With a previously developed method, the safety and optimal dosing of more than 200 drugs in patients with liver cirrhosis were evaluated. In this study an overview of the recommendations is given. |
For the majority of the evaluated drugs, changes in pharmacokinetics or pharmacodynamics occurred in patients with liver cirrhosis. Overall, 30% of drugs required dose adjustment and nearly 70 drugs were classified as unsafe in (a stage of) liver cirrhosis. |
Healthcare professionals in The Netherlands are supported during the prescription or dispensing of drugs to patients with liver cirrhosis by alerts from their clinical decision support system and information on a free website. |
1 Introduction
2 Methods
2.1 Step 1: Collection of Evidence
2.2 Step 2: Data Extraction and Presentation
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Pharmacokinetics: pharmacokinetic parameters (e.g. area under the curve [AUC], maximum plasma concentration [Cmax])
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Safety: number and type of adverse events and data on discontinuation due to these adverse events
2.3 Step 3: Initial Safety Classification and Dosing Advice
Safety class | Description | Action |
---|---|---|
Safe | The drug has been evaluated in patients with liver cirrhosis, and no increase in harm was found compared with persons without liver cirrhosis. The safety of the drug is supported by pharmacokinetic studies and/or safety studies over a long period. It might be necessary to use an adjusted dose | This drug can be used in patients with liver cirrhosis |
No additional risks known | The limited data suggest that this drug does not increase harm in patients with liver cirrhosis in comparison with persons without liver cirrhosis. It might be necessary to use an adjusted dose | The drug can be used in patients with liver cirrhosis Adverse drug reactions need to be monitored |
Additional risks known | The limited data suggest an increase in patient harm in patients with liver cirrhosis compared with persons without liver cirrhosis. However, the number of studies is limited and/or the studies show contradicting results regarding the safety in patients with liver cirrhosis | This drug should preferably not be used in patients with liver cirrhosis if there is a safer alternative available Adverse drug reactions need to be monitored |
Unsafe | Data indicate this drug is not safe in patients with liver cirrhosis | This drug should be avoided in patients with liver cirrhosis |
Unknown | For this drug, insufficient data are available to evaluate the safety in patients with liver cirrhosis | This drug should preferably not be used in patients with liver cirrhosis if there is a safer alternative available Individual judgement of therapeutic need versus additional risks in patients with liver cirrhosis Adverse drug reactions need to be monitored |
Safety class is dependent on the severity of cirrhosis | The safety class and/or the dose adjustment of this drug depends on the severity of liver cirrhosis of the patient, expressed by Child–Pugh class | Retrieve severity of liver cirrhosis (Child–Pugh class) |
2.4 Step 4: Consensus of Recommendations by an Expert Panel
2.5 Step 5: Implementation
2.6 Step 6: Continuity
2.7 Analyses
3 Results
Drug class | Safety class | |||||
---|---|---|---|---|---|---|
Safe | No additional risks known | Additional risks known | Unsafe | Unknown | Dependent on the severity of cirrhosis | |
Analgesics, mild | Paracetamol | Tramadola | All COX-2-inhibitorsb All NSAIDsb | Codeinec | ||
Analgesics, strong | Buprenorphinea Morphine (PO + IV)a Oxycodonea Remifentanil Sufentanil | Methadone | Hydromorphone (PO)a Hydromorphone (IV) Nalbuphine Nicomorphine Piritramidea | Alfentanil Fentanyla Pethidine Tapentadola,d | ||
Antibiotics, chinolones | Ciprofloxacin Norfloxacin Ofloxacin | Moxifloxacin | Levofloxacin Pipemidic acid | |||
