dose reduction in the healthy population seems largely unnecessary, it may be warranted in certain severe or decompensated hepatic disease states, particularly if patients are malnourished, are not eating or have a dry weight less than 50 kg. Whilst a cautious and conservative approach has previously been recommended for all CLD patients, prescribers should be encouraged to consider appropriate dosing for each individual patient, taking into account their underlying disease state and the pharmacological covariates. As the prevalence of lifestyle related liver diseases such as ALD and NAFLD is likely to increase over the coming decades, it is important that clinicians are able to use existing analgesics safely and effectively. To that effect, studies aimed at improving our understanding of changes to metabolism, efficacy and toxicity will be invaluable. Pharmacokinetic studies in patients with liver cirrhosis have shown an increase in the elimination half-life (t½) of ranging from 50% to 100% compared with that in control subjects. The AUC was significantly higher and plasma clearance of the drug was reduced, whereas the mean values for maximum plasma drug concentration (Cmax) and the time to Cmax (tmax) did not differ. In two of these studies, a correlation was found between the t½ of the drug or plasma clearance and prothrombin time as well as the plasma albumin levels. In one of these studies, the t½ was doubled in patients with both low albumin levels (<35 g/l) and high prothrombin time ratios (>1.). The other study showed that a 10% decrease in prothrombin level decreased plasma clearance by 10%. The correlation with albumin levels was statistically less important. None of the studies showed correlation between drug t½ or plasma clearance and plasma bilirubin levels. The possible accumulation of repeatedly administered in subjects with chronic liver disease has been evaluated in two studies. In both studies, six subjects received 1 g four times per day over 5 days. No progressive accumulation of was apparent in the plasma of cirrhotic patients, despite a slight prolongation of its t½. The production of the reactive hepatotoxic intermediate NAPQI, estimated from the urinary concentration of cysteine and N-acetylcysteine conjugates, is enhanced in alcoholic subjects without cirrhosis but unaffected in cirrhotic subjects abstaining from alcohol. Another study confirmed that the metabolic pattern in blood and urinary excretion did not differ between cirrhotic and healthy subjects after administration of a single dose of 1 g. In a study evaluating the pharmacokinetics of in children with nonalcoholic fatty liver disease, higher concentrations of glucuronide were observed, although they did not seem to affect the rate of elimination because no difference in the pharmacokinetic parameters for itself was observed between children with non-alcoholic fatty liver disease and healthy children. The cysteine and mercapturic acid conjugate concentrations were not determined; therefore, it is difficult to evaluate whether the use of in this population increases the risk of hepatic injury. The pharmacokinetics of in patients with acute viral hepatitis without cirrhosis were not significantly altered compared with that in control subjects. However, the t½ and the AUC increased, and the plasma clearance decreased, in subjects during the acute hepatitis phase compared with that during convalescence. The authors suggest that patients 7

8 Safety with hepatitis can take conventional doses of, and prolonged dosage intervals are necessary only in serious cases in which prothrombin time is prolonged. Paracetamol is commonly recommended as a first-choice analgesic for various nociceptive acute or chronic pain conditions and remains one of the safest accessible analgesics for multimorbid patients. However, the use of in patients with hepatic disease is often avoided, probably owing to the well-known association between overdose and hepatotoxicity. Paracetamol is mainly metabolized to glucuronide and sulphate conjugates, and a small proportion (<5%) is oxidized via CYP, mostly CYP2E1, to a hepatotoxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI). This metabolite is rendered nontoxic by conjugation to glutathione. Some studies have shown that patients with alcoholic or non-alcoholic liver disease have lower levels of glutathione. However, in a review of the literature, Lauterburg stated that, with the exception of findings in chronic alcoholic patients, no evidence exists of a higher risk for adverse effects from in patients in which low glutathione has been observed, for example, patients with chronic hepatitis C or non-alcoholic cirrhosis. Retrospective studies analysing hospital admissions for overdose found an increased risk of acute liver injury in patients with pre-existing liver disease. Alcoholic liver disease, non-alcoholic fatty liver disease and hepatitis C virus infection were detected as risk factors for the development of acute liver injury, severe liver failure or increased mortality following overdose. These studies render attentive to the higher vulnerability of this population in case of overdose but state that it remains unclear whether therapeutic doses of would be more toxic in patients with chronic liver disease or cirrhosis. [description study Benson 1983]. Compared with placebo, the use of during this period appeared to have no significant effect on clinical features or laboratory tests. The findings of a casecontrol study evaluating the implication of over-the-counter analgesics in acute decompensation in patients with cirrhosis suggested no association between the occasional use of low-dose (2 3 g/day) and the decompensation of cirrhosis.