Antibiotics, penicillins | Amoxicillin Amoxicillin/clavulanic acid | Piperacillin/tazobactam | Benzylpenicillin Flucloxacillin Phenethicillin Phenoxymethylpenicillin | |||
Antibiotics, tetracyclines | Doxycyline Minocycline Tetracycline | Tigecyclinea | ||||
Antibiotics, sulfonamides and trimethoprim | Sulfamethoxazole/trimethoprim Trimethoprim | Sulfadiazine Sulfametrole/trimethoprim | ||||
Antibiotics, macrolides | Azithromycin Clarithromycin Erythromycin Roxithromycina | |||||
Antibiotics, other | Rifaximin | Clindamycina Fosfomycin (PO) | Fosfomycin (IV) Nitrofurantoin | |||
Antidiabetic drugs | Acarbose Insulin Metformin Tolbutamidea | Dapagliflozina Empagliflozin Glibenclamidea Gliclazidea Glimepiridea Linagliptin Pioglitazonea Saxagliptin Vildagliptin | Alogliptin Canagliflozin Repaglinidea Sitagliptin | |||
Anti-hepatitis B | Adefovir Entecavir Lamivudine Telbivudine Tenofovir | Interferon-α-2ac Interferon-α-2bc Peginterferon-α-2ac PegInterferon-α-2bc | ||||
Anti-hepatitis C | Daclatasvir Ledipasvir Sofosbuvir Velpatasvir | Dasabuvird Elbasvir/grazoprevirc Ombitasvir/paritaprevir/ritonavird Ribavirin Simeprevirc | ||||
β-Blockers | Atenolol Carvedilola Propranolola | Acebutolol Bisoprolola Esmolol Labetalol (PO)a Labetalol (IV) Sotalol | Nebivolol | Celiprolol Pindolol | Metoprolola,d | |
Calcium channel blockers | Amlodipinea Nifedipinea Nimodipine (PO)a | Barnidipine Isradipine Nicardipine (PO) Nitrendipine | Lacidipinea Nicardipine (IV) Nimodipine (IV) | Felodipinea,d Lercanidipined | ||
Calcium channel blockers, other | Diltiazema | Verapamil (PO)a,d Verapamil (IV)a,d | ||||
Coumarins | Acenocoumarola Phenprocoumona | |||||
Diuretics | Furosemide Spironolactone | Amiloride Bumetanide Eplerenone Hydrochlorothiazide | Triamterene | Chlorthalidone Epitizide Indapamide | ||
Drugs for acid-related disorders | Esomeprazolea Famotidine Ranitidine | Cimetidine Lansoprazole Pantoprazole | Algeldrate/magnesium oxide Algeldrate/magnesium oxide/dimethicone Aluminium hydroxide/magnesium carbonate Calcium carbonate/magnesium carbonate Nizatidine | Omeprazolea,d Rabeprazolea,d | ||
Drugs used in hepatorenal syndrome | Albumin Terlipressin | |||||
Drugs used in PBC or AIH | Prednisolone Prednisone Ursodeoxycholic acid | Azathioprine | Budesonide | Mycophenolate mofetil | ||
Heparins | Dalteparina Enoxaparina Nadroparina | Heparina | Tinzaparin | |||
Laxant drugs | Lactitol Lactulose | Bisacodyl Macrogol Macrogol/electrolytes Psyllium Sterculia | Magnesium (hydr)oxide Senna Sennosides A + B Sodium picosulfate | |||
Lipid-lowering agents | Colestyramine | Colesevelam | Atorvastatin | Ciprofibrate Fenofibrate Acipimox | Bezafibrate Ezetimibec Fluvastatina Gemfibrozil Lomitapidea,c Pravastatina Rosuvastatina Simvastatina | |
Platelet aggregation inhibitors | Acetylsalicylic acida Carbasalate calciuma | Clopidogreld Dipyridamole Prasugrel Ticagrelor | ||||
Prokinetics | Metoclopramidea | Domperidonea,d | ||||
RAS inhibitors | All ACE inhibitorsb,d All AT-II antagonistsb,d |
Drug | Safety class | Pharmacokinetic literature | Safety literature | SmPC | ||||
---|---|---|---|---|---|---|---|---|
Studies | Level of evidence | Cirrhotic participants | Studies | Level of evidence | Cirrhotic participants | Recommendation for cirrhosis given? | ||
Furosemide | Safe | 6 | 3, 4 | 52 | 16 | 2 | 374 | Yes |
Lactulose | Safe | 1 | 3 | 26 | 8 | 1 | >750 | No |
Macrogole | No additional risks known | 1 | 3 | 53 | 3 | 2, 3 | 89 | No |
Bumetanide | No additional risks known | 1 | 3 | 8 | 5 | 2, 3 | 81 | Yes |
Azathioprine | Additional risks known | 0 | NA | NA | 7 | 3, 5 | 80 | Yes |
Methadone | Additional risks known | 2 | 3 | 21 | 4 | 4 | 13 | Yes |
Triamterene | Unsafe | 2 | 3, 4 | 11 | 2 | 4 | 3 | Yes |
Nebivolol | Unsafe | 1 | 4 | 0 | 1 | 2 | 10 | No |
Acipimox | Unknown | 0 | NA | NA | 0 | NA | NA | No |
Nitrofurantoin | Unknown | 0 | NA | NA | 1 | 3 | 4 | No |