[70] An especially delicate and often controversial question is the use and hepatotoxicity of therapeutic doses of in chronic alcohol users. Glutathione levels are known to be reduced in chronic alcohol consumers or fasting subjects. It is also known that the CYP2E1 isoenzyme responsible for the metabolism of to the toxic intermediate NAPQI is induced by chronic alcohol consumption. It is therefore not surprising that the production of NAPQI, estimated from the urinary concentration of cysteine and N- acetylcysteine conjugates, is higher in non-cirrhotic chronic alcohol users than in subjects who do not consume alcohol. This makes chronic alcohol users (cirrhotic or not) more vulnerable to elevated doses of. Many reports, mostly retrospective studies or case reports, have found an association between alcohol use and enhanced toxicity in cases of overdose but also when was used at therapeutic doses. A randomized placebo-controlled study demonstrated no increase in serum aminotransferases or international normalized ratio in alcoholic subjects receiving therapeutic doses of ( g/day) for 8 hours. Nevertheless, a more recent randomized placebo controlled study has shown a small but significant increase in ALT at the end of treatment in moderate alcohol consumers taking g daily for 10 days. Serum ALT levels increased from IU/L before treatment to IU/L at the end of the 10-day treatment period. Although the clinical implications of this elevation are unclear, precautions should be taken if is used in alcoholic patients, especially long term. The US Food and Drug Administration requires a warning label for -containing products stating that individuals who consume three or more alcoholic beverages per day should consult their physician before using. In summary, the few available studies suggest that the use of short-term therapeutic doses of in patients with nonalcoholic cirrhotic liver disease cause no accumulation or deterioration of liver-related laboratory tests, indicating that this drug can be used in these patients at normal doses. However, owing to the changes in the pharmacokinetics and the vulnerability of this population, it seems reasonable to limit the adult daily dose to 2 g, half the suggested therapeutic dose. Physicians should remain attentive to any symptoms indicating a possible aggravation of the hepatic function. Doses should be reduced to 2 g/day, or should be avoided as much as possible in chronic alcohol users. 8

9 . Alle publicaties uit literatuursearch 1. Zapater P, et al. Pharmacokinetic variations of acetaminophen according to liver dysfunction and portal hypertension status. Alimen Pharmacol Therap (1) 2. Froomes PR, et al. Comparative effects of oxygen supplementation on theophylline and acetaminophen clearance in human cirrhosis. Gastroenterol () 3. Ueshima Y, et al. Acetaminophen Metabolism in Patients with Different Cytochrome P 502E1 Genotypes. Alc: Clin Exp Res 20.s1 (1996): 25a-28a.. el-azab G, et al. Acetaminophen plasma level after oral administration in liver cirrhotic patients suffering from schistosomal infection. Int J clin pharmacol therap (7) 5. Poulsen HE, et al. The influence of disulfiram on acetaminophen metabolism in man. Xenobiotica Feb 6. Forrest JAH, et al. Paracetamol metabolism in chronic liver disease. Eur j clin pharmacol 15.6 (1979): Andreasen PB, et al. Paracetamol (acetaminophen) clearance in patients with cirrhosis of the liver. Acta Med Scand Suppl Benson GD. Acetaminophen in chronic liver disease Clin Pharmacol Therap (1) 9. Forrest JA, et al. Antipyrine,, and lignocaine elimination in chronic liver disease. Br Med J (1977): Zapater P, et al. Acute effects of dipyrone on renal function in patients with cirrhosis: A randomized controlled. Basic Clin Pharmacol and Toxicol (2015) 116:3 ( ) 11. Fenkel JM, et al. Over-the-counter analgesics in cirrhotic patients: a case-control study examining the risk of hospitalization for liver-associated events. Scand J Gastroenterol (9): Khalid SK, et al. Use of over-the-counter analgesics is not associated with acute decompensation in patients with cirrhosis. Clin Gastroenterol Hepatol Sep 13. Hayward KL, et al. Can (acetaminophen) be administered to patients with liver impairment? Brit J Clin Pharmacol (2016) 81:2 ( ) 1. Bosilkovksa M,et al. Analgesics in patients with hepatic impairment: pharmacology and clinical implications. Drugs Aug Ojeda A, et al. Pain management in patients with liver cirrhosis. Gastroenterol Hepatol Imani F, et al. The therapeutic use of analgesics in patients with liver cirrhosis: A literature review and evidence-based recommendations, Hepat Mon. (201) 1: Ennaifer R, et al. Pain management in cirrhosis: A clinical dilemma? J Afric d'hepato- Gastroenterol (2): Chandok N, et al. Pain management in the cirrhotic patient: The clinical challenge. Mayo Clinic Proceedings (2010) 85:5 (51-58) 19. Dwyer JP,et al. Analgesia for the cirrhotic patient: A literature review and recommendations. J Gastroenterol Hepatol (201) 29:7 ( ) 20. Lewis JH,et al. Review article: prescribing medications in patients with cirrhosis - a practical guide. Alimen Pharm Therap (12) 21. Westphal JF, et al. Drug administration in chronic liver disease. Drug Saf (1) 9